Background Subtle prognostically-important ECG features may not be apparent to physicians. In the course of supervised machine learning (ML), many thousands of ECG features are identified. These are not limited to conventional ECG parameters and morphology.Hypothesis Novel neural network (NN)-derived ECG features can predict future cardiovascular disease and mortalityMethods and Results We extracted 5120 NN-derived ECG features from an AI-ECG model trained for six simple diagnoses and applied unsupervised machine learning to identify three phenogroups. In the derivation cohort (CODE, 1,558,421 subjects), the three phenogroups had significantly different mortality profiles. After adjusting for known covariates, phenogroup B had a 20% increase in long-term mortality compared to phenogroup A (HR 1.20, 95% CI 1.17-1.23, p < 0.0001). The predictive ability of the phenogroups was retained in a group with physician confirmed normal ECGs. We externally validated our findings in five diverse cohorts (Figure) and found phenogroup B had a significantly greater risk of mortality in all cohorts. Phenome-wide association study (PheWAS) showed phenogroup B had a higher rate of future AF, ischaemic heart disease, AV block, heart failure, VT, and cardiac arrest.Phenogroup B had increased cardiac chamber volumes and decreased cardiac output. A single-trait GWAS yielded four loci. SCN10A, SCN5A and CAV1 have roles in cardiac conduction and arrhythmia. ARHGAP24 does not have a clear cardiac role and may be a novel target. Gradient-weighted Class Activation Mapping (Grad-CAM) identified the terminal QRS and terminal T wave as important regions of the ECG for identification of phenogroup B.Conclusion NN-derived ECG features can be used to predict all-cause mortality and future cardiovascular diseases. We have identified biologically plausible and novel phenotypic and genotypic associations that describe mechanisms for the increased risk identified.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementAS is funded by a British Heart Foundation (BHF) clinical research training fellowship (FS/CRTF/21/24183). FSN and NSP are supported by the BHF (RG/F/22/110078). FSN is also supported by the National Institute for Health Research Imperial Biomedical Research Centre. DO'R is supported by the Medical Research Council (MC\_UP\_1605/13); National Institute for Health Research (NIHR) Imperial College Biomedical Research Centre; and the British Heart Foundation (RG/19/6/34387, RE/18/4/34215). IA, TN and partially MM have been supported by MH CZ - DRO (FNBr, 65269705).### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study complies with all relevant ethical regulations. The Clinical Outcomes in Digital Electrocardiography (CODE) study was approved by the Research Ethics Committee of the Universidade Federal de Minas Gerais, protocol 49368496317.7.0000.5149. The Whitehall II study was approved by the Joint University College London/University College London Hospitals Committees on the Ethics of Human Research. The UK Biobank has approval from the North West Multi-Centre Research Ethics Committee as a Research Tissue Bank (application ID 48666). The Longitudinal Study of Adult Health (ELSA-Brasil) was approved by the Research Ethics Committees of the participating institutions and by the National Committee for Research Ethics (CONEP 976/2006) of the Ministry of Health. The Sao Paulo-Minas Gerais Tropical Medicine Research Center (SaMi-Trop) study was approved by the Brazilian National Institutional Review Board (CONEP), No. 179.685/2012. For the Beth Israel Deaconess Medical Center (BIDMC) cohort ethics review and approval was provided by the Beth Israel Deaconess Medical Center Committee on Clinical Investigations, IRB protocol # 2023P000042.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesSaMi-Trop cohort was made openly available (https://doi.org/10.5281/zenodo.4905618). The CODE-15% cohort was also made openly available (https://doi.org/10.5281/ zenodo.4916206). Restrictions apply to additional clinical information on the CODE-15% and SaMi-Trop cohorts; to the full CODE cohort, the ELSA-Brasil cohort, and the Whitehall II cohort. UK Biobank data are available upon application (http://www.ukbiobank.ac.uk/). The BIDMC dataset is restricted due to ethical limitations. Researchers affiliated to educational, or research institutions may make requests to access the datasets. Requests should be made to the corresponding author of this paper. They will be forwarded to the relevant steering committee.

Background The unprecedented public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. Methods and Findings We develop a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care to explore the potential public-health impact of a range of different potential therapeutics, under a range of different scenarios varying: i) healthcare capacity, ii) epidemic trajectories; and iii) drug efficacy in the absence of supportive care. In each case, the outcome of interest was the number of COVID-19 deaths averted in scenarios with the therapeutic compared to scenarios without. We find the impact of drugs like dexamethasone (which are delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics. Conclusions There is a global asymmetry in who is likely to benefit from advances in the treatment of COVID-19 to date, which have been focussed on hospitalised-patients and predicated on an assumption of adequate access to supportive care. Therapeutics that can feasibly be delivered to those earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

The city of Manaus, north Brazil, was stricken by a severe epidemic of SARS-Cov-2 in March 2020, reaching a seroprevalence of 76% by October 2020. Nevertheless, in late November an abrupt increase in hospitalizations and deaths hit Manaus, causing higher number of deaths compared to the first epidemic wave. It has been hypothesized that virus lineages circulating in the second wave, namely the P.1 variant of concern first detected in early December in Manaus, could be better at evading immunity generated in response to previous infection with other lineages. In order to estimate the reinfection rate during the resurgence of SARS-CoV-2 in Manaus, we tested serial samples from 238 unvaccinated repeat blood donors using a SARS-CoV-2 anti-N IgG chemiluminescence microparticle assay. Blood donors were divided into six groups that reflected the inferred sequence of infection and reinfection with non-P.1 and P.1 variants. We assumed that reinfections induce a recrudescence (or boosting) of plasma anti-N IgG antibody levels, yielding a V-shaped time series of antibody reactivity levels. We infer that 16.9% (95% CI [9.48%, 28.5%]) of all presumed P.1 infections that were observed in 2021 were reinfections. If we also include cases of probable or possible reinfections (defined by considering the time period when the antibody levels are expected to grow after recovery and the range of half-lives for antibody waning after seroconversion), these percentages increase respectively to 25.8% (95% CI [16.7%, 37.4%]), and 31.0% (95% CI [21.4%, 42.5%]). Our data suggest that reinfection due to P.1 is common and more frequent than what has been detected by traditional epidemiologic, molecular and genomic surveillance of clinical cases.

Introdução: As úlceras de perna (UP) na doença falciforme (DF) são relativamente comuns, dolorosas e persistentes. A microbiota presente em UP de indivíduos com DF não é conhecida. Objetivo: descreve a microbiota da UP em pacientes com DF e comparar com a microbiota presente na pele integra. Métodos: De junho de 2017 a abril de 2019, 87 pacientes HbSS do Hemocentro de Belo Horizonte (Fundação Hemominas) e 30 participantes saudáveis foram inscritos, pareados por sexo e idade. Quatro grupos de amostras foram obtidas: caso 1 - UP; caso 2 - pele íntegra de pacientes com UP; controle 1 - pele íntegra de pacientes com DF e sem histórico de UP; e controle 2 - pele íntegra de participantes sem DF e sem histórico de outras doenças crônicas. O DNA bacteriano foi extraído utilizando o FastDNA™ Spin Kit (MP Biomedicals) e a amplificação do domínio V4 do gene 16S RNAr foi realizada. As amostras foram quantificadas com o fluorímetro Qubit®2.0 (InvitrogenTM) e a biblioteca foi realizada pelo Ion Chef System. O sequenciamento conduzido pela plataforma Ion Torrent e as sequências analisadas pelo QIIME 2. As métricas das diversidades alfa (OTUs, uniformidade de Pielou, Shannon, Simpson, Chao1 e diversidade filogenética de Faith) e beta (Jaccard, Bray-Curtis, UniFrac não ponderada e UniFrac ponderada) foram estimadas por Kruskal-Wallis e PERMANOVA, respectivamente. Além disso, realizou-se análise de abundância diferencial (ANCOM). Resultados: Foram sequenciadas 84 amostras, sendo 22 amostras de UP, 17 de pele íntegra de pacientes com UP, 23 de pele íntegra de paciente HbSS sem história de UP e 22 de pele íntegra do participante sem DF e outras doenças crônicas. Diferenças estatísticas foram encontradas entre amostras dos diferentes grupos para a diversidade alfa (p < 0,05), com exceção das amostras de pele íntegra dos pacientes DF com UP e sem UP. A diversidade pelo índice de Pielou não apresentou diferenças estatisticamente significativas entre os grupos de pele íntegra. Na diversidade beta, diferenças estatísticas foram observadas (p < 0,05), exceto na comparação da pele íntegra dos pacientes com UP e a dos pacientes sem história de UP pelo índice de Unifrac ponderada. Dos 38 filos de bactérias identificados, os de maior abundância foram Proteobacteria, Firmicutes e Actinobacteria. Na comparação entre as peles íntegras, diferenças significativas foram encontradas na abundância do filo OP3 (p = 0,01890; p = 0,04890) para a pele íntegra dos pacientes com e sem UP e entre a pele íntegra dos pacientes sem UP e dos controles sem história de doenças crônicas, respectivamente. As diferenças também foram observadas nas abundâncias dos filos FBP (p = 0,01560), Nitrospirae (p = 0,00799) e SBR1093 (p = 0,00697) para a pele íntegra dos pacientes com UP e dos sem histórico de doenças crônicas. A espécie Kocuria palustris apresentou maior abundância nas UP (86%). Discussão: O microbioma contribui no equilíbrio da saúde humana e são raros os estudo que o correlacionam com as úlceras de perna na AF. Houve diferenças significativas na microbioma presente na LU e pele íntegra, sugerindo que a microbiota pode contribuir para a persistência da ferida, podendo ser alvo de tratamentos. Conclusão: Nosso estudo mostrou diferenças na diversidade microbiana das UP quando comparada com a pele íntegra. Além disso, descreveu-se pela primeira vez maior abundância da espécie Kocuria palustris na UP, sugerindo associação com a persistência da ferida.

AbstractBackgroundA low prevalence of HIV in sickle cell disease (SCD) patients has been reported in the literature though mechanisms for this are not understood.MethodsHIV risk behaviors were compared between SCD cases and non-SCD controls using a self-administered audio computer-assisted self-interview. SCD cases were recruited from a multi-center SCD cohort established in Brazil; controls were recruited from SCD social contacts. Categorical variables were analyzed using Chi-Square or Fisher exact test. Continuous variables were compared using the Mann-Whitney U test.ResultsThere were 152 SCD cases and 154 age/location matched controls enrolled at three participating Brazilian centers during 2016–17. No significant differences in number of sexual partners (lifetime or previous 12 months), male-to-male sex partners or intravenous drug use were observed. Cases received more transfusions, surgeries, and acupuncture treatment.ConclusionsBesides the risk of transfusion-transmitted HIV, which is now exceedingly rare, SCD and non-SCD participants demonstrated similar HIV risk behaviors. Causes other than risk behaviors such as factors inherent to SCD pathophysiology may explain the reported low prevalence of HIV in SCD.

Abstract Background Chagas disease (CD) is a neglected tropical disease that affects mainly vulnerable population, whose majority has low ability to understand health information. This study aimed to assess the prevalence of health literacy (HL) and its association with sociodemographic, quality of life, health care aspects and worse clinical outcomes. Methods This is a cross-sectional study developed inside a cohort study (SaMi-Trop) including 1959 patients. It has been conducted in an endemic region to CD in Brazil. The eligible criteria for HL evaluation was the ability to read. The HL was assessed with SALPHA-18 scale and literacy was categorized in inadequate HL; adequate HL and; illiterate. Multiple models were adjusted using binary logistic regression, multinomial and beta regression models using the gamlss framework. Results Of the patients included, 1136 (74.1%) are illiterate. For HL assessment, only 397 managed to complete the HL evaluation. The prevalence of inadequate HL was 85.1% (338), only 59 patients (14.9%) had adequate HL. Our results are as following: 1) being illiterate increases the chance of using more drugs when compared to individuals with adequate HL - 1 or 2 drugs (OR: 1.96; CI: 1.06-3.62) and 3 to 4 medications (OR: 3.06; CI:1.44-6.52), to have hypertension (OR: 2.24; CI: 1.29-3.90), report an average self-perceived health (OR: 2.97; IC: 1.63-5.42) and report poor self-perceived health (OR: 3.67; CI: 1.71-7.89); 2) inadequate literacy increases the chance of using 3 to 4 medications (OR: 2.26; CI: 1.04-4.93) and report an average self-perceived health (OR: 2.48; CI: 1.34-4.62); 3) Illiterate patients present worst quality of life scores in Physical (OR: 0,730; CI: 0,583-0,914), Psychological (OR: 0,671; CI: 0,544-0,828) and Environmental (OR: 0,727; CI: 0,601-0,880) domains. Conclusions We found a high prevalence of inadequate HL; it was associated with worse clinical outcomes and poor self-perceived health. Key messages Our findings reinforce the importance of improving health communication in CD patients seeking to avoid unfavorable outcomes. A high prevalence of inadequate health literacy was observed in our study, which can impact the self-care ability of patients with CD.

Torque teno virus (TTV) is an infectious agent of worldwide distribution isolated by the first time as the agent of an acute post-transfusion hepatitis in a patient in Japan. It has been classified into a new floating genus called Anellovirus. Recent studies showed that TTV can also be identified in serum specimens obtained from domesticated farm animals and from non-human primates. To better understand the relationship between TTV and their hosts, a study to detect virus in the serum and whole blood of Brazilian non-human primates and in the plasm of chickens was performed by applying the PCR-UTR-A technique, followed by a genomic sequence and phylogenetic analysis. By nested-PCR-UTR, the DNA of TTV was detected in sera from 4 (5.3%) of 75 Cebus apella, 2 (40%) of 5 Alouata fusca, 1 (20%) of 5 Alouata caraya, 1 (5.2%) of 19 Callithrix penicilata, 1 (4%) of 25 Callithrix jacchus, 1 ( 20%) of 5 Saimiri sciureus and 1 (25%) of 4 Leontopithecus chrysomelas. Phylogenetic analysis revealed that sequences detected in 8 samples clustered with TTV sequences So-TTV2 (Saguinus oedipus) and At-TTV3 (Aotes Trivirgatus). Three sequences showed similarity with a human Torque Teno Minivirus (TLMV). TTV ORF2 DNA was detected in one sera sample and one whole blood sample of non-human primates and in one plasm sample of chicken. Phylogenetic analysis revealed that the sequences amplified by the ORF2 region show no difference between human, non-human primates and chicken. This is the first report of TTV in brazilian new world non-human primates and chicken.

Torque teno virus (TTV) is a recently discovered DNA virus that was originally isolated from a Japanese patient ( initials, TT) with post-transfusion hepatitis of unknown aetiology. TTV is an circular DNA virus classified recently together with related Torque teno minivirus, into a new genus called Anellovirus. Infection TTV has been detected in a range of non-human primates as well as domestic animals. The purpose of this study was to search TTV in the serum and total blood of Brazilian monkeys and in plasma of domestic chickens by seminested PCR of coding region (N22), followed by a genomic sequence and phylogenetic analysis. No serum sample was amplified. TTV DNA was detected in total blood from 3 (4%) out of 75 brown-capuchin ( Cebus apella) and from 1 (25%) out of 4 golden-headed lion-tamarin ( Leontopithecus chrysomelas). Phylogenetic analysis revealed that one sample showed similarity with one sequence of the cotton top tamarin ( Saguinus oedipus) (So-TTV2) and with one of the douroucoulis (Aotes trivirgatus) (At-TTV3). Two samples showed similarity with a human Torque Teno Mini Virus (TLMV). The other sample clustered with one sequence of the chimpanzee (Pt-TTV6) and with the human TTV strain TA278. The plasma chicken samples tested were all negative. The amino acid sequences reported in this study are the first obtained in Brazil from total blood of non-human primates naturally infected by TTV.