The predictive role of symptoms in COVID-19 diagnostic models: A longitudinal insight.

To investigate the symptoms of SARS-CoV-2 infection, their dynamics and their discriminatory power for the disease using longitudinally, prospectively collected information reported at the time of their occurrence. We have analysed data from a large phase 3 clinical UK COVID-19 vaccine trial. The alpha variant was the predominant strain. Participants were assessed for SARS-CoV-2 infection via nasal/throat PCR at recruitment, vaccination appointments, and when symptomatic. Statistical techniques were implemented to infer estimates representative of the UK population, accounting for multiple symptomatic episodes associated with one individual. An optimal diagnostic model for SARS-CoV-2 infection was derived. The 4-month prevalence of SARS-CoV-2 was 2.1%; increasing to 19.4% (16.0%-22.7%) in participants reporting loss of appetite and 31.9% (27.1%-36.8%) in those with anosmia/ageusia. The model identified anosmia and/or ageusia, fever, congestion, and cough to be significantly associated with SARS-CoV-2 infection. Symptoms' dynamics were vastly different in the two groups; after a slow start peaking later and lasting longer in PCR+ participants, whilst exhibiting a consistent decline in PCR- participants, with, on average, fewer than 3 days of symptoms reported. Anosmia/ageusia peaked late in confirmed SARS-CoV-2 infection (day 12), indicating a low discrimination power for early disease diagnosis.

The dynamics and outcomes of AKI progression during the COVID-19 pandemic.

PURPOSE: Acute kidney injury (AKI) associated with COVID-19 is associated with poor prognosis. This study assessed the hitherto uninvestigated impact of COVID-19 on the progression and clinical outcomes of patients with AKI. METHODS: Data from 576 patients with AKI admitted between 13/3/20 and 13/5/20 were studied. Increasingly complex analyses, from logistic regressions to competing-risk and multi-state models, have revealed insights into AKI progression dynamics associated with PCR-confirmed COVID-19 acquisition and death. Meta-analyses of case fatality ratios among patients with AKI were also conducted. RESULTS: The overall case-fatality ratio was 0.33 [95% CI (0.20-0.36)]; higher in COVID-19 positive (COVID+) patients 0.52 [95% CI (0.46-0.58)] than in their negative (COVID-) counterparts 0.16 [95% CI (0.12-0.20)]. In AKI Stage-3 patients, that was 0.71 [95% CI (0.64-0.79)] among COVID+ patients with 45% dead within 14 days and 0.35 [95% CI (0.25-0.44)] in the COVID- group and 28% died within 14 days. Among patients diagnosed with AKI Stage-1 within 24 h, the probability of progression to AKI Stage-3 on day 7 post admission was 0.22 [95% CI (0.17-0.27)] among COVID+ patients, and 0.06 [95% CI (0.03, 0.09)] among those who tested negative. The probability of discharge by day 7 was 0.71 [95% CI (0.66, 0.75)] in COVID- patients, and 0.27 [95% CI (0.21, 0.32)] in COVID+ patients. By day 14, in AKI Stage-3 COVID+ patients, that was 0.35 [95% CI (0.25, 0.44)] with little change by day 10, that is, 0.38 [95% CI (0.29, 0.47)]. CONCLUSION: These results are consistent with either a rapid progression in severity, prolonged hospital care, or high case fatality ratio among AKI Stage-3 patients, significantly exacerbated by COVID-19 infection.

Ethnoracial disparities in childhood growth trajectories in Brazil: a longitudinal nationwide study of four million children.

BACKGROUND: The literature contains scarce data on inequalities in growth trajectories among children born to mothers of diverse ethnoracial background in the first 5 years of life. OBJECTIVE: We aimed to investigate child growth according to maternal ethnoracial group using a nationwide Brazilian database. METHODS: A population-based retrospective cohort study employed linked data from the CIDACS Birth Cohort and the Brazilian Food and Nutrition Surveillance System (SISVAN). Children born at term, aged 5 years or younger who presented two or more measurements of length/height (cm) and weight (kg) were followed up between 2008 and 2017. Prevalence of stunting, underweight, wasting, and thinness were estimated. Nonlinear mixed effect models were used to estimate childhood growth trajectories, among different maternal ethnoracial groups (White, Asian descent, Black, Pardo, and Indigenous), using the raw measures of weight (kg) and height (cm) and the length/height-for-age (L/HAZ) and weight-for-age z-scores (WAZ). The analyses were also adjusted for mother's age, educational level, and marital status. RESULTS: A total of 4,090,271 children were included in the study. Children of Indigenous mothers exhibited higher rates of stunting (26.74%) and underweight (5.90%). Wasting and thinness were more prevalent among children of Pardo, Asian, Black, and Indigenous mothers than those of White mothers. Regarding children's weight (kg) and length/height (cm), those of Indigenous, Pardo, Black, and Asian descent mothers were on average shorter and weighted less than White ones. Regarding WAZ and L/HAZ growth trajectories, a sharp decline in average z-scores was evidenced in the first weeks of life, followed by a period of recovery. Over time, z-scores for most of the subgroups analyzed trended below zero. Children of mother in greater social vulnerability showed less favorable growth. CONCLUSION: We observed racial disparities in nutritional status and childhood growth trajectories, with children of Indigenous mothers presenting less favorable outcomes compared to their White counterparts. The strengthening of policies aimed at protecting Indigenous children should be urgently undertaken to address systematic ethnoracial health inequalities.

Impact of early life geohelminths on wheeze, asthma and atopy in Ecuadorian children at 8 years.

BACKGROUND: Early-life exposures to geohelminths may protect against development of wheeze/asthma and atopy. OBJECTIVE: To study the effect of maternal geohelminths and infections in children during the first 5 years on atopy, wheeze/asthma and airways reactivity/inflammation at 8 years. METHODS: Birth cohort of 2404 neonates followed to 8 years in rural Ecuador. Data on wheeze/asthma were collected by questionnaire and atopy by skin prick test (SPT) reactivity to 9 allergens. We measured airways reactivity to bronchodilator, fractional exhaled nitric oxide (FeNO) and nasal eosinophilia. Stool samples were examined for geohelminths by microscopy. RESULTS: 1933 (80.4%) children were evaluated at 8 years. Geohelminths were detected in 45.8% of mothers and 45.5% of children to 5 years. Frequencies of outcomes at 8 years were as follows: wheeze (6.6%), asthma between 5 and 8 years (7.9%), SPT (14.7%), airways reactivity (10%) and elevated FeNO (10.3%) and nasal eosinophilia (9.2%). Any maternal geohelminth was associated with reduced SPT prevalence (OR 0.72). Childhood Trichuris trichiura infections during the first 5 years were associated with reduced wheeze (OR 0.57) but greater parasite burdens with Ascaris lumbricoides at 5 years were associated with increased wheeze (OR 2.83) and asthma (OR 2.60). Associations between maternal geohelminths and wheeze/asthma were modified by atopy. Parasite-specific effects on wheeze/asthma and airways reactivity and inflammation were observed in non-atopic children. CONCLUSIONS: Our data provide novel evidence for persistent effects of in utero geohelminth exposures on childhood atopy but highlight the complex nature of the relationship between geohelminths and the airways. Registered as an observational study (ISRCTN41239086).

Continuous Infusion of Low-Dose Iohexol Measures Changing Glomerular Filtration Rate in Critically Ill Patients.

OBJECTIVE: Measurement of changing glomerular filtration rate in acute kidney injury remains problematic. We have previously used a continuous infusion of low-dose Iohexol to measure glomerular filtration rate in stable subjects and postulate that changes greater than 10.3% in critically ill patients indicate acute kidney injury. Our objective is to explore the extent to which continuous infusion of low-dose Iohexol can be a measure of changing glomerular filtration rate during acute kidney injury. DESIGN: Clinical observational exploratory study. SETTING: Adult ICU. PATIENTS: Three patient groups were recruited: nephrectomy group: predictable onset of acute kidney injury and outcome (n = 10); surgery group: predictable onset of acute kidney injury, unpredictable outcome (n = 11); and acute kidney injury group: unpredictable onset of acute kidney injury and outcome (n = 13). INTERVENTIONS: Continuous infusion of low-dose Iohexol was administered for 24-80 hours. Plasma (ClP) and renal (ClR) Iohexol clearances were measured at timed intervals. MEASUREMENTS AND MAIN RESULTS: Kidney Disease: Improved Global Outcomes acute kidney injury criteria were fulfilled in 22 patients (nephrectomy = 5, surgery = 4, and acute kidney injury = 13); continuous infusion of low-dose Iohexol demonstrated acute kidney injury in 29 patients (nephrectomy = 10, surgery = 8, acute kidney injury = 11). Dynamic changes in glomerular filtration rate were tracked in all patients. In the nephrectomy group, ClR decreased by an expected 50% (50.8% ± 11.0%). Agreement between ClP and ClR improved with increasing duration of infusion: bias of ClP versus ClR at 48 hours was -0.1 ± 3.6 mL/min/1.73 m (limits of agreement: -7.2 to 7.1 mL/min/1.73 m). Coefficient of variation of laboratory sample analysis was 2.4%. CONCLUSIONS: Continuous infusion of low-dose Iohexol is accurate and precise when measuring glomerular filtration rate and tracks changes in patients with differing risks of acute kidney injury. Continuous infusion of low-dose Iohexol may provide a useful standard against which to test novel biomarkers for the diagnosis of acute kidney injury.

Clinical implications of Plasmodium resistance to atovaquone/proguanil: a systematic review and meta-analysis.

Background: Atovaquone/proguanil, registered as Malarone®, is a fixed-dose combination recommended for first-line treatment of uncomplicated Plasmodium falciparum malaria in non-endemic countries and its prevention in travellers. Mutations in the cytochrome bc1 complex are causally associated with atovaquone resistance. Methods: This systematic review assesses the clinical efficacy of atovaquone/proguanil treatment of uncomplicated malaria and examines the extent to which codon 268 mutation in cytochrome b influences treatment failure and recrudescence based on published information. Results: Data suggest that atovaquone/proguanil treatment efficacy is 89%-98% for P. falciparum malaria (from 27 studies including between 18 and 253 patients in each case) and 20%-26% for Plasmodium vivax malaria (from 1 study including 25 patients). The in vitro P. falciparum phenotype of atovaquone resistance is an IC50 value >28 nM. Case report analyses predict that recrudescence in a patient presenting with parasites carrying cytochrome b codon 268 mutation will occur on average at day 29 (95% CI: 22, 35), 19 (95% CI: 7, 30) days longer than if the mutation is absent. Conclusions: Evidence suggests atovaquone/proguanil treatment for P. falciparum malaria is effective. Late treatment failure is likely to be associated with a codon 268 mutation in cytochrome b, though recent evidence from animal models suggests these mutations may not spread within the population. However, early treatment failure is likely to arise through alternative mechanisms, requiring further investigation.

Adverse Effects and Choice between the Injectable Agents Amikacin and Capreomycin in Multidrug-Resistant Tuberculosis.

The prolonged use of injectable agents in a regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) is recommended by the World Health Organization, despite its association with ototoxicity and nephrotoxicity. We undertook this study to look at the relative adverse effects of capreomycin and amikacin. We reviewed the case notes of 100 consecutive patients treated at four MDR-TB treatment centers in the United Kingdom. The median total duration of treatment with an injectable agent was 178 days (interquartile range [IQR], 109 to 192 days; n = 73) for those with MDR-TB, 179 days (IQR, 104 to 192 days; n = 12) for those with MDR-TB plus fluoroquinolone resistance, and 558 days (IQR, 324 to 735 days; n = 8) for those with extensively drug-resistant tuberculosis (XDR-TB). Injectable use was longer for those started with capreomycin (183 days; IQR, 123 to 197 days) than those started with amikacin (119 days; IQR, 83 to 177 days) (P = 0.002). Excluding patients with XDR-TB, 51 of 85 (60%) patients were treated with an injectable for over 6 months and 12 of 85 (14%) were treated with an injectable for over 8 months. Forty percent of all patients discontinued the injectable due to hearing loss. Fifty-five percent of patients experienced ototoxicity, which was 5 times (hazard ratio [HR], 5.2; 95% confidence interval [CI], 1.2 to 22.6; P = 0.03) more likely to occur in those started on amikacin than in those treated with capreomycin only. Amikacin was associated with less hypokalemia than capreomycin (odds ratio, 0.28; 95% CI, 0.11 to 0.72), with 5 of 37 (14%) patients stopping capreomycin due to recurrent electrolyte loss. There was no difference in the number of patients experiencing a rise in the creatinine level of >1.5 times the baseline level. Hearing loss is frequent in this cohort, though its incidence is significantly lower in those starting capreomycin, which should be given greater consideration as a first-line agent.

Hemodynamic Effect of Different Doses of Fluids for a Fluid Challenge: A Quasi-Randomized Controlled Study.

OBJECTIVE: The objectives of this study are to determine what is the minimal volume required to perform an effective fluid challenge and to investigate how different doses of IV fluids in an fluid challenge affect the changes in cardiac output and the proportion of responders and nonresponders. DESIGN: Quasi-randomized controlled trial. SETTING: Cardiothoracic ICU, tertiary university hospital. PATIENTS: Eighty postcardiac surgery patients. INTERVENTION: IV infusion of 1, 2, 3, or 4 mL/Kg (body weight) of crystalloid over 5 minutes. MEASUREMENTS AND MAIN RESULTS: Mean systemic filling pressure measured using the transient stop-flow arm arterial-venous equilibrium pressure, arterial and central venous pressure, cardiac output (LiDCOplus; LiDCO, Cambridge, United Kingdom), and heart rate. The groups were well matched with respect to demographic and baseline physiologic variables. The proportion of responders increased from 20% in the group of 1 mL/kg to 65% in the group of 4 mL/kg (p = 0.04). The predicted minimal volume required for an fluid challenge was between 321 and 509 mL. Only 4 mL/Kg increases transient stop-flow arm arterial-venous equilibrium pressure beyond the limits of precision and was significantly associated with a positive response (odds ratio, 7.73; 95% CI, 1.78-31.04). CONCLUSION: The doses of fluids used for an fluid challenge modify the proportions of responders in postoperative patients. A dose of 4 mL/Kg increases transient stop-flow arm arterial-venous equilibrium pressure and reliably detects responders and nonresponders.

Effect of admission fascia iliaca compartment blocks on post-operative abbreviated mental test scores in elderly fractured neck of femur patients: a retrospective cohort study.

BACKGROUND: Post-operative cognitive impairment is common in elderly patients following surgery for hip fracture, with undertreated pain being an important etiological factor. Non-opioid based analgesic techniques, such as nerve blocks, may help reduce the risk of cognitive complications. The aim of this study was to investigate whether receiving a fascia iliaca compartment block (FICB) as part of a pre-operative analgesic regime increased the odds of high post-operative abbreviated mental test scores (AMTS) when compared with conventional analgesia without a nerve block. METHODS: A retrospective data analysis of a cohort of 959 patients, aged ≥ 65 years with a diagnosis of hip fracture and admitted to a single hospital over a two-year period was performed. A standardized analgesic regime was used on all patients, and 541/959 (56.4%) of included patients received a FICB. Provision of the FICB was primarily determined by availability of an anesthetist, rather than by patient status and condition. Post-operative cognitive ordinal outcomes were defined by AMTS severity as high (score of ≥9/10), moderate, (score of 7-8) and low (score of ≤6). A multivariable ordinal logistic regression analysis was performed on patient status and clinical care factors, including admission AMTS, age, gender, source of admission, time to surgery, type of anesthesia and ASA score. RESULTS: Admission FICB was associated with higher adjusted odds for a high AMTS (score of ≥9) relative to lower AMTS (score of ≤8) than conventional analgesia only (OR = 1.80, 95% CI 1.27-2.54; p = 0.001). Increasing age, lower AMTS on admission to hospital, and being admitted from a residential or nursing home were associated with worse cognitive outcomes. Mode of anesthesia or surgery did not significantly influence post-operative AMTS. CONCLUSION: Post-operative AMTS is influenced by pre-operative analgesic regimes in elderly patients with hip fracture. Provision of a FICB to patients on arrival to hospital may improve early post-operative cognitive performance in this population.

Long-term adherence to a 5 day antibiotic course guideline for treatment of intensive care unit (ICU)-associated Gram-negative infections.

OBJECTIVES: To determine long-term adherence to a 5 day antibiotic course guideline for treating intensive care unit (ICU)-acquired Gram-negative bacteria (GNB) infections. METHODS: Descriptive analysis of patient-level data on all GNB-active antibiotics prescribed from day 3 and all GNB identified in clinical samples in 5350 patients admitted to a 30 bed general ICU between 2002 and 2009. RESULTS: Four thousand five hundred and eleven of 5350 (84%) patients were treated with one or more antibiotics active against GNB commenced from day 3. Gentamicin was the most frequently prescribed antibiotic (92.2 days of therapy/1000 patient-days). Only 6% of courses spanned >6 days of therapy and 89% of antibiotic therapy days were with a single antibiotic active against GNB. There was no significant difference between gentamicin and meropenem in the number of first courses in which a resistant GNB was identified in blood cultures [11/1177 (0.9%) versus 5/351 (1.4%); P = 0.43] or respiratory tract specimens [59/951 (6.2%) versus 17/246 (6.9%); P = 0.68] at the time of starting therapy. CONCLUSIONS: This study demonstrates long-term adherence to a 5 day course antibiotic guideline for treatment of ICU-associated GNB infections. This guideline is a potential antibiotic-sparing alternative to currently recommended dual empirical courses extending to ≥7 days.

Comparison of high-intensity interval training versus moderate-intensity continuous training in pulmonary rehabilitation for interstitial lung disease: a randomised controlled pilot feasibility trial.

OBJECTIVES: This study aimed to investigate the feasibility and efficacy of high-intensity interval training (HIIT) compared with moderate-intensity continuous training (MICT) in pulmonary rehabilitation (PR) for people with interstitial lung disease (ILD). DESIGN: Single-centre, randomised controlled feasibility, pilot trial. SETTING: Patients were recruited from the chest clinic of a tertiary ILD centre and attended circuit-based PR in the hospital's gym, followed by a personalised 6-month community programme. PARTICIPANTS: 58 patients, stratified per ILD type, were randomised into two groups: 33 to HIIT (18 males:15 females) (mean age (SD): 70.2 (11.4) years) and 25 to the MICT exercise mode (14 males:11 females) (mean age (SD): 69.8 (10.8) years). INTERVENTIONS: 8-week, twice weekly, circuit-based PR programme of exercise and education, followed by a personalised 6-month community exercise programme. OUTCOME MEASURES: Feasibility outcomes included staff-to-patient ratio and dropout rates per group. Primary outcome was the 6 min walk distance (6MWD). Secondary outcomes included the sniff nasal pressure, mouth inspiratory and expiratory pressures, handgrip and quadriceps strength and health status. Random-effects models were used to evaluate average variation in outcomes through time across the two groups. RESULTS: The 6MWD peaked earlier with HIIT compared with MICT (at 4 months vs 5 months) but values were lower at peak (mean (95% CI): 26.3 m (3.5 to 49.1) vs 51.6 m (29.2 to 73.9)) and declined faster at 6 months post-PR. Secondary outcomes showed similar faster but smaller improvements with HIIT over MICT and more consistent maintenance 6 months post-PR with MICT than HIIT. CONCLUSIONS: HIIT is feasible in circuit-based ILD PR programmes and provides quick improvements but requires closer supervision of training and resources than MICT and benefits may be less well sustained. This would make it a less attractive option for clinical PR programmes. A definitive, multicentre randomised controlled trial is required to address the role of HIIT in ILD. TRIAL REGISTRATION NUMBER: ISRCTN55846300.

Epidemiology of giardiasis and assemblages A and B and effects on diarrhea and growth trajectories during the first 8 years of life: Analysis of a birth cohort in a rural district in tropical Ecuador.

BACKGROUND: There are limited longitudinal data on the acquisition of Giardia lamblia infections in childhood using molecular assays to detect and type assemblages, and measure effects of infections on diarrhea risk and childhood growth. METHODS: We analysed stool samples from a surveillance sample within a birth cohort in a rural district in tropical Ecuador. The cohort was followed to 8 years of age for the presence of G. lamblia in stools by quantitative PCR and A and B assemblages by Taqman assay or Sanger sequencing. We explored risk factors associated with infection using generalized estimating equations applied to longitudinal binary outcomes, and longitudinal panel data analysis to estimate effects of infection on diarrhea and growth trajectories. RESULTS: 2,812 stool samples collected between 1 month and 8 years of age from 498 children were analyzed and showed high rates of infection: 79.7% were infected at least once with peak prevalence (53.9%) at 5 years. Assemblage B was accounted for 56.8% of genotyped infections. Risk factors for infection included male sex (P = 0.001), daycare attendance (P<0.001), having a household latrine (P = 0.04), childhood (P<0.001) and maternal soil-transmitted helminth (P = 0.029) infections, and exposures to donkeys (age interaction P = 0.034). G. lamblia was associated with increased risk of diarrhea (per episode, RR 1.03, 95% CI 1.01-1.06, P = 0.011) during the first 3 years of life and a transient impairment of weight (age interaction P = 0.017) and height-for-age (age interaction P = 0.025) trajectories between 1 and 4 years of age. There was no increased risk of either assemblage being associated with outcomes. CONCLUSION: Our data show a relatively high edemicity of G. lamblia transmission during childhood in coastal Ecuador, and evidence that infection is associated with a transiently increased risk of diarrhea during the first 3 years of life and impairment of weight and height between 1 and 4 years.

Effect of video self-observations vs. observations of others on insight in psychotic disorders.

Improving insight in patients with schizophrenia and related disorders is a worthwhile goal. Previous work has suggested that patients' insight may improve if they see videos of themselves taken when ill. Our aim was to test the hypothesis that schizophrenia patients improve their insight after viewing videos of themselves when unwell more so than after viewing an actor. Forty patients admitted with an acute psychotic disorder underwent a videotaped recording of a clinical interview. The patients were then randomized to viewing this or a "control" video of a same-sex actor displaying psychotic symptoms approximately 3 weeks later. Insight, psychopathology, and mood were assessed before and 24 to 48 hours after viewing the videos. All participants showed general improvement across all measures. There was a trend for scores on the Schedule for the Assessment of Insight to improve more in those who viewed themselves when ill, but there were no clear statistically significant differences between the "self" and "other" video groups. In conclusion, video self-confrontation seems to be a safe and potentially effective means of enhancing insight, but evidence for a specific effect is lacking.

Evaluating the role of transthoracic echocardiography in hospitalised patients with COVID-19 infection.

OBJECTIVE: To identify the most common transthoracic echocardiogram (TTE) parameters in patients hospitalised with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19) and their association with myocardial injury and outcomes. METHODS: A retrospective, single-centre, observational, exploratory cohort study was performed at the height of the COVID-19 pandemic. All SARS-CoV-2 polymerase chain reaction (PCR) positive patients who underwent a TTE during their inpatient admission between 1 March 2020 and 31 October 2020 were analysed. The most frequent cardiovascular risk factor profile and echocardiographic features were investigated. RESULTS: A total of 87 patients met the eligibility criteria. A salient 41.4% (n=36) of our cohort succumbed to this devastating virus. More than half of our hospital population (58.6%) were admitted to the intensive care unit (ITU) and this was significantly associated with inpatient mortality (OR: 7.14, CI 2.53 to 20.19, p<0.001). Hypertension was the most common cardiovascular risk factor (51.7%) with no additional prominence in non-survivors (OR: 2.33, CI 0.97 to 5.61, p=0.059). Remarkably, 90.8% of our cohort demonstrated a preserved left ventricular ejection fraction, although 69.1% had elevated troponin levels. Only 1 patient (1.1%) was given a diagnostic label of myocarditis. A raised pulmonary artery systolic pressure (36.8%) andright ventricle (RV) dysfunction (26.4%) were the most common echocardiographic features. In particular, the presence of RV dysfunction was significantly related to adverse outcomes (OR: 2.97, CI 1.11 to 7.94, p<0.03). CONCLUSIONS: In this cohort of extremely unwell patients hospitalised with COVID-19 pneumonitis, the presence of RV dysfunction or admission to ITU was significantly associated with inpatient case fatality ratio. Moreover, COVID-19-induced myocarditis remains extremely rare.

The dynamics and determinants of specific systemic and mucosal antibody responses to SARS-CoV-2 in three adult cohorts in the Ecuadorian Andes: a study protocol.

Introduction: There are limited longitudinal data on the systemic and mucosal antibody responses to SARS-CoV-2 from Latin America, a region severely affected by COVID-19, and where vaccine strategies have been implemented during the evolving pandemic. Objective: To evaluate determinants of seroprevalence and changes in levels of anti-SARS-CoV-2 antibodies longitudinally in adults with different levels of exposure to SARS-CoV-2 (defined a priori as low, medium, and high based on presumed occupational risk), in two Andean cities in Ecuador. Methods: Longitudinal cohort study of 1,000 adults aged 18 years and older with questionnaire data and sample collection done at 0, 3, 6, and 12 months during the period 2020-2023. Observations collected included WHO-ISARIC questionnaire and peripheral blood and saliva samples for measurement of IgG and IgA antibodies, respectively. Planned analyses are tailored to the longitudinal nature of the outcomes defined by participants' antibody levels and aim at estimating their average trends with time since infection in each of the occupational groups, adjusted for demographics and calendar-time levels of SARS-CoV-2 infection in the general population. The latter reflect the impact of the national control measures such as vaccinations and movement restrictions. Importance: Understanding the duration and the dynamics of waning immunity to SARS-CoV-2, in the context of exposures to emerging virus variants and immunization, will inform the implementation of targeted public health strategies in the Latin American region. Ethics and Dissemination: This study will observe the bioethical principles of the Declaration of Helsinki. Informed written consent will be obtained. Samples from participants will be stored for up to three years after which they will be destroyed. The study protocol was approved by the Ecuadorian Ministry of Public Health Ethics Committee for COVID-19 Research. Antibody results will be provided to participants and participating institutions and to the national health authorities.

Prospective study of factors associated with asthma attack recurrence (ATTACK) in children from three Ecuadorian cities during COVID-19: a study protocol.

INTRODUCTION: Asthma is a growing health problem in children in marginalised urban settings in low-income and middle-income countries. Asthma attacks are an important cause of emergency care attendance and long-term morbidity. We designed a prospective study, the Asthma Attacks study, to identify factors associated with recurrence of asthma attacks (or exacerbations) among children and adolescents attending emergency care in three Ecuadorian cities. METHODS AND ANALYSIS: Prospective cohort study designed to identify risk factors associated with recurrence of asthma attacks in 450 children and adolescents aged 5-17 years attending emergency care in public hospitals in three Ecuadorian cities (Quito, Cuenca and Portoviejo). The primary outcome will be rate of asthma attack recurrence during up to 12 months of follow-up. Data are being collected at baseline and during follow-up by questionnaire: sociodemographic data, asthma history and management (baseline only); recurrence of asthma symptoms and attacks (monthly); economic costs of asthma to family; Asthma Control Test; Pediatric Asthma Quality of life Questionnaire; and Newcastle Asthma Knowledge Questionnaire (baseline only). In addition, the following are being measured at baseline and during follow-up: lung function and reversibility by spirometry before and after salbutamol; fractional exhaled nitric oxide (FeNO); and presence of IgG antibodies to SARS-CoV-2 in blood. Recruitment started in 2019 but because of severe disruption to emergency services caused by the COVID-19 pandemic, eligibility criteria were modified to include asthmatic children with uncontrolled symptoms and registered with collaborating hospitals. Data will be analysed using logistic regression and survival analyses. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Hospital General Docente de Calderon (CEISH-HGDC 2019-001) and Ecuadorian Ministry of Public Health (MSP-CGDES-2021-0041-O N° 096-2021). The study results will be disseminated through presentations at conferences and to key stakeholder groups including policy-makers, postgraduate theses, peer-review publications and a study website. Participants gave informed consent to participate in the study before taking part.

Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome.

BACKGROUND: Acquired long QT syndrome (aLQTS) is a serious unpredictable adverse drug reaction. Pharmacogenomic markers may predict risk. METHODS: Among 153 aLQTS patients (mean age 58 years [range, 14-88], 98.7% White, 85.6% symptomatic), computational methods identified proteins interacting most significantly with 216 QT-prolonging drugs. All cases underwent sequencing of 31 candidate genes arising from this analysis or associating with congenital LQTS. Variants were filtered using a minor allele frequency <1% and classified for susceptibility for aLQTS. Gene-burden analyses were then performed comparing the primary cohort to control exomes (n=452) and an independent replication aLQTS exome sequencing cohort. RESULTS: In 25.5% of cases, at least one rare variant was identified: 22.2% of cases carried a rare variant in a gene associated with congenital LQTS, and in 4% of cases that variant was known to be pathogenic or likely pathogenic for congenital LQTS; 7.8% cases carried a cytochrome-P450 (CYP) gene variant. Of 12 identified CYP variants, 11 (92%) were in an enzyme known to metabolize at least one culprit drug to which the subject had been exposed. Drug-drug interactions that affected culprit drug metabolism were found in 19% of cases. More than one congenital LQTS variant, CYP gene variant, or drug interaction was present in 7.8% of cases. Gene-burden analyses of the primary cohort compared to control exomes (n=452), and an independent replication aLQTS exome sequencing cohort (n=67) and drug-tolerant controls (n=148) demonstrated an increased burden of rare (minor allele frequency<0.01) variants in CYP genes but not LQTS genes. CONCLUSIONS: Rare susceptibility variants in CYP genes are emerging as potentially important pharmacogenomic risk markers for aLQTS and could form part of personalized medicine approaches in the future.

The epidemiology of soil-transmitted helminth infections in children up to 8 years of age: Findings from an Ecuadorian birth cohort.

BACKGROUND: There are few prospective longitudinal studies of soil-transmitted helminth (STH) infections during early childhood. We studied the epidemiology of and risk factors for soil-transmitted helminth infections from birth to 8 years of age in tropical Ecuador. METHODS: 2,404 newborns were followed to 8 years of age with periodic stool sample collections. Stool samples were collected also from household members at the time of the child's birth and examined by microscopy. Data on social, environmental, and demographic characteristics were collected by maternal questionnaire. Associations between potential risk factors and STH infections were estimated using generalized estimated equations applied to longitudinal binary outcomes for presence or absence of infections at collection times. RESULTS: Of 2,404 children, 1,120 (46.6%) were infected with at least one STH infection during the first 8 years of life. The risk of A. lumbricoides (16.2%) was greatest at 3 years, while risks of any STH (25.1%) and T. trichiura (16.5%) peaked at 5 years. Factors significantly associated with any STH infection in multivariable analyses included age, day-care (OR 1.34, 95% CI 1.03-1.73), maternal Afro-Ecuadorian ethnicity (non-Afro vs. Afro, OR 0.55, 95% CI 0.43-0.70) and lower educational level (secondary vs. illiterate, OR 0.31, 95% CI 0.22-0.45)), household overcrowding (OR 1.53, 95% CI 1.21-1.94)), having a latrine rather than a water closet (WC vs. latrine, OR 0.77, 95% CI 0.62-0.95)), and STH infections among household members (OR 2.03, 95% CI 1.59-2.58)). T. trichiura was more associated with poverty (high vs. low socioeconomic status, OR, 0.63, 95% CI 0.40-0.99)] and presence of infected siblings in the household (OR 3.42, 95% CI 2.24-5.22). CONCLUSION: STH infections, principally with A. lumbricoides and T. trichiura, peaked between 3 and 5 years in this cohort of children in tropical Ecuador. STH infections among household members were an important determinant of infection risk and could be targeted for control and elimination strategies.

A prospective seroepidemiological study of toxocariasis during early childhood in coastal Ecuador: potential for congenital transmission and risk factors for infection.

BACKGROUND: Although Toxocara spp. infection has a worldwide distribution, to our knowledge, no data from birth cohorts have been reported in published studies on the potential for congenital transmission and determinants of infection in early childhood. METHODS: We followed 290 mother-infant pairs from birth to 5 years of age through periodic collection of data and samples at birth, 7 and 13 months and 2, 3 and 5 years of age. Data on potential risk factors and confounders were collected by maternal questionnaire. Blood for plasma was collected from the mother at time of birth and periodically from the child for detection of anti-Toxocara spp. immunoglobulin G (IgG) antibodies using a Toxocara canis larval excretory-secretory antigen-based enzyme-linked immunosorbent assay. Stool samples were collected from the mother around the time of birth and periodically from the child for microscopic detection of soil-transmitted helminths (STH). Associations between potential risk factors and Toxocara spp. seroprevalence and seroconversion were estimated using multivariable logistic regression and generalized estimating equations. RESULTS: Toxocara spp. seroprevalence was 80.7% in mothers and in children was 0%, 9.3%, 48.4%, 64.9%, and 80.9% at 7 months, 13 months, 2, 3 and 5 years, respectively. Risk factors significantly associated with increases in seroprevalence over the first 5 years of life in multivariable analyses were age [Odds ratio (OR) 2.06, 95% confidence interval (CI) 1.39-2.27, P < 0001], male sex (female vs. male: OR 0.66, 95% CI 0.48-0.89, P = 0.006), maternal ethnicity (non-Afro vs. Afro-Ecuadorian: OR 0.65, 95% CI 0.47-0.91, P = 0.011), lower maternal educational and socioeconomic level, and childhood STH (OR 2.29, 95% CI 1.51-3.47, P < 0.001). Seroconversion rates for infection were greatest at 2 years of age (3.8%/month). Factors associated significantly with seroconversion at 2, 3 or 5 years were childhood STH infection, male sex, and more frequent domestic cat exposure. CONCLUSIONS: Our data, from an area of high Toxocara spp. endemicity, indicate no congenital transmission but high rates of seroconversion after 13 months of age reaching maternal levels of seroprevalence by 5 years of age. Factors associated with seroprevalence and seroconversion included STH infections, domestic cats, maternal ethnicity, male sex, STH infections, and markers of greater poverty.

Impact of COVID-19 pandemic on asthma symptoms and management: A prospective analysis of asthmatic children in Ecuador.

BACKGROUND: Asthma affects up to 33% of children in Latin American settings. The ongoing COVID-19 pandemic has had a significant impact on access to and use of health services. We aimed to evaluate the impact of the COVID-19 lockdown on asthma exacerbations, medical facility visits, and use of asthma medications in children. METHODS: We used data from a prospective cohort of 213 children aged 5-17 years in 3 Ecuadorian cities and analysed the impact of the COVID-19 lockdown on asthma. Outcomes (asthma exacerbations, emergency room [ER] visits, planned and unplanned outpatient visits, and use of inhaled corticosteroids and Beta-2 agonists) were analysed using repeated Poisson counts (ie, number of events per participant before and during the COVID-19 lockdown). RESULTS: During compared to before lockdown: a) the number of asthma exacerbations remained constant (IRR, 0.87; 95% CI: 0.72-1.05; p = 0.152); b) outpatient visits (IRR 0.26, 95% CI 0.14-0.47, p < 0.001) declined 74% while ER visits declined 89% (IRR 0.11, 95% CI 0.04-0.32, p < 0.001); and c) there was no change in inhaled corticosteroids use (IRR 1.03, 95% CI 0.90-1.16, P = 0.699) while Beta-2 agonist use increased (IRR 1.32, 95% CI 1.10-1.58, P = 0.003). CONCLUSIONS: In a cohort of Ecuadorian children with asthma, health services attendance decreased dramatically after COVID-19 lockdown, but asthma exacerbations and use of inhaled corticosteroids were unchanged. Future analyses will address the question of the effect of SARS-CoV-2 infection on asthma exacerbations and control in this paediatric population.