To assess whether a faecal immunochemical test (FIT) could be used to select patients with suspected colorectal cancer (CRC) symptoms for urgent investigation.Multicentre, double-blinded diagnostic accuracy study in 50 National Health Service (NHS) hospitals across England between October 2017 and December 2019. Patients referred to secondary care with suspected CRC symptoms meeting NHS England criteria for urgent 2 weeks wait referral and triaged to investigation with colonoscopy were invited to perform a quantitative FIT. The sensitivity of FIT for CRC, and effect of relevant variables on its diagnostic accuracy was assessed.9822 patients were included in the final analysis. The prevalence of CRC at colonoscopy was 3.3%. The FIT positivity decreased from 37.2% to 19.0% and 7.6%, respectively, at cut-offs of 2, 10 and 150 µg haemoglobin/g faeces (µg/g). The positive predictive values of FIT for CRC at these cut-offs were 8.7% , 16.1% (95% CI 14.4% to 17.8%) and 31.1% (95% CI 27.8% to 34.6%), respectively, and the negative predictive values were 99.8% (95% CI 99.7% to 99.9%), 99.6% (95% CI 99.5% to 99.7%) and 98.9% (95% CI 98.7% to 99.1%), respectively. The sensitivity of FIT for CRC decreased at the same cut-offs from 97.0% (95% CI 94.5% to 98.5%) to 90.9% (95% CI 87.2% to 93.8%) and 70.8% (95% CI 65.6% to 75.7%), respectively, while the specificity increased from 64.9% (95% CI 63.9% to 65.8%) to 83.5% (95% CI 82.8% to 84.3%) and 94.6% (95% CI 94.1% to 95.0%), respectively. The area under the receiver operating characteristic curve was 0.93 (95% CI 0.92 to 0.95).FIT sensitivity is maximised to 97.0% at the lowest cut-off (2 µg/g); a negative FIT result at this cut-off can effectively rule out CRC and a positive FIT result is better than symptoms to select patients for urgent investigations.ISRCTN49676259. Faecal immunochemical tests (FIT) are already recommended by the National Institute for Heath and Care Excellence to guide referral of patients with low-risk bowel symptoms but has not been recommended for all symptomatic patients due to concerns over the quality and power of previous studies.FIT sensitivity for colorectal cancer (CRC) is maximised to 97.0% at the limit of detection of 2 µg haemoglobin (Hb)/g faeces (µg/g).f-Hb) result less than the limit of detection in symptomatic patients indicates that their chances of not having CRC is 99.8%.A faecal Hb concentration  to the nearest microgram of Hb per gram of faeces (µg/g).f-Hb concentrations by patient-level variables such as age,The faecal immunochemical test (FIT) was recommended by NICE (DG30)The NICE guidelines and FIT (NICE FIT) study was designed to investigate whether FIT could be used to rule out CRC in symptomatic patients in primary care meeting NICE 2WW criteria, and guide referral for further investigation.The study met Standards for Reporting of Diagnostic Accuracy Studies (STARD) guidelines.f-Hb cut-off that would maximise sensitivity for CRC. The secondary outcome measures were to establish the diagnostic accuracy of FIT for CRC and other serious bowel disease (SBD) at different f-Hb cut-offs, and investigate the impact of other variables, such as age, sex, ethnicity and deprivation.The primary outcome measure was to identify a suitable https://www.nicefitstudy.com/), to other healthcare professionals at scientific conferences and through press releases.Patient and public representatives were consulted through a process of in-depth interviews during the development of the study protocol. All relevant feedback was considered and incorporated into patient information sheets. Study progress and feedback was provided regularly to the Royal Marsden Partners (RM Partners) Patient Advisory Group by the senior research manager. The chief investigator regularly reported to the RM Partners Clinical Oversight Group which includedpatient and public involvement representatives throughout all phases of the study. The results will be disseminated to trial participants directly via email and the website  team once they had been booked for colonoscopy and contacted by post or telephone and invited to participate in the study. Patients were sent an FIT specimen collection device and asked to collect one sample of faeces prior to commencing bowel preparation for their colonoscopy. A first-class return envelope was enclosed for patients to post their sample directly to the study laboratory. Patients initially provided written consent, and after approval from the National Confidentiality Advisory Group, gave implied consent by returning an FIT sample.Patients were not included if they did not return an FIT sample, did not have a complete colonoscopy unless due to CRC, were retriaged to another investigation , or withdrew consent. Patients due to undergo colonoscopy within 3 days of identification were not invited to participate in the study, as there would not have been sufficient time to return a sample. In the original NG12 guidance,f-Hb cut-off of 10 µg/g in the DG30 guidelines.f-Hb cut-off recommended in NICE DG30 as cut-offs to investigate sensitivity. To investigate the specificity and PPV at higher f-Hb, we also chose a higher cut-off of 150 µg/g that had previously been reported to predict high rates of significant pathology.FIT analysis was performed at one centralised laboratory where staff were blinded to patient clinical information. One HM-JACKarc analytical system  was used to analyse all samples. The analytical working range is 7–400 µg/g. The limit of detection (LoD) of the assay is 2 µg/g and the limit of quantitation is 7 µg/g. NICE recommended an 10.1136/gutjnl-2020-321956.supp1Supplementary dataColonoscopy was chosen as the reference standard since it is acknowledged to be the gold-standard investigation for colorectal disease. Colonoscopists were blinded to the FIT results. Colonoscopy results were entered onto a secured online database designed specifically for the study by an external clinical research organisation (Hammersmith Medicines Research) and based on the national endoscopy logbook. Patients with incomplete colonoscopies (except when due to the presence of CRC) were excluded.Clinical data extraction was performed initially by the local CRN team. A rigorous system of quality assurance was implemented. All colonoscopy and pathology results, as well as clinical and pathological tumour staging. were checked by the central study team, and then again by a team of senior colorectal clinicians blinded to the FIT laboratory results.To determine the sample size, calculations were based on a significance level of 5%, power of 80% and prevalence of CRC within the NICE 2WW symptomatic population estimated at 3.5% based on data from the RM Partners Network. To demonstrate a lowest acceptable sensitivity of FIT for CRC of 98% with CI width of 2%, a total sample size of 5379 patients was required. Given that previous studies had reported a 50% non-completion rate, it was determined that at least 10 000 patients would need to be invited to participate in the study. The study was funded to over-recruit beyond this sample size to address the secondary endpoints and investigate the impact of other factors on FIT diagnostic accuracy. Accurate power calculations were not possible for the secondary endpoints, due to the lack of data on these covariates on the diagnostic accuracy of FIT for CRC in the symptomatic populations.Patients with multiple findings at colonoscopy were recategorised with one diagnosis in a hierarchy; CRC ranked highest followed by high-risk adenoma (HRA) and then inflammatory bowel disease (IBD). These were grouped together as SBD. This was followed by low-risk adenoma (LRA) which was ranked above other non-malignant diagnoses, including diverticular disease, microscopic colitis, benign perianal disease , angiodysplasia, or rare findings such as melanosis coli, parasites or lipomas. HRA was defined by the NICE FIT Steering group as any polyp with high-grade dysplasia or polyps over 10 mm in size with low grade dysplasia, and serrated lesions in the right colon. Other polyps less than 10 mm were classified as LRA.The indices of multiple deprivation were derived from postcodes (1=most deprived and 10=least deprived).2 tests. Sensitivity, specificity, PPV and negative predictive value (NPV) were reported for each f-Hb cut-off, with 95% CIs. Receiver operating characteristic (ROC) curves were plotted for f-Hb. These were done using an initial threshold of 0.1 to calculate sensitivity and specificity, and then recalculated with increments of 0.1 to plot the ROC curve. In every statistical analysis, p<0.05 was considered significant. All analyses were performed using SAS V.9.4 (SAS Institute).Data were assessed for normality by the Shapiro test and Q-Q plot analysis. Mann-Whitney and Kruskal Wallis tests were used for non-normally distributed data. Analysis of variancewas used across multiple groups, with separate models for each factor; age was pooled for analysis. Categorical data were compared with χBetween October 2017 and December 2019, 21 126 patients were sent recruitment packs, 13 219 (62.6%) returned FIT devices. Complete FIT and colonoscopy outcomes were available for 9 822 patients, who were included in the study results. A study flow diagram is shown in Patient demographics are summarised in Tests that were older than 14 days or sampled inadequately (n=330) could not be analysed. FIT analysis was performed within 7 days of sample collection in 94.8% of specimens, and within a day of receipt by the laboratory in 94.6% of specimens.Findings at colonoscopy are reported in f-Hb cut-offs of 2 µg/g, 10 µg/g and 150 µg/g are summarised in f-Hb cut-offs of 2, 10 and 150 µg/g, respectively, decreased significantly (p<0.0001) from 37.2% to 19.0% and 7.6%, respectively. At the same cut-offs, the PPV for CRC increased from 8.7%  to 16.1% (95% CI 14.4% to 17.8%) and 31.1% (95% CI 27.8% to 34.6%), but the sensitivity for CRC declined from 97.0% (95% CI 94.5% to 98.5%) to 90.9% (95% CI 87.2% to 93.8%) and 70.8% (95% CI 65.6% to 75.7%), as illustrated in f-Hb cut-offs of 2, 10 and 150 µg/g, compared with 29.9 for all patients referred on the current 2WW pathway. Some CRCs were not detected even a cut-off of 2 µg/g, but significantly more CRCs  were not detected at a cut-off of 10 µg/g. When f-Hb was undetectable (<2 µg/g), the PPV for CRC was 0.2% (0.1%–0.3%), and 617 patients would require colonoscopy to detect 1 CRC.The diagnostic accuracy of FIT for CRC at f-Hb cut-off. The PPV for SBD increases significantly at higher f-Hb cut-offs; 24.8% at 2 µg/g, 39.6% at 10 µg/g and 64.5% at 150 µg/g.The diagnostic accuracy of FIT for SBD is summarised in On ROC curve analysis , the aref-Hb <10 µg/g were analysed in further detail  compared with 10 µg/g, the cut-off recommended in NICE DG30. No significant difference was found in FIT sensitivity on subgroup analysis by age, sex, deprivation, ethnicity and tumour characteristics, suggesting FIT can be used in all symptomatic patients that meet 2WW referral criteria. Employing a higher cut-off for investigation will result in a smaller group of FIT positive patients with a higher PPV or prevalence for CRC, but at the expense of detecting fewer CRC; this strategy may be adopted when endoscopy capacity is restricted or paused as occurred at the height of the current COVID-19 pandemic.f-Hb concentrations (above 150 µg/g), and consequently, FIT could be used to rule-in cancer or prioritise patients for investigation.This is the first powered, multicentre, double-blinded diagnostic accuracy study to demonstrate that FIT can be used to select patients with NICE 2WW symptoms for urgent investigation. FIT can be used to rule out CRC when f-Hb, 617 patients would need to undergo colonoscopy to detect 1 CRC; hence clinical acumen and safety-netting remains essential to identify patients with CRC and false negative FIT.The most common finding at colonoscopy in symptomatic patients in our study was the absence of disease (31.3%) in keeping with other reports on 2WW referralsf-Hb; the PPV of 64.5% for SBD at 150 ug/g is clinically significant. However, the poor sensitivity of FIT for HRA at 65.8% and IBD at 73,1% at a cut-off of 2% and 45.4% and 57.8% at a cut-off of 10 suggest that FIT does not reliably identify these conditions.Colonoscopy currently remains the gold-standard investigation to diagnose or exclude CRC but can fail to detect CRC. The sensitivity of colonoscopy for CRC in a meta-analysis of 9223 patients in 25 studies was 94.7% (95% CI 90.4% to 92.7%), although the largest trials reported data from asymptomatic participants in screening programmes.f-Hb are known to vary by age,f-Hb across these variablesFIT has already been recommended by NICE DG30 to triage patients with low-risk symptomset alet alAlthough not yet recommended by NICE, FIT is already being used by some services for high-risk symptoms. The largest two reports on the diagnostic accuracy of FIT in high risk symptoms were from service evaluations within NottinghamOur system of quality assurance is the first described in the symptomatic FIT literature; over 30% of errors in colonoscopy data coding were detected by clinicians, including misclassification of CRC. The missed CRC rate is unknown, since the volume and key performance indicators of individual endoscopists are unknown, although the majority of endoscopy units in this study were accredited by the Joint Advisory Group on Gastrointestinal Endoscopy. As 11% of colonoscopies were incomplete and excluded from analysis, it is possible that the true prevalence of pathology present in a 2WW population was not captured by this study but at 3.3%, CRC prevalence in this study is equivalent to CRC prevalence in the 2WW population recorded nationally.f-Hb down to 2 µg/g; an international group is working on FIT method standardisation.We found no obvious pattern or cause for false negative FIT results in patients with CRC, which may require further research into patient-level (genetic or medication) variables. Sampling studies in symptomatic patients  may provide possible strategies to improve sensitivity. Sequential use of further biomarkers  following FIT might reduce the number of false positive and false negative results.f-Hb cut-off for onwards referral should be set at the LoD (2 µg/g) to provide sensitivity equivalent to colonoscopy, the current gold standard for investigation and yet reduce referrals by 60%. While not the primary intention of the 2WW pathway, more cases of HRA (20.4%) and IBD (15.3%) will also be detected at the LOD than 10 µg/g. Alternatively, the f-Hb cut-offs could be set higher to reduce referrals further to match existing colonoscopy resource and maximise the PPV for CRC.Finally, the optimal FIT pathway remains unclear. When FIT was used in primary care in Scotland, referrals reduced by 15.1%.f-Hb cut-off may be set to match capacity in resource-limited settings; this will reduce the number of positive results, onwards referral for investigation and demand for colonoscopy but at the expense of detecting fewer cancers. High f-Hb levels are associated with a high PPV for CRC and SBD and can be used to prioritise investigations.FIT is superior to 2WW symptoms in predicting pathology in patients with suspected CRC. At a cut-off of the LoD of the FIT analytical system used, FIT detects CRC with equivalent diagnostic accuracy to colonoscopy. A higher


In high-income countries, mortality related to hospitalized patients with the Coronavirus disease 2019 (COVID-19) is approximately 4–5%. However, data on COVID-19 admissions from sub-Saharan Africa are scanty.To describe the clinical profile and determinants of outcomes of patients with confirmed COVID-19 admitted at a hospital in Ghana.st June to 27th July, 2020. They were managed and followed up for outcomes. Data were analysed descriptively, and predictors of mortality assessed using a multivariate logistic regression modelling.A prospective study involving 25 patients with real time polymerase chain reaction confirmed COVID-19 admitted to the treatment centre of the University Hospital, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana from 1The mean age of the patients was 59.3 ± 20.6 years, and 14 (56%) were males. The main symptoms at presentation were breathlessness (68%) followed by fever (56%). The cases were categorized as mild (6), moderate (6), severe (10) and critical (3). Hypertension was the commonest comorbidity present in 72% of patients. Medications used in patient management included dexamethasone (68%), azithromycin (96%), and hydroxychloroquine (4%). Five of 25 cases died . Increasing age and high systolic blood pressure were associated with mortality.Case fatality in this sample of hospitalized COVID-19 patients was high. Thorough clinical assessment, severity stratification, aggressive management of underlying co-morbidities and standardized protocols incountry might improve outcomes.None declared The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an enveloped, single-stranded RNA virus identified in December, 2019 in Wuhan City, China.2The virus attaches itself to the host cell membrane, penetrates it, releases its contents into the host cell, produces new viral proteins from the mRNA which undergo maturation. Replication occurs when the RNA enters the cell nucleus.Symptoms associated with COVID-19 are mainly respiratory as the SARS-Cov-2 has a predilection for angiotensin converting enzyme 2 (ACE2), found commonly in lung epithelial cells, heart, kidneys and gastrointestinal tract.5So far, COVID-19 has shown regional variability. The hardest hit areas are South-East Asia , Europe  and the Americas  ..32%), EuThe University Hospital is a 125-bed district-level facility located on the campus of KNUST, Kumasi in the Ashanti Region of Ghana. The hospital provides general and specialist services to students and staff of the University as well as private patients. It has an estimated catchment population of 200,000. Since 12th March, 2020 when the first two cases of COVID-19 were detected in Ghana,83; Neutrophils 1.5 – 7.0 × 103; Lymphocytes 1.0 – 3.7 × 103; Hb 11.5 – 16.5 × 103; platelets 140 – 400 × 103 µmol/l Urea 2.5 – 8.3mmol/l; Creatinine 60 – 106µmol/l. Patients' values below the lower limit was categorised as low, those within the range was normal and those above the reference range was categorised as high.This study captured data from a total number of 25 patients (over a period of 8 weeks) with laboratory-confirmed SARS-Cov-2 infection using real time polymerase chain reaction (RT-PCR) at the Kumasi Centre for Collaborative Research. They were all admitted in the hospital for varying duration from 1 day to 18 days and were followed up prospectively from admission till discharge. We recorded their sociodemographic data, symptoms at the time of presentation, comorbidities, blood pressure and pulse rate readings, laboratory and radiological investigations, medications given and treatment outcomes. Based on previously published guidelines, cases managed were categorized as mild, moderate, severe or critical.® version 14 to determine associations among variables. Associations between mortality and demographic and clinical parameters were assessed using an exploratory multivariable logistic regression analysis. p-value of ≤0.05 was considered statistically significant.Data was entered into Excel and descriptive analysis of parameters done then exported to STATAEthical approval was sought from the Committee on Human Research Publications and Ethics of the KNUST (CHPRE/AP/462/19).Between 1st June to 27th July, 2020, 25 adults with COVID-19 were admitted to our facility. The basic demographic characteristics are shown in In order of decreasing frequency, the commonest symptoms of hospitalized patients at presentation were difficulty breathing (17), fever (14), cough (10), confusion or altered level of consciousness (7) and anosmia (2). All of them presented with a combination of two or more of these symptoms. One of the patients reported to the hospital with mainly diarrhoea and fever.Approximately 40.0% (n=10) of the cases were classified as severe . Their tMean temperature was 37.3°C (±1.44) with lowest of 36°C and highest 40°C. BP ≥ 140/90mmHg was classified as high. Mean systolic blood pressure (BP) was 161.5 mmHg (± 27.38) ranging from 116mmHg and 217mmHg; mean diastolic BP 95mmHg (±20.04) ranging from 57mmHg and 160mmHg and mean pulse rate was 113.3bpm (±18.84), with the lowest being 80bpm and highest 162bpm.Past medical history of hypertension was the commonest comorbidity comprising 18 out of the 25 (72.0%) admitted cases followed by diabetes mellitus which recorded 9 (36.0%). They had been on medications for hypertension and/or diabetes mellitus prior to admission. Of the 18 patients with hypertension, 9 (50.0%) had severe COVID-19 and three (16.7%) each were categorised as having critical, mild or moderate COVID-19. Five [27.8%] of those with hypertension had cardiovascular complications such as heart failure and ischaemic stroke. Three of the patients presented with stroke, two had left ventricular failure and one had bilateral extensive deep venous thrombosis.All patients with COVID-19 presenting with acute stroke died. Other comorbidities included aplastic anaemia, sickle cell disease, asthma and hepatoma with lung metastasis. Only 2 (8.0%) of the patients did not have any comorbidity. Ten (10) of the hospitalized patients had ground glass appearance and opacifications in the lungs suggestive of COVID-19 pneumonia on computed tomography (CT) scan and/or chest x-ray .3 (± 4.96), lymphocytes was 1.99 × 103 (±1.17), haemoglobin level was 12.5g/dl (± 2.64) and platelet values ranged from a minimum of 0 (patient with aplastic anaemia) to a maximum of 743 cells/ul.Full blood count (FBC) data was available for 19 of the patients whilst urea and creatinine tests were done for 15. The mean absolute white blood cell (WBC) count was 10.2 × 10Approximately 47.4% (9/19) had elevated total WBC, 42.1% (8/19) had neutrophilia and 10.5% (2/19) had neutropoenia. Lymphopoenia was observed in 10.5% (2/19) of patients and lymphocytosis was in 13.3% (2/15). Seven (36.8%) patients had haemoglobin below 11g/dl with two presenting with severe anaemia (Hbs of 7.2g/dl and 6.3g/dl). Among the different categories of patients, we observed leucocytosis and neutrophilia in one patient with critical condition, Thrombocytopenia was observed in one patient with severe condition and lymphopenia also occurred in two patients with severe condition.The mean urea level was 7.9 mmol/l and the creatinine level was 157.15 umol/l. Of the 15 patients whose urea and creatinine tests were done, 5 (33.3%) had elevated urea only, 12 (80.0%) had elevated creatinine levels only and 3 (20%) patients categorised as severe cases had both elevated urea and creatinine, suggestive of acute kidney injury.As part of the real time polymerase chain reaction (RT-PCR) testing, we recorded the cycle thresholds (Cts) of the patients. The Cts describe the number of cycles required for the PCR fluorescent signal to exceed background level and this is inversely proportional to the starting viral load in the patient. The minimum Ct was 21.88 and the highest Ct was 39.64. Both Cts were found in severe patients. The average Ct was similar for all categories of cases .The rate of dexamethasone use was 64.0% (16) and supplemental oxygen use was 19 (76.0%). This was indicated in patients experiencing respiratory distress with oxygen saturation below 93%. Use of vitamin C and Zinc tablets was 100%, Azithromycin 96% and hydroxychloroquine use was 4%.We recorded 5 (20.0%) mortalities, three of which were ‘critical’ cases and the other two, severe. The unadjusted odds ratio (95% CI) for mortality as expected increased with age with each 10-year increase in age associated with 8% (95% CI: 0 – 16%), p=0.05. Also, for each 10mmHg rise in systolic blood pressure, the odds ratio of mortality was 65% (95% CI: 1 – 169%), p=0.05.These were exploratory analysis due to the small sample size overall and a fully adjusted analysis did not yield any independent risk factors for mortality.Due to the varied presentations of COVID-19, it presents a fascinating clinical picture which challenges clinicians as well as health care systems. In Ghana, approximately 95% of individuals confirmed with COVID-19 are asymptomatic or have mild symptoms.Though the role of steroids in the management of patients with COVID-19 has been widely debated, we employed parenteral and oral dexamethasone in these patients out of which 14 were weaned off oxygen and were discharged. Dexamethasone, a glucocorticoid, has been shown to modulate inflammatory activities and ameliorates respiratory failure and death associated with COVID-19. It is reported to reduce mortality by up to 33% in patients who need mechanical ventilation and by 20% in those requiring oxygen.This was to avoid the high risk of arrhythmias associated with it, especially among patients with hypertension and cardiac problems.Cardiac abnormalities have been found among infected patients with no previous history of cardiovascular disease.Majority of patients with COVID-19 have normal full blood count but lymphopoenia, the commonest haematological abnormality, has been detected in 28% to 63% of patients.19Abnormal levels of urea and creatinine among our patients are similar to studies from other COVID-19 treatment sites. Angiotensin-converting enzyme 2 (ACE-2) receptors expression in human kidneys, bladder and testis reveals a potential route of coronavirus-mediated renal dysfunction, which may cause death in infected patients.Apart from the clinical presentations, we sought to assess the disease severity based on the cycle threshold (Ct) or viral load of patients recruited into this study. However, we could not establish this since the Cts recorded were similar for all categories of cases. In a previous study, viral load was undetectable in early stage of some infected patients.25 which has been heightened during the COVID-19 pandemic, making it difficult for us to step-up care for some of our patients who needed it. In this study, we did not explore how much this contributed to the deaths of our patients who had severe-to-critical COVID-19.Mortality is relatively high among hospitalized patients as 5 out of 25 patients succumbed to the disease . In the United Kingdom, among hospitalized patients, the CFR is between 26 to 37%We relied solely on data of confirmed cases of COVID-19 at the hospital. Working in a resource-limited setting, we were constrained by a lack of resources to conduct the same laboratory and radiological investigations for all the patients. Some markers of disease severity such as d-dimer and lactate dehydrogenase were not employed. Decisions to undertake some tests were mainly based on patients' clinical picture. This, notwithstanding, this paper is a significant step in providing information on the clinical and diagnostic profile of hospitalized patients with COVID-19 in Ghana.We have demonstrated the contrasting but intriguing clinical and laboratory presentation of COVID-19 among a small sample of confirmed cases hospitalized in Ghana. Cardiovascular complications, haematological and renal abnormalities are common. Although there was no independent predictor of treatment outcomes, risk factors that require critical attention include older age and comorbidities such as hypertension. We encourage multi-centre bigger studies on COVID-19, especially in sub-Saharan Africa.


Streptococcus pneumoniae (20.4%), Haemophilus influenzae (11.8%), and Mycoplasma pneumoniae (10.8%). The burden of hospitalization for children with community-acquired pneumonia was highest among less than 2 years, in whom respiratory viruses were the most commonly detected causes of pneumonia. The share of vaccine-preventable diseases  remains high. With the vaccination requirement imposed since 1 January 2018 against pneumococcus, Haemophilus influenzae, and whooping cough and the possibility of practicing multiplex PCR in our hospital, it will be interesting to study the impact of this law enforcement on new child generations and compare these new data to our study.Community-acquired pneumonia remains a leading cause of hospitalizations among children worldwide. The diagnosis is based on the history, the physical examination results in children with fever plus respiratory signs and symptoms, and chest radiography. The microbiological etiology is confirmed by viral testing and hemocultures. The most likely etiology depends on the age of the child. The features of childhood pneumonia vary between countries and territories. The purpose of this study was to describe the epidemiological characteristics and current microbial ecology of community-acquired pneumonia in children in French Guiana. We performed a retrospective, descriptive, and monocentric study between January 1, 2015, and December 31, 2017, in the pediatric ward of the Cayenne Hospital in French Guiana. The studied population was aged from 0 to 15 years and 3 months and hospitalized for acute community-acquired pneumonia. A total of 415 patients (mean age 3.62 years) were included. A pathogen was identifiable in 22.4% of cases, including bacteria in 61.3%, viruses in 43%, and coinfections in 14%. The main pathogens were respiratory syncytial virus (31.2%),  Community-acquired pneumonia (CAP) is a leading cause of hospitalizations among children worldwide . It reman = 11). In addition, patients were excluded if no medical record information was available (n = 11) and if, after a thorough review of the file, the diagnosis of pneumonia was incorrect (n = 8). Patients meeting the inclusion criteria (n = 415) were categorized into 3 mutually exclusive categories: (i) those with documented microorganisms on blood culture or pleural fluid culture; (ii) those without microorganisms documented by a negative or contaminated blood culture or a negative virological research by polymerase chain reaction (PCR), on nasopharyngeal aspiration; and (iii) those in whom a blood culture, any other culture, or PCR had not been performed (no culture). All culture data were obtained within 48 hours of hospital admission.This monocenter retrospective study was conducted on children hospitalized for CAP. This study included patients from 30 days to 15 years and 3 months of age. Medical charts from all patients were identified using the Pediatric Hospital Information System with the International Classification of Diseases, 10th edition, with a discharge code of pneumonia, from January 1, 2015, to December 31, 2017. Patients hospitalized with a nosocomial infection were excluded Probable bacterial pneumonia: (i) consolidated pneumonia according to the World Health Organization (WHO) criteria for interpretation of chest X-rays  and (ii)Nonbacterial pneumonia: chest X-rays with interstitial infiltrate or without any pathological findingCAP was categorized by the following:Organ dysfunction was based on consensus pediatric guidelines . OutcomeFor bacterial etiological diagnosis, blood cultures and pleural fluid cultures (if the patient required thoracocentesis) were performed in all hospitalized patients.The parasite and fungal infections were also diagnosed by blood or pleural fluid cultures.A nasopharyngeal aspiration was performed in case of epidemiological and/or clinical suspicion of a respiratory viral infection.Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. Bacteria considered as contaminants  were considered as pathogenic as they were found in blood cultures.Pathogenic bacteria included Antimicrobial therapy was recorded daily and initially consisted of penicillin/ampicillin with or without an aminoglycoside and co-amoxyclavulanic acid and third-generation cephalosporin as second-line therapies .Streptococcus pneumoniae and Staphylococcus aureus.Blood culture–directed changes in antibiotics were classified as broadened, narrowed, or unchanged relative to χ2 test or Fisher's exact test. The prevalence of bacteremia and other etiologies was determined for all patients, patients with good outcome and poor outcome, using binomial exact 95% confidence intervals. Statistical analysis was performed using Stata 15.The characteristics of the study population were described overall and within their outcome groups. Continuous variables were summarized using median and interquartile range (IQR) and compared between children with good outcomes and poor outcomes using the Wilcoxon rank-sum test. Categorical variables were described using counts and frequencies and compared between those with good outcome and poor outcome using the Streptococcus pneumoniae. In regard to risk factors, 14.4% of our patients were asthmatic or had a history of three episodes of bronchiolitis before the age of 3 years.Overall, 415 patients were finally included in this study . Table 110.6% of the patients were sickle cells 4.1% had congenital heart disease3.8% had bronchopulmonary dysplasia 2% had trisomy 21 or 18, Alagille disease, or Pompe diseaseRegarding other comorbidities,These comorbidities (34.2%) concerned only 123 patients because 14 of them had been hospitalized several times during the 3 years of study. 25.2% of our patients had received antibiotics before hospitalization, for most of them penicillin. 24.1% of them have been hospitalized in the previous 6 months .The average consultation time was 2.3 ± 2 days. 53.4% of the patients had fever at home and 48% at the initial clinical examination (emergency or consultation) with an average temperature of 102.74°F.The average heart rate was 146 ± 29.7 per minute, and the average respiratory rate 44 ± 14.6 per minute. The median oxygen saturation in ambient air was 95.2%. Auscultation was abnormal in 74.3% of cases: crackling rattles (43.07%). 98.6% of patients had an initial chest X-ray. Among radiographs performed (387 patients), condensation (60.9%), infiltration (20.4%), or effusion (4.4%) was mostly visible. Radiography was interpreted as normal  in 69 patients (17.8%). The bilateral image rate was 27.8% of cases (108 patients), with 4 effusions among them .Staphylococcus epidermidis, two Mycoplasma pneumoniae, one Staphylococcus aureus, three Streptococcus pneumoniae, and one Klebsiella pneumoniae; and there was no germ found for the 9 others.The etiology of CAP was identified in 93 cases (22.4%). Among them, 41.2% had no specific identification exam  and 88 patients without identified microorganisms have been treated with antibiotics before hospitalization (against 15 patients with an etiology). A bacterial etiology was found in 57 cases, out of a total of 93 blood cultures (61.3%)  . A viralStaphylococcus aureus levels remained stable during the 3 years of study , on a hundred samples per year.There were 106 pathogens identified in 93 patients. RSV and of study . However3.2.In our study, the vast majority of RSV was found in patients less than 2 years old (28 patients versus one patient between 2 and 5 years).3.3.Streptococcus pneumoniae was more present during the months of January, February, and September. The number of hospitalized patients appears to be correlated with rainfall during the months of May, June, and July.The RSV was more present during the months of January and March. Streptococcus pneumoniae, information on pneumococcal vaccination was available for 14 patients. Among them, 11 were not up to date: 78.6%  not made). Among the 11 patients with Haemophilus influenzae, immunization information was available for 9.Of the 19 μg/L. In patients with an identified virus, the mean leukocyte count was 12.00 ± 5.44 G/L with 6.18 ± 4.34 G/L neutrophils. Their average CRP was 24.20 ± 4.19 mg/L and PCT 0.68 ± 0.43 μg/L. These calculations did not take into account bacterioviral coinfections.In patients with an identified bacterium, the average white blood cell count was 17.31 ± 9.23 G/L with 10.73 ± 8.30 G/L neutrophils. The average CRP was 101.1 ± 10.8 mg/L and PCT 2.76 ± 1.04 The multivariate analysis showed that patients who have bacterial pneumonia and CRP > 130 mg/L were at risk of bad outcome. 98% of patients without these anomalies had a favorable evolution .Haemophilus influenzae, four showed decreased susceptibility to amoxicillin and 4 to cefalotin. And three of the seven strains tested exhibited decreased susceptibility to rifampicin. Of the six strains of Streptococcus pneumoniae, two had decreased susceptibility to amoxicillin, two to gentamicin, two to erythromycin, and two to tetracycline. And two of the five strains tested showed decreased sensitivity to trimebutine sulfadiazine. Two of the eight strains tested for Staphylococcus aureus exhibited decreased susceptibility to oxacillin, cefotaxime, and erythromycin. And three of these eight strains exhibited diminished sensitivity to tetracycline.Of the nine strains of 172 patients were treated with amoxicillin 46.2%, 92 (24.7%) with amoxicillin+clavulanic acid, 113 (30.4%) with cefotaxime, 40 (10.8%) with ceftriaxone, 100 (26.9%) with azithromycin, 21 (5.6%) with josamycin, 10 (2.7%) with clarithromycin, 12 (3.2%) with ciprofloxacin, 88 (23.7%) with gentamycin, 39 (10.5%) with vancomycin, 20 (5.4%) with rifampicin, and 14 (3.8%) with clindamycin in case of severe staphylococcal pneumonia. The mean duration before apyrexia was 2.14 ± 1.6 days with a mean duration of antibiotic therapy of 10.4 ± 2.6 days. The mean total length of stay was 7.35 ± 2. 17 (4.1%) patients required a transition to the resuscitation unit among the 110 patients in the intensive care unit.n = 88, 21%) had been treated with antibiotics before hospitalization. However, as part of routine care, in the event of a bronchiolitis or influenza epidemic, virological testing is not performed in all children, which might be the reason why the virus detection rate is lower than that of bacteria. There were 13 coinfections (14%) with identified pathogens. The rate of pathogens identified in studies comparable to ours is 20 to 60%, according to the diagnostic possibilities [This study allows attracting attention to some characteristics of childhood CAP in French Guiana. 45.3% of our patients had comorbidities, mostly history of preterm birth (25.5%), asthma 14.4%), and sickle cell disease (10.6%). Vaccination was up to date for only 52.8% of our study population. An etiology was found in 93 patients (22.4%). A bacterial origin was found in 57 (61.3%) of these patients with 40 (43%) with a viral origin. This low detection of bacteria could be explained by the fact that some children (.4%, and bilities . Howeverbilities –19. HowePlasmodium vivax, Cryptococcus neoformans, or hookworm parasite in coinfection with a bacterium. There was no identification of Q fever or Amazonian toxoplasmosis, two pathogens that are the main causes of pneumonia in adult patients in French Guiana. Indeed, in French Guiana, Q fever pneumonia represented 24.4% of CAP adult inpatients [Our study highlights the impact of the low vaccination coverage rate in French Guiana. However, this argument does not seem to be sufficient to explain the difference with the other countries of Latin America and the Caribbean, since these countries also do not have an optimal vaccination coverage rate. According to Jiang et al. , coinfecpatients . Regardipatients –25. Howepatients –30. The Pneumococcus, Haemophilus influenzae, and whooping cough and the possibility of practicing multiplex PCR in our hospital, it will be interesting to study the impact of this law enforcement on new child generations and compare these new data to our study.To date, this article provides the most comprehensive analysis of the contributing causes of CAP in children in French Guiana. With the vaccination requirement imposed since 1 January 2018 against


The Global Registry of Acute Coronary Events (GRACE) score was developed to evaluate risk in patients with myocardial infarction. However, its performance in type 2 myocardial infarction is uncertain.n = 48 282) and a tertiary care hospital in Sweden (n = 22 589), we calculated the GRACE 2.0 score to estimate death at 1 year. Discrimination was evaluated by the area under the receiver operating curve (AUC), and compared for those with an adjudicated diagnosis of type 1 and type 2 myocardial infarction using DeLong’s test. Type 1 myocardial infarction was diagnosed in 4981 (10%) and 1080 (5%) patients in Scotland and Sweden, respectively. At 1 year, 720 (15%) and 112 (10%) patients died with an AUC for the GRACE 2.0 score of 0.83 [95% confidence interval (CI) 0.82–0.85] and 0.85 (95% CI 0.81–0.89). Type 2 myocardial infarction occurred in 1121 (2%) and 247 (1%) patients in Scotland and Sweden, respectively, with 258 (23%) and 57 (23%) deaths at 1 year. The AUC was 0.73 (95% CI 0.70–0.77) and 0.73 (95% CI 0.66–0.81) in type 2 myocardial infarction, which was lower than for type 1 myocardial infarction in both cohorts .In two cohorts of consecutive patients with suspected acute coronary syndrome from 10 hospitals in Scotland (The GRACE 2.0 score provided good discrimination for all-cause death at 1 year in patients with type 1 myocardial infarction, and moderate discrimination for those with type 2 myocardial infarction.ClinicalTrials.gov number, NCT01852123. This assay has an inter-assay coefficient of variation of <10% at 4.7 ng/L and a 99th centile of 16 ng/L in women and 34 ng/L in men., 2. The obtained data, together with laboratory data, were sent to the Swedish National Board of Health and Welfare who linked information on comorbidities and outcomes, use of medication, and dates and causes of death from the National Patient Register, the Prescribed Drug Register, and the Cause-of-Death register, respectively. The Patient Register has nationwide coverage on diagnoses at discharge and surgical procedures coded according to the International Classification of Disease. Details of study approvals are contained in the The study population from the Karolinska University Hospital in Stockholm was derived from an observational cohort study of all patients >25 years old with a visit to the Emergency Department with chest pain and at least one hs-cTn measurement from January 2011 to October 2014.All diagnoses were adjudicated in accordance with the Fourth Universal Definition of Myocardial Infarction.The primary outcome was all-cause death at 1 year, and the secondary outcome was all-cause death or type 1 myocardial infarction at 1 year. All in-hospital and community deaths are recorded on the National General Register of Scotland, and the Swedish Patient Register. Subsequent myocardial infarction events were identified through the electronic patient record in Scotland with adjudication as for the index diagnosis, and using ICD-10 coding (I21 and I22) from the Swedish Patient Register in the Swedish cohort.2, Kruskal–Wallis, or one-way analysis of variance tests as appropriate. We determined the GRACE 2.0 score for all-cause death, and for all-cause death or type 1 myocardial infarction at 1 year. This score includes age, heart rate, systolic blood pressure, creatinine as continuous variables, with categorical variables for Killip class, cardiac arrest at admission, ST-segment deviation, and elevated cardiac biomarkers (defined here as any hs-cTn concentration above the 99th centile). Where data were missing within the Scottish cohort, this was assumed to be at random, and we applied multiple imputation using chained equations with five imputations of the dataset. For imputation, we applied Bayesian linear regression models for continuous data , multinomial logistic regression for ordinal data (Killip class) and logistic regression for binary data (e.g. cardiac arrest status). We assessed overall GRACE 2.0 model discrimination by determining the area under the receiver operating curve (AUC) and compared performance in patients with type 1 and type 2 myocardial infarction using the DeLong method. We assessed model calibration both graphically, and by using the Hosmer–Lemeshow goodness of fit test. In addition, we assessed GRACE performance by evaluating previously defined categories of mortality risk  using the Kaplan–Meier method. We explored the impact of multiple imputation by performing a sensitivity analysis in which we evaluated the complete dataset only. These results were similar to the primary analysis and are presented in the Table S1. In post hoc analyses, we also determined performance of the GRACE 2.0 score for in-hospital death and of hs-cTn alone to predict all-cause death at 1 year. All analyses were performed in R (Version 3.5.1) and the code required to calculate the GRACE 2.0 score is available in S1.Baseline characteristics were summarized for each cohort and in groups by according to adjudicated diagnosis. Group-wise comparisons were performed using χThe Scottish cohort consisted of 48 282 consecutive patients  with suspected acute coronary syndrome of whom 10 360 (21%) had hs-cTnI concentrations above the 99th centile. It was possible to adjudicate the diagnosis in 88% (9115/10 360) of patients. The final diagnosis was type 1 myocardial infarction in 55% (4981/9115), type 2 myocardial infarction in 12% (1121/9115), and acute or chronic myocardial injury in 18% (1676/9115) and 14% (1287/9115), respectively. The remainder of patients had type 4a (9/9115) or 4b (41/9115) myocardial infarction.The Swedish cohort consisted of 22 589 consecutive patients with suspected acute coronary syndrome of whom 3853 (17%) patients had hs-cTnT concentrations above the 99th centile. The final diagnosis was type 1 myocardial infarction in 28% (1080/3853) of patients, and type 2 myocardial infarction in 6% (247/3853), with acute or chronic myocardial injury in 30% (1144/3853) and 35% (1347/3853), respectively.Table 1). Patients with type 2 myocardial infarction were less likely to be offered coronary angiography, revascularization or secondary prevention than those with type 1 myocardial infarction (Table 2). There were differences in the covariates which influence the GRACE 2.0 score between groups, with higher heart rates (101 vs. 77 b.p.m.), lower systolic blood pressures (130 vs. 141 mmHg) and a higher proportion of patients with increased Killip class observed in those with type 2 myocardial infarction (Table 3).Compared to patients with a diagnosis of type 1 myocardial infarction, those with type 2 myocardial infarction were older (74 ± 14 vs. 68 ± 14 years), more likely to be women (55% vs. 40%), and more likely to have a history of cardiovascular disease. Similar differences were apparent in both cohorts (Table 3) and had good discriminative ability with an AUC of 0.83 [95% confidence interval (CI) 0.82–0.85] and 0.85 (95% CI 0.81–0.89), respectively .We obtained follow-up in 100% of participants for primary and secondary outcomes at 1 year. In patients with type 1 myocardial infarction, 15% (720/4981) and 10% (112/1080) died from any cause at 1 year in the Scottish and Swedish cohorts, respectively. The GRACE 2.0 score was higher in those with type 2 compared to type 1 myocardial infarction across both cohorts .In patients with type 2 myocardial infarction, 23% (258/1121) and 23% (57/247) died from any cause at 1 year in the Scottish and Swedish cohorts, respectively. The GRACE 2.0 score had moderate discriminative ability, with an AUC of 0.73 (95% CI 0.70–0.77) and 0.73 (95% CI 0.66–0.81), respectively, and performed less well than in patients with type 1 myocardial infarction . Calibration plots and the Hosmer–Lemeshow test indicated the GRACE 2.0 score underestimated future all-cause death across all deciles of risk in both type 1 and type 2 myocardial infarction .Similar performance was observed in men and women with type 1 and type 2 myocardial infarction in both cohorts . Baseline demographic information was similar across all categories of risk irrespective of the diagnosis of type 1 and type 2 myocardial infarction (Table S4). In patients with type 2 myocardial infarction in the Scottish cohort at low risk of death, there were fewer new prescription for aspirin (25% vs. 67%), statin (11% vs. 56%), angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (15% vs. 49%) compared to those with type 1 myocardial infarction. Similar patterns were observed in patients at intermediate or high risk of death.In the Scottish cohort, we evaluated conventional GRACE categories of low, intermediate, and high predicted risk of mortality. Observed event rates were higher in patients with type 2 myocardial infarction who had a low or intermediate predicted risk of death  and 16% (173/1080) of patients died or had a myocardial infarction at 1 year in the Scottish and Swedish cohorts, respectively. The AUC for the GRACE 2.0 model incorporating death or future myocardial infarction was 0.76 (95% CI 0.74–0.77) and 0.81 (95% CI 0.77–0.85), respectively.P = 0.007 and P = 0.042 vs. type 1 myocardial infarction). Calibration plots showed the GRACE 2.0 model underestimated future risk in type 1 and type 2 myocardial infarction across both cohorts .In patients with type 2 myocardial infarction, there were 27% (297/1121) and 26% (63/247) deaths or myocardial infarctions at 1 year. Here, the GRACE 2.0 score gave an AUC of 0.70 (95% CI 0.67–0.74) and 0.72 (95% CI 0.65–0.80), respectively . When applied as a continuous variable, both hs-cTnI and hs-cTnT were moderate predictors of all-cause death at 1 year (Table S6).In a We evaluated the performance of the GRACE 2.0 score for the prediction of all-cause death, and all-cause death or myocardial infarction in consecutive patients with type 1 and type 2 myocardial infarction from two independent cohorts across two countries. We observe that the GRACE 2.0 score provides good discrimination for all-cause death in patients with type 1 myocardial infarction diagnosed using hs-cTn assays and for both cardiac troponin I and T. Consistent with the original validation study,The GRACE 2.0 score was derived prior to the publication of the first Universal Definition of Myocardial Infarction,, We recently demonstrated future cardiovascular risk was increased in all patients with myocardial injury and infarction, irrespective of diagnostic classification, despite a vast excess in non-cardiovascular death in patients without type 1 myocardial infarction. Patients with type 2 myocardial infarction were at almost four-fold increased risk of cardiovascular events relative to those without myocardial injury. This risk appears to be highest in those with a history of prior coronary artery disease, suggesting underlying coronary atheroma may at least in part be driving future cardiovascular risk., In this analysis, we demonstrate the GRACE 2.0 score performed well in the prediction of all-cause mortality and future cardiovascular events in patients with type 1 myocardial infarction, but discrimination was lower in those with type 2 myocardial infarction. At the time the GRACE was derived, the diagnosis of myocardial infarction was based on contemporary cardiac biomarkers with a diagnostic threshold at least 10-fold higher than advocated in current guidelines.Some attempts have been made to derive risk stratification tools in patients with type 2 myocardial infarction. The TARRACO risk score was derived in 611 patients with type 2 myocardial infarction and myocardial injury.post hoc analysis, incorporating troponin concentration as a continuous variable could offer improved performance. Whether the inclusion of absolute troponin concentration, comorbidities or additional covariates, such as haemoglobin concentration, could improve model performance requires exploration.Analysis of the calibration of the GRACE 2.0 model in type 1 and type 2 myocardial infarction identified underestimation of risk across all outcomes. This likely reflects differences between the population of consented patients recruited into the GRACE registry, and the consecutive patient cohort evaluated here. There are a number of potentially important comorbidities not included in the GRACE 2.0 score which are common in clinical practice and could influence survival, particularly in those with type 2 myocardial infarction. These include atrial fibrillation, chronic obstructive pulmonary disease, heart failure, malignancy, dementia, and frailty. Furthermore, as suggested in a Given the implementation of hs-cTn assays has been shown to increase recognition and the prevalence of type 2 myocardial infarction, there is an urgent and unmet need to improve risk prediction in these patients. Until bespoke risk prediction tools are available for patients with type 2 myocardial infarction, the GRACE 2.0 allows identification of patients at increased risk of death, both in-hospital and at 1 year. This may be helpful to guide clinicians when reviewing patients with type 2 myocardial infarction and deciding who may benefit from more intensive monitoring or further investigation for underlying coronary disease. We observed lower prescription rates for secondary prevention therapy in patients with type 2 myocardial infarction. This was most evident in those classified by GRACE as low- or intermediate risk, where rates of prescriptions for new antiplatelet or statin therapies in type 2 myocardial infarction were half those of type 1 myocardial infarction, and outcomes were worse. In those classified as high risk, prescription rates and outcomes between patients with type 1 and type 2 myocardial infarction were similar. Whether secondary prevention therapy in patients with type 2 myocardial infarction will improve clinical outcomes requires evaluation in prospective trials.post hoc and is limited by a small number of events. Finally, we acknowledge that the rates of coronary angiography were lower here than in other registries or clinical trials of selected patient populations., We acknowledge some limitations. Firstly, whilst the GRACE 2.0 score was derived and validated across 14 countries, we only evaluate performance in Scotland and Sweden. However, we included consecutive patients across two different healthcare systems using different high-sensitivity troponin assays and found consistent results. The consistency in results was evident despite differences in the original study design and in the selection of patients between the two healthcare sites. Second, whilst we adjudicated all diagnoses according to the latest Fourth Universal Definition of Myocardial Infarction using all available clinical information, we acknowledge that diagnostic misclassification is possible. In the Scottish cohort where there was consensus amongst the adjudication panel that there was insufficient clinical information to make a definitive diagnosis, because of missing admission or discharge letters, we did not attempt to adjudicate the diagnosis. Third, where information on covariates required for calculating the GRACE score was missing this was determined to be at random, and to minimize bias we applied multiple imputation. As data were missing in patients with type 1 and type 2 myocardial infarction in equal proportion, and we observed consistent performance in a sensitivity analysis restricted to the dataset where complete case data were available, we do not think this impacted on the results observed. Fourth, we acknowledge that our analysis of in-hospital events was The GRACE 2.0 score provided good discrimination for all-cause death at 1 year in patients with type 1 myocardial infarction, and moderate discrimination for those with type 2 myocardial infarction. Until specific risk prediction tools are derived and validated, clinicians should consider applying the GRACE 2.0 score to guide prognosis and subsequent management in patients with type 2 myocardial infarction.European Heart Journal online.This trial was funded by a Special Project Grant from the British Heart Foundation (BHF) (SP/12/10/29922) with additional support from a BHF Research Excellence Award (RE/18/5/34216). A.R.C. and N.L.M. are supported by Clinical Research Training Fellowship (FS/16/75/32533) and the Butler Senior Clinical Research Fellowship (FS/16/14/32023) from the BHF. A.R.C. is supported by a Starter Grant for Clinical Lecturers from the Academy of Medical Sciences, which is supported by the Wellcome Trust, the Medical Research Council, the British Heart Foundation, vs. Arthritis, Diabetes UK, and the British Thoracic Society [SGL021/1075]. A.R. holds a research position funded by the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet (20160644). D.M.K. was supported by a grant from Health Data Research UK which receives its funding from HDR UK Ltd (HDR-5012) funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation, and the Wellcome Trust. M.J.H. holds research positions funded by the Swedish Heart-Lung Foundation (20170804) and the Stockholm County Council (20170686). Abbott Laboratories provided cardiac troponin assay reagents, calibrators, and controls without charge for the High-STEACS trial. The funders played no role in the design, conduct, data collection, analysis or reporting of the trial.Conflict of interest: A.S.V.S. and A.R.C. have received honoraria from Abbott Diagnostics. N.L.M. has received honoraria from Abbott Diagnostics, Siemens Healthineers, Roche Diagnostics and Singulex, and the University of Edinburgh has received research grants from Abbott Diagnostics and Siemens Healthineers. M.J.H. has received consultancy honoraria from Idorsia.ehaa375_Supplementary_DataClick here for additional data file.


Healthcare workers are always at the risk of exposure to different diseases like respiratory illness including COVID-19. Using appropriate face mask or respiratory protective equipment correctly can prevent transmission of diseases from and to healthcare workers while caring for patients. The study aimed to find out the practice regarding use of face masks during the COVID-19 pandemic in a tertiary care center.A descriptive cross-sectional study was conducted at a tertiary care hospital during June-July 2020 after receiving ethical approval from the review committee regarding practice of use of face masks. Convenience sampling method was used and a sample size of 162 was taken. Descriptive statistical analysis was done. Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data.Among 162 participants, 123 (75.9%) knew the correct way of using the masks .In this study regarding practice of use of face masks, most of the healthcare workers knew the correct way of using masks and practised hygiene before and after using masks. All HCWs need to be trained for appropriate use of Respiratory Protection Equipment (RPE).3Healthcare workers (HCWs) are at high risk of various respiratory hazards including coronavirus disease-19 (COVID-19). World Health Organization (WHO) recommends use of medical mask for all HCWs working in an area with community transmission of COVID-19 and respirators for those working in aerosolgenerating procedures.6 The search of literatures doesn't reveal any such study from Nepal.There are few studies about the practice of HCWs regarding the use of RPE especially from developing countries. These studies highlight the deficient supply and improper use of RPE.Hence, the study aimed to know the practice regarding use of face masks during the COVID-19 pandemic in a tertiary care hospital of Nepal.6This was a descriptive cross-sectional study conducted among the healthcare workers including doctors, nurses, paramedical staff and laboratory and medical technicians at Kanti Children's Hospital (KCH), a tertiary care children's hospital in Kathmandu, in June-July 2020. During the study period, due to the increasing number of COVID-19 cases in the country, there was a lockdown imposed by the government and HCWs were advised to manage duty alternately to minimize exposure in the latter half of the study period when the lockdown was partially relieved. However, the daily new diagnosis of COVID-19 was on the rise and there was no rampant community transmission. There were few kinds of literature and diagnostic facilities available. Ethical approval for this study was obtained from the institutional review committee at KCH (Ref. no. 842) and informed written consent was taken. All healthcare workers (HCWs) working at the study site, who consented to participate, were included in the study. Healthcare workers working part-time or visiting from other institutes for practices or observership were excluded A convenient sampling method was used and a sample size of 109 was calculated, considering the margin of error at 6% and confidence interval of 95%, and 88.5% as the correct knowledge and practice of using face masks in the previous study.The sample size was calculated using the formula:where,n = sample sizeZ = 1.96 at 95% Confidence Interval (CI)6p = prevalence of previous study, 88.5%q = 1-p = 1-0.885 = 0.115e = margin of error, 6%7 The questionnaire included basic demographic characteristics , and knowledge, and practice related questions regarding the use of a face mask to limit COVID-19 exposure. During sample collection, some participants did not respond to some of the questions leading to missing data so a valid percentage was considered while finding out results. The information obtained from the participants was entered and calculated using Statistical Package for the Social Sciences (SPSS) Statistics for Windows, Version 20.0. Mean with standard deviations were calculated for age and frequency with percentages for responses with categorical variables.Taking 10% non-response rate, the total sample size becomes 120. However, the total sample taken was 162. The study was conducted by interview using a structured questionnaire. The questionnaire was developed after a review of previous literature on the proper use of surgical face masks and the guidelines of the CDC.A total of 162 participants were included in the study. One hundred twenty-three (75.9%)  knew the correct way of wearing a surgical mask. On the question about areas required to be covered by surgical masks, 151 (93.2%) answered correctly . One hundred fifty eight (97.5%) HCWs had the practice of putting on masks while going out and had a practice of wearing masks on hospital premises as well. About 156 (96.3%) practised hand hygiene before and after using face masks. One hundred twenty-five (77.2%) of participants reused the face masks.The mean age of participants was 32.78±8.55 years. Among the participants 66 (40.7%) were doctors, 72 (44.4%) were nurses, 7 (4.3%) were laboratory staff, 2 (1.2%) were physiotherapists and 6 (3.7%) were others. The median work experience of the participants was 60.0 months. Among them 106 (65.4%) participants were directly involved in the care of suspected or proven COVID-19 cases.Fifty-two (32.1%) responded eight hours as the maximum duration for wearing a face mask with no compromise in safety. About 147 (90.7%) of participants believed face masks can prevent transmission of respiratory disease like COVID-19. About 58 (35.8%) of participants believed that both surgical and N95 masks or equivalents are equally effective in preventing respiratory illness like COVID-19.Out of 162 respondents, 125 (77.2%) of participants used one mask for the whole day, either new or reused one. About 126 (77.8%) used surgical masks while 36 (22.2%) used N95 or equivalent masks but no participants used fabric masks. Five (3.1%) of them used to remove the mask but 155 (95.7%) didn't while talking to patients and visitors. About 84 (51.9%) touched face masks/RPE 1-5 times while 35 (21.6%) touched 5-10 times and 29 (17.9%) touched more than 10 times in a shift but 13 (8.0%) didn't touch their RPE in a shift. Seventy-four (45.7%) took off face masks/ RPE 1-2 times while 55 (34.0%) took off 3-5 times and 14 (8.6%) took off more than 5 times in a shift but only 12 (7.4%) didn't take off their RPE in a shift.Meanwhile, 117 (72.2%) of participants stored RPE before reuse. About 45 (27.8%) stored N95 masks, 27 (16.7%) stored surgical masks while 75 (46.3%) stored both masks but 13 (8.0%) didn't store. Fifty-four (33.3%) stored surgical masks and 67 (41.4%) stored N95 masks for 2-3 days before reuse.Ninety-four (58.0%) reused surgical masks consecutively for 1-3 days, 20 (12.3%) for 3-7 days and 46 (28.4%) did not use a single mask consecutively for more than one day. While 51 (31.5%) reuse N95 masks consecutively for 1-3 days, 70 (43.2%) for 3-7 days and 10 (6.2%) did not use the mask consecutively for more than one day.For disinfection of mask, 58 (35.8%) of them used sunlight exposure, 38 (23.5%) stored, 26 (16.0%) washed face masks but 18 (11.1%) did not practise disinfection. About 150 (92.6%) of participants removed face masks from behind the ear or head. During disposal of used face masks, 92 (56.8%) used a closed lid bin while 67 (41.4%) used an open dustbin and 2 (1.2%) disposed of open .6 This study aimed to know the practice of HCWs on the use of RPE. The results indicated that most of the studied HCWs had good practice regarding the use of RPE. All the participants who responded had the practice of putting on masks while going out and in hospital premises. This study showed 75.9% of the participants knew the correct way of wearing a surgical mask and 93.2% knew about areas required to be covered by surgical masks. As compared to the study in Pakistan by Kumar J, and et al.6 showed, 88.5% of participants knew the proper steps of wearing a surgical face mask. The correct way of wearing a surgical mask is by facing out the coloured side independent of health status.8From developing countries, very few studies on the subject have been published.9 participants wearing a face mask were reported to be practising additional preventive hygiene measures while in this study, 96.3% practised hand hygiene before and after using face masks.In the study by Wada K and et al.6 found 13.8% of them removed the mask to talk with patients.This study found that only 3.1% of them used to remove the mask while talking to patients and visitors, but 51.9% touched face masks/RPE 1-5 times in a shift and 45.7% took off face masks/RPE 1-2 times in a shift while in the study by Kumar J et al.10 As compared to study by Kumar J et al.6 found only 20.2% reused face masks. Although statistically not significant, 69.7% of doctors as compared to 83.2% of other staff reused face masks. The reason for more than 85% reuse is decreased supply.11The proportion of reuse is very high. We found 77.2% of participants reused the RPE (face masks) and 72.2% stored RPE before reuse; 27.8% stored N95 masks, 16.7% stored surgical masks and 46.3% stored both masks.Consecutive use is not safe but 58% of our HCWs are practicing consecutive use. People tend to use N95 or equivalents for more days consecutively than surgical masks.12 Kumar J et al.6 found 44.9% disposed of in the yellow-coded bag for disposal of face mask; while our study found that 56.8% used closed lid bins for disposal.A colour-coded bin system is recommended for the proper disposal of biomedical waste in hospitals.The limitations of this study include the cross-sectional nature of the study design limited to one hospital with a small sample size. Further studies should be carried out on a larger sample size so that the results could be generalized.The practice of the use of respiratory protective equipment or face masks among the healthcare workers at a tertiary care children's hospital was found that HCWs knew the correct way of using masks and areas to be covered by masks. HCWs practised hygiene before and after using face masks. However, due to inadequate supply, they were reusing the face masks. All the participants who responded had the practice of putting on masks while going out and when on hospital premises. It was found that very few participants used to remove the mask while talking to patients and visitors, but around half of them touched face masks/RPE 1-5 times and took off face masks/RPE 1-2 times in a shift. More than half of the participants used a closed lid bin during the disposal of used face masks. More studies of similar nature are urgently required from different countries.


Stigma continues to be a major barrier to tuberculosis (TB) control particularly in urban populations. Stigma can influence health seeking behaviour and affect adherence to TB treatment, yet few studies have examined TB related stigma and associated factors in Uganda. This study was therefore conducted to determine the level of stigma and associated factors among TB patients in an urban setting in Kampala, Uganda.A cross-sectional study was conducted in Makindye division, Kampala among 204 patients with TB aged 18 years and above. Data were collected on socio-demographic, individual patient and HIV/AIDS related factors using an interviewer administered questionnaire. The outcome variable (stigma) was assessed on a four-point Likert scale from the participants' perspective. Stigma scores ranged from 0 to 36 which were summed up and a median stigma score calculated. Individuals with a stigma score equal or greater than the median were categorized as having high stigma. A multivariable logistic regression analysis was performed to determine factors associated with TB stigma.Over half (52%) of the participants were found to have high TB stigma. Knowing someone who had died of TBAOR = 4.42, 95% CI (1.69 – 11.50) and believing that TB and HIV symptoms were similarAOR = 3.05, 95% CI (1.29 – 7.22) were positively associated with high TB stigma. The odds of having high stigma were 79% lower among individuals who had been previously treated for TBAOR = 0.21, 95% CI (0.09 – 0.52).Stigma towards TB was high in this urban population and mainly associated with knowing a person who had died of TB, perception that symptoms of TB are similar to those of HIV/AIDS, and previous TB treatment. Interventions to mitigate TB stigma are needed in urban populations and should also address HIV/AIDS related stigma. Makindye is located in the south-eastern region of Kampala and comprises 21 parishes with a population of 439,300 people29. This study was conducted at four health facilities in the division, including: Kisugu Health Center, Touch Namuwongo Clinic, Alive Medical Center, and Nsambya Homecare Clinic. These health facilities were purposively selected as they had the highest patient volumeCA3 in the division. Kisugu Health Center is operated by Kampala Capital City Authority (KCCA) whereas Alive Medical Centre, Touch Namuwongo and Nsambya Homecare Clinic are private-not-for-profit facilities. All these facilities offer outpatient services which include smear microscopy and TB treatment as well as have integrated HIV and TB services. Patients seen at these clinics are typically walk-ins and referrals from practitioners within and outside Kampala.The study design was cross sectional using quantitative methods and was conducted between April and June 2014.CA4 The study sample was drawn from all the TB patients that were registered for treatment at the four health facilities and included only patients aged 18 years and above. Initial sample size of 382 was obtained using the formula by Kish Leslie with Zα = 1.96, p = 0.47 from a previous study30 and a precision (σ) of 5%. Since the total number of TB patients that were receiving treatment in health facilities in the division was approximately equal to the estimated sample size, the computed sample size was adjusted since it was not possible to include all the TB patients in the study due to decline to participate and other reasons. A formula for sample size calculation was therefore used to obtain a new sample size (SS): new SS = SS / (1+ (SS-1)/population size of TB patients. Therefore, new SS = 382 /(1+ (382-1)/400) = 196. Considering, a non-response rate of 10%, a final sample size of 217 participants was obtained.A semi-structured questionnaire was designed based on reviewed literatureData were entered in Epi data version 3.1 , and later exported to Stata version 12  for cleaning and analysis. Descriptive statistics were used to run frequencies and proportions of socio-demographic characteristics, knowledge on TB and experiences of TB stigma. The dependent variable for this study was TB stigma. The scale used to measure stigma was adopted from reviewed literatureA total of 204CA9 patients participated in the survey representing a 94.0% response rate. More than half 56.9% (116/204) were male and Catholics 51.5% (105/204). Nearly forty percent 39.7% (81/204) of the participants were never married, and 33.2% (66/204) unemployed. The median age of participants was 30 years and ranged from 18 to 76 years .The majority of participants knew that TB was spread by infection from others 94.6% (193/204), could be transmitted through coughing and sneezing 98.5% (201/204), and that TB was curable 97.1% (198/204). Most participants thought that TB could be transmitted by: eating and drinking with infected persons 77.5% (158/204); smoking and drinking alcohol 78.4% (160/204); sexual intercourse 66.2% (138/204); and touching an infected person 68.6% (140/204). Less than half 47.6% (97/204) of the participants had been previously treated for TB. In addition, majority of participants had tested for HIV/AIDS 95.1% (194/204) with nearly half 49.0% (95/194) of them being HIV positive .The median TB stigma score was 22 and ranged from 3 to 36. Over half 106/204 (52.0%) of the participants had high stigma. Bivariable analysis results indicated that participants who were married or cohabiting COR= 2.97, 95% CI (1.55 – 5.68), formerly married or widowed COR = 5.08, 95% CI (2.30 – 11.19), and Catholics by religionCOR = 3.17, 95% CI (1.37 – 7.37) were more likely to have high TB stigma. Regarding knowledge, we found that participants who thought that TB could be transmitted through smoking and drinking alcoholCOR = 4.36, 95% CI (1.63 – 11.67), TB transmission was hereditaryCOR = 2.86, 95% CI (1.34 – 6.09), or transmitted sexuallyCOR = 2.72, 95% CI (1.31 – 5.66) were more likely to have TB stigma. Individual and HIV/AIDS risk factors for TB stigma included knowing someone who died of TBCOR = 5.13, 95% CI (2.66 – 9.89), being HIV/AIDS positiveCOR = 2.05, 95% CI (1.15 – 3.64) and thinking that TB and HIV symptoms appear similarCOR = 4.22, 95% CI (2.27 – 7.84) which were all associated with TB stigma. Participants with previous TB treatment were less likely to have high TB stigmaCOR = 0.18, 95% CI (0.10 – 0.33). After controlling for potential confounders, the final multivariable logistic regression model indicated that the odds of having high TB stigma were four times higher among individuals who knew someone who died of TB compared to those who did notAOR = 4.42, 95% CI (1.69 - 11.50). Participants who had previously been treated for TB were 79% less likely to have high TB stigma compared to non-rereatment casesAOR = 0.21, 95% CI (0.09 – 0.52). However, participants who believed that TB and HIV symptoms appear similar were three times more likely to suffer with high TB stigma compared to those who did not think soAOR = 3.05, 95% CI (1.29 – 7.22) .The study assessed the level of TB stigma and associated factors among TB patients in an urban population in UgandaCA10. Our study showed that over half of the participants in this urban setting had high stigma. In the study, knowing someone who died of TB, previous TB treatment, and having a perception that TB and HIV appear similar emerged as predictors for TB stigma. These findings are likely to be important in designing interventions to reduce TB stigma in urban settings in Uganda.Most participants stated that TB could be spread through drinking alcohol or smoking which is in line with other studiesOur study found that more than half of the participants suffered high TB stigma. This finding is consistent with those of other studies in Ethiopia Nearly half of the TB patients in our study were co-infected with HIVCARegarding predictors of TB stigma, individuals who knew someone who died of TB were significantly more likely to have high TB stigma. This relationship may partly be explained by the fact that whereas TB deaths may be independent, a section of the public associates them with those of HIV/AIDS. Indeed, a study on TBHIV stigma in high HIV prevalence settings in Zambia confirmed that TB stigma may be compounded by HIV stigmaIn our study, the belief among participants that TB and HIV symptoms appear similar was significantly associated with higher TB stigma. This finding further highlights the effect of HIV and HIV stigma on pre-existing TB stigma. In the context of HIV, TB symptoms and diagnosis are often accompanied by the assumption that HIV co-infection is very likely. In addition, progressive, severe and reoccurring TB usually confirms community's perceived diagnosis of HIV. Indeed, symptoms like extreme weight loss, productive cough and some side effects of TB treatment such as skin rash further confound the perception that a TB patient is HIV positivePrevious treatment for TB was negatively associated with high TB stigma as retreatment cases were significantly less likely to have high TB stigma. It is widely believed that TB stigma negatively affects adherence to treatmentThis study had limitations that should be noted. This was a facility based study on TB patients enrolled on treatment and care. It is possible that to some extent, these patients had coped with stigma towards the disease. Therefore, low stigma levels in some respondents could be attributed to this. Additionally, higher levels of stigma could have prevented TB patients in the community from seeking care and treatment. It is also important to note that summarizing Likert scores during analysis may have caused a loss of power and inaccurate estimation. This may lead to difficulty comparing results across studies due to the data driven cut points used to define categories. Stigma towards TB has been closely linked to associations of TB to HIV/AIDS yet our study did not measure HIV/AIDS stigma. Therefore, the implications of TB-HIV stigma on TB control may not be fully explored using findings from this study.Our study showed that TB stigma was high in this urban population and found to be significantly associated with knowing a person who died of TB, being co-infected with HIV/AIDS and perception that TB symptoms are similar to those of HIV/AIDS. The findings suggest that TB stigma is compounded by HIV stigma which underscores the importance of integrating TB and HIV programmes. More effort is needed to address stigma in TB control programmes.


Over the 24-month period, the mean number of IVA injections and clinic visits was 7.4 (3.3) and 11.1 (2.0), respectively. The mTAE regimen of IVA injections for ME due to BRVO was effective for improving BCVA and reducing CST over 24 months. This regimen shows promise for reducing the number of injections and clinic visits. This study aimed to evaluate the long-term (24-month) efficacy and safety of a modified treat-and-extend (mTAE) regimen of aflibercept for macular edema (ME) due to branch retinal vein occlusion (BRVO). This was a prospective multicenter intervention study. We evaluated 50 eyes in 50 patients with ME due to BRVO enrolled between October 2016 and September 2017. The patients received intravitreal aflibercept (IVA) injections according to a mTAE regimen for 24 months. This study reports the secondary endpoints of best-corrected visual acuity (BCVA) and central subfield thickness (CST) at 24 months and compares them with previously reported primary endpoints. Compared with baseline BCVA and CST of 0.33 (0.27) and 488 (165) µm (mean (standard deviation)), respectively, BCVA and CST were significantly improved at 12 and 24 months (12 months: 0.059 (0.19) LogMAR and 299 (112) µm; 24 months: 0.034 (0.18) LogMAR and 272 (81) µm, respectively; both  Branch retinal vein occlusion (BRVO) is one of the most common retinal vascular diseases. The prevalence of BRVO reported by studies conducted in the United States, Europe, Asia, and Australia is 0.4%, whereas in Japan it is 2.0% ,2. Anti-To this end, we developed a modified treat-and extend (mTAE) regimen of intravitreal aflibercept (IVA) injections for ME due to BRVO and initiated a prospective multicenter intervention study to assess the effectiveness of the regimen. We previously reported the primary outcomes of best-corrected visual acuity (BCVA) and reduced central subfield thickness (CST) at 12 months after the initial injection and found that the mTAE regimen was effective and required fewer injections and clinic visits .Here, to evaluate whether the efficacy and safety of the regimen is maintained and whether the reduced burden on patients and healthcare staff continues over the long term, we report the 24-month results of this mTAE regimen.We have described the materials and methods in detail in our previous report on outcomes at 12 months  and provThis prospective multicenter intervention study involving patients with treatment-naïve ME due to BRVO commenced in October 2016 with the last patient completing the 1-year study in September 2018.The study protocol was approved by the institutional review board of Jichi Medical University (B18-003). The study followed the tenets laid out in the Declaration of Helsinki. Written informed consent was obtained from all patients. The study was registered in the University Hospital Medical Information Network Clinical Trials registry prior to study commencement .This study was conducted at 6 sites in Japan . The detailed inclusion and exclusion criteria are described in our previous report . BrieflyPatients were treated with aflibercept according to the mTAE regimen we described in detail previously . SupplemThe main outcome measures were mean changes in BCVA and CST, with the primary outcomes evaluated at 12 months  and the t-test. As in our evaluation of the primary outcomes , statistp < 0.0001; Mean BCVA was significantly improved at 1, 12, and 24 months (0.11 (0.16), 0.059 (0.18), and 0.034 (0.18), respectively) compared with baseline (0.33 (0.27); all p < 0.0001; In three eyes, the final BCVA was less than logMAR0.3: in two of these eyes, the BCVA was equivalent to that at the first visit, and in one eye, it declined due to cataract progression. The mean CST was significantly decreased after IVA injections at 1, 12, and 24 months (248 (36) µm, 299 (112) µm, and 272 (81) µm, respectively) compared with baseline (480 (165) µm; all p = 0.024, paired t-test). Five eyes received only one injection (The mean number of IVA injections over the 24 months was 7.4 (3.3), with significantly fewer injections administered in the second year compared with the first year (2.9 (1.4) vs. 4.7 (2.0); njection . p < 0.0001, paired t-test). (The mean number of clinic visits was 11.1 (2.0) over the 24 months, with significantly fewer visits occurring in the second year than in the first year (3.9 (1.4) vs. 7.1 (1.0); t-test). .Recurrence occurred most frequently at 3 months (15 eyes). Recurrence of exudative changes was apparent in eight eyes at 1 month and in two eyes at 7 months. These two eyes showed no recurrence of exudative change after the TAE regimen was started. Five eyes showed no recurrence over the 24 months, three with major BRVO, and two with macular BRVO.The IVA injection interval could be extended to more than 5 months in 21 eyes (54%), including the 5 eyes that showed no recurrence over the 24 months .p < 0.0001, paired t-test). Mean CST in major and macular BRVO was significantly decreased at 12 and 24 months (12 months: 299 (135) µm and 258 (52) µm; 24 months: 270 (38) µm and 259 (90) µm, respectively) compared with baseline (494 (168) µm and 454 (141) µm, respectively; both p < 0.0001, paired t-test).Mean BCVA in major and macular BRVO was significantly improved at 12 and 24 months after the initial injection (12 months: 0.058 (0.18) and 0.037 (0.20); 24 months: 0.061 (0.20) and 0.029 (0.15), respectively) compared with baseline (0.32 (0.25) and 0.34 (0.30), respectively; both p = 0.84 and p = 0.53, respectively; paired t-test). There was also no significant difference between major and macular BRVO in the mean number of IVA injections administered (7.5 (3.6) and 7.1 (3.0), respectively; p = 0.69, paired t-test) or in the mean number of clinic visits required (11.3 (2.2) and 10.6 (1.6), respectively; p = 0.31, paired t-test). The mean time from awareness of symptoms to diagnosis was significantly shorter in major BRVO than in macular BRVO (1.5 (1.6) and 3.3 (3.8), respectively; p = 0.041, paired t-test).There was no significant difference in either BCVA or CST at 24 months between major and macular BRVO , we believe that the improvement in BCVA and the reduction in CST values are comparable with those in previous studies, such as the VIBRANT study, a randomized controlled trial conducted using aflibercept in a fixed protocol for regulatory approval , and theWe believe that the “modified” TAE regimen in this study contributes to avoiding overtreatment. Specifically, in this study, the time of the first recurrence varied, highlighting the need to individualize the administration method for each patient. Five eyes showed no recurrence at all. As such, we believe that choosing a “standard” TAE regimen from the beginning might have led to overtreatment in such patients, and our mTAE regimen may prevent this from occurring. Importantly, the IVA injection interval could be extended to more than 5 months in 21 eyes (54%) in this study (including in the 5 eyes that showed no recurrence). Our results may also indicate that IVA injections can be stopped if the injection interval can be extended to 4 months because patients in this study for whom the injection interval could be extended to 4 months or longer did not have recurrence or had only small exudative changes over the entire observation period. For patients who require frequent injections, it is important that the administration regimen and the interval between hospital visits place as low a burden as possible. In this aspect, the injection interval could not be extended beyond 3 months in nine eyes (23.1%). In the RETAIN study, 50% of patients still required IVR injections 4 years after the first treatment . Thus, aBased on previous studies, it is generally assumed that major BRVO is more aggressive than macular BRVO. A previous study found that macular BRVO responded better than major BRVO to treatment, with clearer improvement of vision and fewer injections . SimilarThere are some limitations to this study. First, the study was designed as a single-arm trial and the sample size was relatively small. Second, only Japanese patients were included. Therefore, further prospective studies with larger study populations and longer follow-up are needed to confirm the usefulness of our regimen. In this prospective study, an mTAE regimen of IVA injections for treating ME due to BRVO effectively improved BCVA and reduced CST over a 2-year period. We believe that this mTAE regimen of aflibercept may be useful in actual clinical practice, by improving VA and structural outcomes as well as reducing the number of required injections and hospital visits, thereby also helping to reduce burden on both patients and healthcare workers.


Mortality at 180 days was significantly higher in those with OIs than without OIs . In one year, this program decreased the OI mortality by 7% and increased the OI treatment by 5.1%. Early OI diagnosis and appropriate therapy reduced OI mortality among newly diagnosed HIV patients in Guatemala. Screening for OIs should be considered in all newly diagnosed HIV patients who have a CD4 cell count < 350 cells/mm3 or those without a CD4 cell count available. To improve results, interventions such as early HIV detection and access to flucytosine and liposomal amphotericin B are required.Opportunistic infections (OIs) and advanced HIV disease (AHD) contribute to HIV-related mortality. Here, we analyzed the situation of AHD and OIs in a cohort of newly diagnosed HIV patients from Guatemala. We included 2127 adult patients from 13 facilities across the country during 2017 to 2018. Patients were screened for tuberculosis (TB), nontuberculous mycobacteria (NTM), histoplasmosis, and cryptococcal disease, independently of their CD4 cell count. Of the 2127 enrolled patients, 1682 (79.1%) had a CD4 cell count available; of which 52% presented with AHD. Of the Mayan population, 65% had AHD. The overall OI incidence was 21%. Histoplasmosis was the most frequent OI (7.9%), followed by TB (7.1%); 94.4% of these infections occurred in patients with a CD4 < 350 cells/mm Opportunistic infections (OIs) remain a major cause of death in HIV-infected patients, especially in low- and middle-income countries (LMICs) . DespiteIn 2017, the World Health Organization (WHO) published the first guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy . These gPatients were enrolled in the OIs program, which was established in Guatemala in 2017. This program encompasses a network of 13 health care facilities (HCFs) and a central Diagnostic Laboratory Hub (DLH) . This woM. tuberculosis and H. capsulatum; (v) Detection of urine antigen of H. capsulatum by IgG monoclonal antibodies (Immuno-Mycologics (IMMY), Norman, Oklahoma, USA); and (vi) the cryptococcal antigen lateral flow assay (CrAg) . If serum CrAg was positive, a lumbar puncture was advised. The relative diagnostic performance of these tests has been described by Medina et al. [Demographic data were collected in the HCFs using a standard electronic form. Patients were screened for the following OIs: tuberculosis (TB), nontuberculous mycobacteria (NTM), histoplasmosis, and cryptococcosis. Screening was performed independently of the CD4 cell count. The following samples were requested: whole blood in an isolator tube , serum, urine, and sputum. Additional samples were also received based on clinical criteria. Specimens were referred to the DLH to be processed as previously described ,7. LaborC. neoformans in cerebrospinal fluid (CSF). AHD was defined as having a CD4 count < 200 cells/mm3. CD4 cell counts were obtained by the different HCFs. An available CD4 cell count was defined as a cell count obtained 90 days before or after the moment of the OI screening. Patients from Guatemala City and other cities were categorized as urban while other areas were defined as rural.Disseminated histoplasmosis was considered when an Isolator blood culture and/or urine antigen was positive, and cryptococcal meningitis when we detected a positive CrAg test or isolated Patients were treated in the HCFs and antiretroviral therapy was started in accordance with the national guidelines ,9.Because this study analyzed data obtained during the implementation of a routine program that provided diagnostic services to newly diagnosed HIV patients, informed consent was not requested for the OI screening; however, a written informed consent for HIV testing was obtained by the HCFs of the network. For the analysis, no personally identifiable data information was collected, and confidentiality of patients was assured.The participants were categorized according to the OI diagnosis. Baseline characteristics were compared with chi-square or Fisher’s exact test for categorical variables and Mann-Whitney U-test for continuous variables. We performed univariate and multivariable analyses to identify demographic factors associated with AHD. Receiver operator curves (ROCs) were carried out to evaluate different CD4 thresholds among the OI cases for screening purposes. Sensitivity, specificity, and their two-sided 95% confidence intervals (95% CI) were determined.p = 0.623); however, heterosexual men had significantly lower CD4 counts than men who have sex with men (MSM) . The difference of AHD between the Mayan and Ladino population was statistically significant , but no difference was observed in OI rate . Mayan women and men had similar CD4 cell counts .A total of 2127 newly diagnosed HIV patients were enrolled between January 2017 and December 2018. This study encompassed 58.3% (2127 out of 3646) of the new HIV infections reported by the HIV national program. 3, 202 (23%) between 50–99 cells/mm3, and 353 (40.2%) between 100–199 cells/mm3. In the univariate analysis, risk factors associated with AHD were older age at the moment of diagnosis, belonging to a Mayan ethnic group, heterosexual category, and patients who live in rural areas. In the multivariate analysis, the risk factors significantly associated with AHD were: (i) age 30–50 years , p < 0.0001), (ii) >50 years , p < 0.0001), and (iii) Mayan ethnic group , p = 0.009). Compared with heterosexuals, MSM were less associated with AHD , p < 0.0001).Among 877 patients with AHD, 322 (36.7%) had CD4 cell counts between 0–49 cells/mmp < 0.0001), tended to be heterosexual , and had higher HIV viral load (Log10 5.2 OIs vs. 4.7 p < 0.0001) than those without OIs (p = 0.018). Among country regions, histoplasmosis and cryptococcal disease were frequent in the East (10.1% and 8.1%), West (10.9% and 5.7%), and Central regions (8.8% and 4.5%). In Guatemala City, TB was more frequent (8.3%).Of the 2127 participants, 1821 (85.6%) had full screening done. Three hundred eighty-five patients (18.1%) had OIs: 140 (36.4%) histoplasmosis, 121 (31.4%) TB, 78 (20.3%) cryptococcal disease, 31 (8.1%) multiple OIs, and 15 (3.9%) NTM infection. In patients with multiple OIs, we found histoplasmosis/cryptococcosis (35.5%), histoplasmosis/tuberculosis (32.3%), and cryptococcosis/tuberculosis (12.9%) as the most frequent. In 2018, the incidence of OIs increased 3.9% (from 15.9% to 19.8%). Patients with OIs were significantly older . Among those with AHD, the incidence of OIs was 30.3%. In patients who had a CD4 cell count ≥ 350 cells/mm3, TB was more frequent than histoplasmosis   .3. Fifteen OIs were diagnosed in patients with ≥350 CD4 cells/mm3: 10 TB, 4 histoplasmosis, and 1 cryptococcal disease. Eighty-one (63.3%) of 128 patients with disseminated histoplasmosis had a CD4 cell count available. If histoplasmosis screening had been limited to patients with CD4 cell counts < 100 or <200 CD4 cells/mm3, 16 (19.7%) and 6 (7.4%) cases would have been missed, respectively. For cryptococcal disease, 5 (13.8%) and 1 (2.8%) cases would have been missed, respectively. A total of 117 (30.4%) OIs were diagnosed in patients without a CD4 cell count result available.We analyzed, by means of a ROC curve, OIs (Yes/No) against CD4 cell counts to determine the best threshold to screen patients for OIs. The AUC was 0.771 . 3). Treatment information for the OI cases is shown in A total of 324 (84.1%) patients with OIs were treated. Information was available for 36 (59%) out of the 61 patients who did not receive treatment: 18 (50%) died before initiation of treatment, 12 (33.3%) were lost to follow-up, and 6 (16.7%) refused treatment  patients died. The OIs investigated in this program accounted for 111 of the 213 deaths (52.1%): 18.3% were due to histoplasmosis, 12.7% to TB, 11.3% to cryptococcosis, 7.0% to multiple OIs, and 2.8% to NTM. Unknown etiology accounted for 24.9% of deaths and other causes for 23.0%. One hundred fifteen deaths (53.9%) occurred in the first month after enrollment.p < 0.0001). In 2018, mortality from OIs was 7% lower than in 2017 . Regarding each OI, and including cases of multiple infections, patients with tuberculosis had a lower mortality in 2018 compared to 2017  with a similar trend for cryptococcal disease ; treatments for these infections increased in 2018 compared to 2017 ; and cryptococcal disease 67.6% to 90.2% (p = 0.008)). In NTM cases, mortality increased from 17.5% in 2017 to 42.5% in 2018 (p = 0.126), with fewer patients receiving treatment (80% vs. 37.5%); 4 deaths (60%) occurred between 90–180 days. In patients with multiple OIs, overall mortality decreased 16.2% . Histoplasmosis mortality was similar in 2017 and 2018 , but 3% fewer patients were treated in 2018 . In patients without OIs, mortality rate was lower in MSM compared with heterosexuals . p < 0.0001). Of those with multiple OIs and a CD4 cell count available, 24 (95.8%) had AHD. Concerning histoplasmosis (p < 0.0001). Mortality was also higher in patients with cryptococcal meningitis than those with a negative lumbar puncture . However, in patients with a positive CrAg in serum who did not undergo a lumbar puncture, the mortality was 37% (10 out of 27 cases).lasmosis C, the moThis study analyzes the situation of newly diagnosed HIV patients in Guatemala. The data are able to provide robust evidence since they account for 58.3% (2127 out of 3646) of the new HIV infections reported by the national HIV program during 2017–2018. The proportion of the newly diagnosed HIV patients presenting with AHD was 52%, which was 6% higher than the estimated frequency by UNAIDS of 46% ,12,13,143 and routine clinical evaluation for TB [3  [Mortality among newly diagnosed HIV patients was high with 52.1% of deaths attributed to the OIs screened. A substantial number of patients also died with an unknown diagnosis. This should be improved with the expansion of the diagnostic portfolio. It is important to highlight that the diagnosis has to be made quickly since 53.9% of deaths occurred in the first 30 days. The highest mortality rate was observed in patients with multiple OIs (48.4%). Contributing factors to this increased mortality could include severe immunosuppression (96% had AHD), complicated management, and drug–drug interactions . HistoplThe present study has its limitations. The OI status was based on the available laboratory techniques in this program, but other OIs have been missed. This will have led to an underestimation of the burden of OIs. Other factors such as ARV treatment were not determined. The integration of all HCFs in the network will improve the accuracy of the data. Despite the limitations, our findings show that Guatemala has one of the highest rates of AHD in newly diagnosed HIV patients, the burden of OIs among newly diagnosed HIV patients is substantial, the burden of fungal infections has been previously underestimated, and access to rapid diagnosis of OIs has decreased the overall mortality by 7% in a single year, showing that it is an essential tool to achieve the goal of eliminating AIDS and reducing deaths.