Infectious Diseases Institute Research Articles

174-LB: Autoantibodies against PTM-IA2 Extracellular Domain Are Only Associated with Late Progression of Type 1 Diabetes

Background: Autoantibodies directed against the extracellular domain of IA2 (IA2ecA) with post-translationally modified (PTM) (deamidated) epitopes have been identified in new-onset T1D patients. The prevalence and timing of appearance of PTM-IA2ecA in pre-T1D individuals is evaluated in the current study. Methods: A PTM-IA2ec protein antigen probe containing four T-cell responsive deamidated Q>E peptides (aa 198-216, aa 467-482, aa 523-536 and aa 545-562) was produced. The study subjects included 269 children and 260 adults with new-onset T1D, 271 adults with LADA, 274 children with new-onset diabetes but negative for all islet autoantibodies (IAbs) (IAA, GADA, IA-2A and ZnT8A), and 222 pre-T1D children who were longitudinally followed from birth to stage 1-3 T1D. The longitudinal follow-up serum samples included samples prior to seroconversion, samples at the first appearance on an IAb and the last follow-up samples. All serum samples were tested for PTM-IA2ecA and the wide type (WT-IA2ecA) with a radio binding assay. Results: In new-onset T1D, positivity for PTM-IA2ecA and WT-IA2ecA were 60.6% (163/269) and 19.3% (52/269), respectively in children, while significantly less in adults, 14.2% (37/260, P<0.0001) and 8.8% (23/260, P=0.0007), respectively. The positivity for PTM-IA2ecA and WT-IA2ecA were only 4.1% (11/271) and 1.5% (4/271) in LADA patients, 1.5% (4/274) and 1.1% (3/274) in diabetic children who were otherwise IAb negative. In 222 longitudinally followed children with pre-T1D, only 13 were tested positive for PTM-IA2ecA and 8 positives for WT-IA2ecA, with most detected at diagnosis of stage 3 T1D. Conclusion: Autoantibodies against either WT-IA2ec or PTM-IA2ec were not frequently seen in pre-T1D as shown in new onset T1D. These autoantibodies develop in the late stage of T1D progression with overt clinical disease. Disclosure X. Jia: None. J. M. Wenzlau: None. M. Rewers: Research Support; Provention Bio, Juvenile Diabetes Research Foundation (JDRF), Hemsley Charitable Trust, Dexcom, Inc., Janssen Research & Development, LLC. A. W. Michels: Stock/Shareholder; Immnomolecular Therapeutics. L. Yu: None. Funding National Institute of Allergy and Infectious Diseases (AI53665); National Institute of Diabetes and Digestive and Kidney Diseases (DK032083)

137-OR: Metabolite Ratios and Development of Type 1 Diabetes

Ratios between metabolites more directly reflect flux through chemical reactions than individual metabolites. Variation in metabolites and their ratios are determined, in part, by genetic factors. Thus, genetic loci associated with variation in metabolite ratios may help disentangle genetic from non-genetic processes captured by the metabolome. We integrated metabolite ratios with genetics to predict changes preceding type 1 diabetes (T1D) in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Quantitative trait loci (QTLs) were identified for 132 metabolite ratios previously associated with progression from islet autoimmunity (IA) to T1D. Ratios were calculated from untargeted metabolomics data available at the time of seroconversion to IA for 338 cases and 921 matched controls in TEDDY. Genotyping was performed using a genome-wide array with custom content with imputation to the TOPMed reference panel. Ratio-SNP associations were estimated using Matrix eQTL software, adjusting for case-control status and genetic relatedness. Genome-wide significant association (P < 4.9×10-9) was observed at 202 independent loci, involving 49 metabolite ratios. Twenty-six loci (12.9%) involved ratios between polyunsaturated fatty-acids (PUFAs) and fatty acid esters of hydroxy fatty acids (FAHFAs), a novel class of bioactive lipids with antidiabetic and anti-inflammatory effects. Variation in the metabolite ratio of eicosadienoic acid to FAHFA (18:1/O-15:1) was significantly determined by a site on chromosome 3 (ITPR1); ITPR1 encodes a receptor integral to calcium signaling and glucose-induced insulin secretion. Other genetic loci contributing to variation of PUFA:FAHFA ratios reside in genes controlling inflammatory and innate immune response (e.g., TSPO, TTLL12, NCAM1) and apoptosis (PPM1L). These novel metabolite ratio QTLs, some with known association with T1D risk, expand potential biomarkers of T1D risk, with PUFA:FAHFA ratios representing candidate FAHFA biosynthesis genes. Disclosure R.K. Johnson: None. A. Romero: None. E. Willems: Employee; Amgen Inc. S.S. Rich: None. M. Rewers: Research Support; Provention Bio, Juvenile Diabetes Research Foundation (JDRF), Hemsley Charitable Trust, Dexcom, Inc., Janssen Research & Development, LLC. O. Fiehn: None. J.M. Norris: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R03DK127472); National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; JDRF; Centers for Disease Control and Prevention

President Biden Chooses Monica M. Bertagnolli, MD, to Lead the NIH

President Biden Chooses Monica M. Bertagnolli, MD, to Lead the NIH

202-LB: Association between Diabetes and the Vaginal Microbiota

Type 2 diabetes is a known risk factor for urinary tract infection and vulvovaginal candidiasis, and this risk is modulated in part by vaginal microbiota. We sought to assess the associations between diabetes and the vaginal microbiota, specifically whether diabetes may reduce vaginal Lactobacillus spp., which produce lactic acid and protect the urogenital tract. This study included 811 participants (2,301 person-visits) aged 35-60 recruited to a 2-year observational cohort with mid-vaginal sampling every 6 months. Diabetes was defined as self-reported diabetes medications, history, or serum glycated albumin (GA) levels >16.5% (HbA1c not available). Vaginal microbiota was characterized by 16S rRNA gene sequencing and clustered into community state types (CSTs) by VALENCIA, a nearest centroid algorithm based on a reference dataset. Mixed-effects multinomial logistic regression with bootstrapping was used to assess the association between case status and CSTs. Among diabetes cases (n=45, 130 person-visits), 45% had L. crispatus, L. jensenii, L. gasseri-dominated (CST I/II/V), 12% had L. iners-dominated (CST III) and 43% had low-Lactobacillus (CST IV) microbiota. Diabetes cases had reduced odds of L. iners-dominated CST III (aOR: 0.54, 95% CI: 0.31-0.81) than controls (12% vs 24%) and no association with low-Lactobacillus CST IV (aOR=01.05, 95% CI: 0.76-1.44) compared to Lactobacillus-dominated CST I/II/V in a model adjusted for menopause status and race. Estimates were similar when only GA was used for a diabetes case definition on a subset (1,001 person-visits). The results suggest diabetes is associated with reduced L. iners dominance. Diabetes cases had even frequencies of low-Lactobacillus or the optimal Lactobacillus-dominated CSTs. L. iners is metabolically distinct from other lactobacilli, producing only L-lactic acid (not the more protective D-lactic acid), and is associated with increased reproductive tract infection risk. This data informs how diabetes may affect the vaginal microenvironment. Disclosure S. J. Robbins: None. R. M. Brotman: None. R. S. Miller: None. A. L. Beitelshees: None. M. Shardell: None. J. Ravel: None. S. I. Taylor: Consultant; Ionis Pharmaceuticals. Funding National Institute of Allergy and Infectious Diseases (F31-AI164859)

Pregnancy, pregnancy outcomes, and infant growth and development after recovery from Ebola virus disease in Liberia: an observational cohort study

Minimal data exist on pregnancy following recovery from Ebola in people of child-bearing potential (females aged roughly 18-45 years). The aim of this study was to assess viral persistence or reactivation in pregnancy, the frequency of placental transfer of anti-Ebola IgG antibodies, and pregnancy outcomes in this population. In this observational cohort study, we studied self-reported pregnancies in two groups: seropositive people who had recovered from Ebola virus disease (seropositive group) and seronegative people who had close contact with people with Ebola (seronegative group). Participants had enrolled in the PREVAIL III longitudinal study and were exposed during the 2014-2016 Liberian Ebola outbreak. The primary outcome was pregnancy result. We assessed rates of livebirths and other pregnancy results in both study groups, and presence of Ebola RNA by PCR in samples of placenta, maternal and cord blood, breastmilk, and vaginal secretions from people who had recovered from Ebola who conceived a median of 14 months after acute Ebola virus disease. Mixed-model logistic regression evaluated associations between first-reported pregnancy outcome, age, and study group. Growth and neurodevelopment in the infants born to people in the seropositive group were assessed at 6-month intervals for 2 years. Data were accrued by PREVAIL III study staff. 1566 participants were enrolled between June 17, 2015, and Dec 14, 2017, of whom 639 became pregnant (215 seropositive, 424 seronegative) and 589 reported pregnancy outcomes (206 seropositive, 383 seronegative). 105 infants born to 98 mothers in the seropositive group were enrolled in the birth cohort. Ebola RNA was not detected in 205 samples of placenta, cord blood, or maternal blood taken at birth from 54 mothers in the seropositive group, nor in 367 vaginal swabs. Viral RNA was found in two of 354 longitudinal breastmilk samples. All but one of 57 infants born during these 54 births were seropositive for anti-Ebola antibodies. Neonates showed high concentrations of anti-Ebola IgG, which declined after 6 months. Odds of adverse pregnancy outcome among the two groups were indistinguishable (OR 1·13, 95% CI 0·71-1·79). Compared with WHO standards, infants born to those in the seropositive group had lower median weight and length, and larger median head circumference over 2 years. Compared with a cohort from the USA accrual of gross motor developmental milestones was similar, whereas attainment of pincer grasp and early vocalisation were mildly delayed. The risks of Ebola virus reactivation in the peripartum and postpartum period and of adverse birth outcomes are low in those who have recovered from Ebola virus disease and become pregnant approximately 1 year after acute Ebola virus disease. The implication for clinical practice is that care of people who are pregnant and who have recovered from Ebola can be offered without risks to health-care providers or stigmatisation of the mothers and their offspring. The implication for prospective mothers is that safe pregnancies are entirely possible after recovery from Ebola. National Institute of Allergy and Infectious Diseases and Liberia Ministry of Health.

Current HIV/SIV Reservoir Assays for Preclinical and Clinical Applications: Recommendations from the Experts 2022 NIAID Workshop Summary.

Since the first HIV-cured person was reported in 2009, a strong interest in developing highly sensitive HIV and SIV reservoir assays has emerged. In particular, the question arose about the comparative value of state-of-the-art assays to measure and characterize the HIV reservoir, and how these assays can be applied to accurately detect changes in the reservoir during efforts to develop a cure for HIV infection. Second, it is important to consider the impact on the outcome of clinical trials if these relatively new HIV reservoir assays are incorporated into clinical trial endpoints and/or used for clinical decision-making. To understand the advantages and limitations and the regulatory implications of HIV reservoir assays, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored and convened a meeting on September 16, 2022, to discuss the state of knowledge concerning these questions and best practices for selecting HIV reservoir assays for a particular research question or clinical trial protocol.

Benralizumab for eosinophilic gastritis: a single-site, randomised, double-blind, placebo-controlled, phase 2 trial

In eosinophilic gastrointestinal diseases, the role of eosinophils in disease pathogenesis and the effect of eosinophil depletion on patient outcomes are unclear. Benralizumab, an eosinophil-depleting monoclonal antibody that targets the interleukin-5 receptor α, might eliminate gastric tissue eosinophils and improve outcomes in eosinophilic gastritis. We aimed to assess the efficacy and safety of benralizumab in patients with eosinophilic gastritis. We conducted a single-site, randomised, double-blind, placebo-controlled, phase 2 trial at Cincinnati Children's Hospital Medical Center (Cincinnati, OH, USA). Individuals aged 12-60 years with symptomatic, histologically active eosinophilic gastritis (peak gastric eosinophil count ≥30 eosinophils per high-power field [eos/hpf] in at least five hpfs) and blood eosinophilia (>500 eosinophils per μL [eos/μL]) were randomly assigned (1:1, block size of four) to benralizumab 30 mg or placebo, stratified by the use of glucocorticoids for gastric disease. Investigators, study staff, and study participants were masked to treatment assignment; statisticians were unmasked when analysing data. Treatments were administered subcutaneously once every 4 weeks for a 12-week double-blind period (three total injections). The primary endpoint was the proportion of patients who achieved histological remission (peak gastric eosinophil count <30 eos/hpf) at week 12. Key secondary endpoints were the changes from baseline to week 12 in peak gastric eosinophil count, blood eosinophil count, eosinophilic gastritis histology (total, inflammatory, and structural feature scores), Eosinophilic Gastritis Endoscopic Reference System (EG-REFS) score, and patient-reported outcome symptom measures (Severity of Dyspepsia Assessment [SODA] and Patient-Reported Outcome Measurement Information System [PROMIS] short-form questionnaire). After the 12-week double-blind period, patients were eligible for entry into two open-label extension (OLE) periods up to week 88, in which all patients received benralizumab. Efficacy was analysed in the intention-to-treat (ITT) population and safety was assessed in all patients who received at least one dose of study drug. The trial was registered on ClinicalTrials.gov, NCT03473977, and is completed. Between April 23, 2018, and Jan 13, 2020, 34 patients were screened, and 26 were subsequently randomly assigned to benralizumab (n=13) or placebo (n=13) and included in the ITT and safety populations (mean age 19·5 years [SD 7·3]; 19 [73%] male patients and seven [27%] female patients). At week 12, ten (77% [95% CI 50 to 92]) of 13 patients who received benralizumab and one (8% [1 to 33]) of 13 who received placebo achieved histological remission (difference 69 percentage points [95% CI 32 to 85]; p=0·0010). Changes from baseline to week 12 were significantly greater in the benralizumab group versus the placebo group for peak gastric eosinophil counts (mean -137 eos/hpf [95% CI -186 to -88] vs -38 eos/hpf [-94 to 18]; p=0·0080), eosinophilic gastritis histology total score (mean -0·31 [-0·42 to -0·20] vs -0·02 [-0·16 to 0·12]; p=0·0016), histology inflammatory score (mean -0·46 [-0·60 to -0·31] vs -0·04 [-0·22 to 0·13]; p=0·0006), and blood eosinophil counts (median -1060 eos/μL [IQR -1740 to -830] vs -160 eos/μL [-710 to 120]; p=0·0044). Changes were not significantly different between the groups for eosinophilic gastritis histology structural score (mean -0·07 [95% CI -0·19 to 0·05] vs 0·03 [-0·09 to 0·15]; p=0·23), EG-REFS score (mean -1·0 [-2·3 to 0·3] vs -0·5 [-2·0 to 1·0]; p=0·62), or in patient-reported outcomes (SODA and PROMIS). During the double-blind period, treatment-emergent adverse events occurred in 11 (85%) of 13 patients in the benralizumab group and six (46%) of 13 in the placebo group; the most common treatment-emergent adverse events were headache (six [46%] vs two [15%] patients), nausea (three [23%] vs two [15%]), and vomiting (two [15%] vs three [23%]). There were no treatment-related deaths. Two patients had serious adverse events (dizziness and rhabdomyolysis in one patient; aspiration in one patient) during the OLE periods, which were considered unrelated to study treatment. Benralizumab treatment induced histological remission, as defined by absence of tissue eosinophilia, in most patients with eosinophilic gastritis. However, the persistence of histological, endoscopic, and other features of the disease suggest a co-existing, eosinophil-independent pathogenic mechanism and the need for broader targeting of type 2 immunity. AstraZeneca and the Division of Intramural Research (National Institute of Allergy and Infectious Diseases, US National Institutes of Health).

Global trends of monkeypox-related articles: A bibliometric analysis over the last five decades (1964 – July 14, 2022)

BackgroundThe first human monkeypox (MPX) case was identified in the Democratic Republic of Congo (DRC) in 1970 with an outbreak in 2010 and the first human MPX case in the UK in 2022. In this study, we conducted a bibliometric analysis of the literature on monkeypox based on the Web of Science Core Collection (WOSCC) of the Institute for Scientific Information (ISI) to identify relevant topics and trends in monkeypox research. MethodsWe searched the Web of Science from 1964 until July 14, 2022, for all publications using the keywords “Monkeypox” and “Monkeypox virus.” Results were compared using numerous bibliometric methodologies and stratified by journal, author, year, institution, and country-specific metrics. ResultsOut of 1170 publications initially selected, 1163 entered our analysis, with 65.26 % (n = 759) being original research articles and 9.37 % (n = 109) being review articles. Most MPX publications were in 2010, with 6.02 % (n = 70), followed by 2009 and 2022 at 5.67 % (n = 66) each. The USA was the country with the highest number of publications, with n = 662 (56.92 %) of total publications, followed by Germany with n = 82 (7.05 %), the UK with n = 74 (6.36 %), and Congo with n = 65 (5.59 %). Journal of Virology published the highest number of MPX publications, followed by Virology Journal and Emerging Infectious Diseases with n = 52 (9.25 %), n = 43 (7.65 %), and n = 32 (5.69 %) publications, respectively. The top contributing institutions were the Centers for Disease Control and Prevention (CDC), the US Army Medical Research Institute of Infectious Diseases, and the National Institutes of Health (NIH)National Institute of Allergy and Infectious Diseases (NIAID). ConclusionOur analysis provides an objective and robust overview of the current literature on MPX and its global trends; this information could serve as a reference guide for those aiming to conduct further MPX-related research and as a source for those seeking information about MPX.

Approach for sustainable district-led production and distribution of alcohol-based hand rub in Uganda

Background: A sustainable, continuous supply of alcohol-based hand rub (ABHR) is essential for healthcare workers in health facilities. The WHO provides guidance for production in individual health facilities. In Uganda, using this guidance, an innovative approach was implemented at the district local government level to produce and subsequently distribute ABHR to primary-care health facilities that have limited capacity for local facility-level production. This project was supported by the CDC in collaboration with the Infectious Diseases Institute (IDI) and targeted governmental or district engagement with local partners to ensure sustainability. Methods: District stakeholders were engaged to obtain buy-in and define roles and responsibilities. Overall, 4 staff members in each of 6 supported districts were nominated by District Health Officers for training: 2 staff members were trained to produce ABHR and conduct internal quality control and 2 were trained on external quality control. Districts provided ABHR production-unit facilities and facilitated integration within the government essential supplies delivery system, National Medical Stores in Uganda, which supports last-mile delivery to facilities. An implementing partner purchased initial raw materials necessary for production. The cost of materials for local production was compared to the price of commercial ABHR available in Uganda. Results: Between January and August 2021, 23 staff members were trained, and 380 batches of quality-assured ABHR (17,820 L) were produced and distributed to 278 health facilities. Consumption of ABHR in the first distribution was used to benchmark predicted ABHR consumption per targeted facility in subsequent months. Increased demand for ABHR due to the COVID-19 pandemic and the Ebola virus disease outbreak in central Uganda (September 2022) was addressed through emergency requests on a case-by-case basis. ABHR local production costs $3 per liter for materials, less than half of commercial ABHR ($8 per liter). Conclusions: Early results suggest that this approach is potentially sustainable but requires national advocacy as well. Leveraging existing distribution systems while building local capacity for ABHR production and distribution may improve longevity of such innovations in similar resource-limited settings.Disclosure: None

Incomplete HPV vaccination among individuals aged 27-45 years in the United States: A mixed effect analysis of individual and contextual factors.

10546 Background: In the United States, the Human papillomavirus (HPV) vaccine is approved for use up to age 45. Incomplete HPV vaccination rates among those over age 26, however, remain high. The aim of this study was to examine the independent effects of individual- and neighborhood-level factors on incomplete HPV vaccine series in the United States (US) among those aged 27-45 years. Methods: This retrospective cohort study used administrative data from Optum’s Clinformatics DataMart Database to identify individuals aged 27-45 years who received 1 or more doses of HPV vaccine between July 2019 and June 2022. Multilevel multivariable logistic regression models were applied to the data on 7,662 individuals aged 27-45 years who were fully vaccinated against HPV or not, nested within 3839 neighborhoods across the US. Results: More than half of the participants in this study (52.93%) were not completely vaccinated against HPV. About 64% of the eligible participants aged 27-30 years did not complete their HPV vaccine series. After adjusting for all other covariates in the final model, being older than 30 years old decreased the odds of incomplete HPV vaccine series. Participants living in neighborhoods of South region of the US had enhanced odds of incomplete HPV vaccine series compared to those residing in Northeast region (aOR 1.21; 95% CrI 1.03–1.42). There was significant clustering of incomplete HPV vaccine series at the neighborhood level. Conclusions: This study revealed that individual- and neighborhood-level factors significantly influence HPV vaccination incompleteness in the US. Interventions to improve HPV vaccination uptake and completion should take into consideration both individual- and contextual-level characteristics during design, planning and implementation of policies and programs to improve HPV vaccination coverage and completion in the US and other similar countries. Acknowledgement Dr. Adekanmbi is supported by a research career development award (K12HD052023: Building Interdisciplinary Research Careers in Women’s Health Program-BIRCWH; Berenson, PI) from the National Institutes of Health/Office of the Director (OD), National Institute of Allergy and Infectious Diseases (NIAID), and Eunice Kennedy Shriver National Institute of Child Health &amp; Human Development (NICHD). Dr. Guo is currently supported by an award (K07CA222343) from the National Institutes of Health, National Cancer Institute (NIH/NCI). Dr. Berenson is supported by an award (PP200048) from the Cancer Prevention and Research Institute of Texas (CPRIT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or CPRIT. Conflict of Interest: All authors report no conflicts of interest.

The effects of cash transfer programmes on HIV/AIDS prevention and care outcomes: a systematic review and meta-analysis of intervention studies

Poverty and social inequality are risk factors for poor health outcomes in patients with HIV/AIDS. In addition to eligibility, cash transfer programmes can be divided into two categories: those with specific requirements (conditional cash transfers [CCTs]) and those without specific requirements (unconditional cash transfers). Common CCT requirements include health care (eg, undergoing an HIV test) and education (eg, children attending school). Trials assessing the effect of cash transfer programmes on HIV/AIDS outcomes have yielded divergent findings. This review aimed to summarise evidence to evaluate the effects of cash transfer programmes on HIV/AIDS prevention and care outcomes. For this systematic review and meta-analysis, we searched PubMed, EMBASE, Cochrane Library, LILACS, WHO IRIS, PAHO-IRIS, BDENF, Secretaria Estadual de Saúde SP, Localizador de Informação em Saúde, Coleciona SUS, BINACIS, IBECS, CUMED, SciELO, and Web of Science up to Nov 28, 2022. We included randomised controlled trials (RCTs) that evaluated the effects of cash transfer programmes on HIV incidence, HIV testing, retention in HIV care, and antiretroviral therapy adherence, and conducted risk of bias and quality of evidence assessments using the Cochrane Risk of Bias tool and the Grading of Recommendations, Assessment, Development, and Evaluations approach. A random-effects meta-analysis model was used to combine studies and calculate risk ratios (RRs). Subgroup analyses were performed using conditionality types (ie, school attendance or health care). The protocol was registered with PROSPERO, CRD42021274452. 16 RCTs, which included 5241 individuals, fulfilled the inclusion criteria. Of these, 13 studies included conditionalities for receiving cash transfer programmes. The results showed that receiving a cash transfer was associated with lowered HIV incidence among individuals who had to meet health-care conditionalities (RR 0·74, 95% CI 0·56-0·98) and with increased retention in HIV care for pregnant women (1·14, 95% CI 1·03-1·27). No significant effect was observed for HIV testing (RR 0·45, 95% CI 0·18-1·12) or antiretroviral therapy adherence (1·13, 0·73-1·75). Lower risk of bias was observed for HIV incidence and having an HIV test. The strength of available evidence can be classified as moderate. Cash transfer programmes have a positive effect on mitigating HIV incidence for individuals who have to meet health-care conditionalities and on increasing retention in HIV care for pregnant women. These results show the potential of cash transfer programmes for HIV prevention and care, especially among people in extreme poverty, and highlight that cash transfer programmes must be considered when developing policies for HIV/AIDS control, as indicated by the UNAIDS 95-95-95 target of the HIV care continuum. National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA.

Temporal characterization of Alzheimer's Disease with sequences of clinical records.

Alzheimer's Disease (AD) is a complex clinical phenotype with unprecedented social and economic tolls on an ageing global population. Real-world data (RWD) from electronic health records (EHRs) offer opportunities to accelerate precision drug development and scale epidemiological research on AD. A precise characterization of AD cohorts is needed to address the noise abundant in RWD. We conducted a retrospective cohort study to develop and test computational models for AD cohort identification using clinical data from 8 Massachusetts healthcare systems. We mined temporal representations from EHR data using the transitive sequential pattern mining algorithm (tSPM) to train and validate our models. We then tested our models against a held-out test set from a review of medical records to adjudicate the presence of AD. We trained two classes of Machine Learning models, using Gradient Boosting Machine (GBM), to compare the utility of AD diagnosis records versus the tSPM temporal representations (comprising sequences of diagnosis and medication observations) from electronic medical records for characterizing AD cohorts. In a group of 4985 patients, we identified 219 tSPM temporal representations (i.e., transitive sequences) of medical records for constructing the best classification models. The models with sequential features improved AD classification by a magnitude of 3-16 percent over the use of AD diagnosis codes alone. The computed cohort included 663 patients, 35 of whom had no record of AD. Six groups of tSPM sequences were identified for characterizing the AD cohorts. We present sequential patterns of diagnosis and medication codes from electronic medical records, as digital markers of Alzheimer's Disease. Classification algorithms developed on sequential patterns can replace standard features from EHRs to enrich phenotype modelling. National Institutes of Health: the National Institute on Aging (RF1AG074372) and the National Institute of Allergy and Infectious Diseases (R01AI165535).

Trends of Mismatches in Real-Time RT-PCR Assays Developed by the National Institute of Infectious Diseases, Japan for Omicron Variant of Severe Acute Respiratory Syndrome Coronavirus 2.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2021 and gradually overtook the Delta variant, which was the predominant variant at that time. The Omicron variant has been consecutively replaced by related sublineages. The real-time RT-PCR assays developed by the National Institute of Infectious Diseases (NIID), Japan (i.e., the NIID-N2 and NIID-S2 assays) are the reference assays that have been used in Japan since the outbreak of SARS-CoV-2. To evaluate the applicability of the NIID assays for the Omicron variants, trends in the prevalence of nucleotide mismatches in the primer/probe sequences were traced using sequences registered in the Global Initiative on Sharing Avian Influenza Data database. Approximately 99% of the deposited Omicron variant sequences did not have any mismatches in the NIID assay primer/probes from January to August 2022. This indicates that the NIID assays have been able to detect the changing SARS-CoV-2 Omicron variants.

Providing Expert Consultation in a World Living with COVID-19

After a welcome by Paolo Antonio Grossi, the appointed chair by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Department of Medicine &amp; Surgery, University of Insubria, Varese, Italy; Ann-Brit Eg Hansen, Department of Infectious Diseases, Copenhagen University Hospital – Amager and Hvidovre, Denmark and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, summarised the objectives of the meeting and introduced the speakers. In their opening presentation, Tobias Welte, Department of Pulmonary and Infectious Diseases, Hannover University School of Medicine, Germany, described how the COVID-19 pandemic has evolved, in terms of variants, mortality rates, vaccinations, immunity, and antivirals. Welte then presented a hypothetical case study to illustrate how older patients with comorbidities can initially have mild symptoms, but may then deteriorate and require hospitalisation. Stephen Thomas, State University of New York Upstate Medical University, Syracuse, USA, then described the efficacy and potential side effects of the BNT162b2 (Pfizer–BioNTech, New York City, USA, and Mainz, Germany, respectively) vaccine, and the need for, and benefits of, booster doses. Thomas also described the added benefits of the newer bivalent vaccines in a world where COVID-19 is constantly mutating. Marta Boffito, HIV, Sexual and Gender Health, Dermatology, Chelsea and Westminster Hospital NHS Foundation Trust, Imperial College London, UK, then outlined various factors that increase the risk of progression to severe COVID-19 disease, including older age, immunocompromised status, and underlying health conditions (e.g., obesity, hypertension, heart disease, and chronic kidney disease [CKD]). Such patients can benefit from antiviral medications such as nirmatrelvir/ritonavir, although potential drug–drug interactions must be considered. Roger Paredes, Department of Infectious Diseases and IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain, and Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA, revisited the case study to highlight the importance of early COVID-19 diagnosis among high-risk patients to enable the use of nirmatrelvir/ritonavir, which is only approved within 5 days of symptom onset for non-hospitalised adults at increased risk of progression to severe COVID-19. Paredes went on to discuss antiviral treatments in more detail, describing a randomised controlled trial (EPIC-HR) and two large real-world studies that showed that nirmatrelvir/ritonavir could significantly reduce the risk of hospitalisation and death due to COVID-19 among high-risk patients. To conclude, Hansen highlighted the importance of regular updates to COVID-19 management guidelines, given the ongoing and evolving nature of COVID-19, as well as the importance of identifying high-risk patients early in their disease course to enable the use of nirmatrelvir/ritonavir.

Antimicrobial Resistance of Staphylococcus aureus Isolated between 2017 and 2022 from Infections at a Tertiary Care Hospital in Romania.

This study aimed to evaluate the frequency of isolation of Staphylococcus aureus from different pathological samples processed in the Microbiology Laboratory of the National Institute of Infectious Diseases "Prof. Dr. Matei Balș", Romania, between 1 January 2017 and 31 December 2022, aiming to establish the ratio of methicillin-resistant to methicillin-susceptible Staphylococcus aureus strains and the antibiotic resistance pattern of isolated microorganisms. The data of isolates originating from routine diagnostic tasks were analyzed retrospectively using laboratory data from the microbiology department. Up to 39.11% of Staphylococcus aureus strains were resistant to oxacillin (MRSA), with 49.97% resistance to erythromycin and 36.06% inducible resistance to clindamycin. Resistance rates to ciprofloxacin, rifampicin, gentamicin, and trimethoprim-sulfamethoxazole were 9.98%, 5.38%, 5.95%, and 0.96%, respectively. There was no resistance to vancomycin. Between 2017 and 2022, the percentage of MRSA strains decreased from 41.71% to 33.63%, sharply increasing to 42.42% in 2021 (the year of the COVID-19 pandemic, when the percentage of strains isolated from lower respiratory tract infections was higher than that of strains isolated from wounds or blood, as in previous years). This study showed a high percentage of MRSA strains (39.11% overall) with a higher proportion of these strains isolated from the blood (42.49%) compared to other clinical specimens.

Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis

Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis

Heterologous versus homologous boosting elicits qualitatively distinct, BA.5-cross-reactive T cells in transplant recipients.

BackgroundThe SARS-CoV-2 Omicron BA.5 subvariant escapes vaccination-induced neutralizing antibodies because of mutations in the spike (S) protein. Solid organ transplant recipients (SOTRs) develop high COVID-19 morbidity and poor Omicron variant recognition after COVID-19 vaccination. T cell responses may provide a second line of defense. Therefore, understanding which vaccine regimens induce robust, conserved T cell responses is critical.MethodsWe evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4+ and CD8+ T cell responses from SOTRs in a national, prospective, observational trial (n = 75). Participants were selected if they received 3 doses of mRNA (homologous boosting) or 2 doses of mRNA followed by Ad26.COV2.S (heterologous boosting).ResultsHomologous boosting with 3 mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated lower pseudo-neutralization against BA.5 compared with the ancestral strain. In contrast, vaccine-induced S-specific T cells maintained cross-reactivity against BA.5 compared with ancestral recognition. Homologous boosting induced higher frequencies of activated polyfunctional CD4+ T cell responses, with polyfunctional IL-21+ peripheral T follicular helper cells increased in mRNA-1273 compared with BNT162b2. IL-21+ cells correlated with antibody titers. Heterologous boosting with Ad26.COV2.S did not increase CD8+ responses compared to homologous boosting.ConclusionBoosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants in SOTRs, but alternative vaccine strategies are required to induce robust CD8+ T cell responses.FundingBen-Dov Family; NIH National Institute of Allergy and Infectious Diseases (NIAID) K24AI144954, NIAID K08AI156021, NIAID K23AI157893, NIAID U01AI138897, National Institute of Diabetes and Digestive and Kidney Diseases T32DK007713, and National Cancer Institute 1U54CA260492; Johns Hopkins Vice Dean of Research Support for COVID-19 Research in Immunopathogenesis; and Emory COVID-19 research repository.

Maintaining Warp Speed: Policy Requirements for a Just-in-Time, Capability-Based, Scalable Medical Countermeasure Research and Development Enterprise.

Maintaining Warp Speed: Policy Requirements for a Just-in-Time, Capability-Based, Scalable Medical Countermeasure Research and Development Enterprise.

Use of Oral Corticosteroids to Treat HTLV-1-Associated Myelopathy (HAM) in São Paulo, Brazil

Background: During the development of human T-cell lymphotropic virus (HTLV-1)-associated myelopathy (HAM), the inflammatory phenomenon is very prominent and is a major factor in the outcome of the disease. The use of corticosteroids can modify their natural history, and in this study, we evaluated the effectiveness of using daily low-dose prednisone. Methods: This was a cross-sectional study using data collected by physicians monitoring patients with HAM at the Institute of Infectious Diseases “Emilio Ribas”, the main referral center for patients with infectious diseases in São Paulo, Brazil. The objective was to determine if daily low-dose oral prednisone would be able to stabilize the progression of HAM. The outcome measure was a change in the Osame Motor Disability Score (OMDS). Results: Fifty-four patients used treatment with oral prednisone, 5 milligrams daily. Nine cases were excluded from the study because they did not have at least two rating scales within a minimum interval of one year, and six were excluded for being co-infected with HIV and/or HCV. Thirty-nine patients met this criterion and were included for analysis. The majority were women (71.8%), the mean age was 56.51 years old (SD ± 9.74), and the median time of use of prednisone was 16 months. Thirty-two patients (82.05%) maintained the same OMDS, 5/39 (12.82%) had clinical worsening, and 2/39 (5.13%) improved. Conclusions: There was a trend toward clinical stability with the use of oral corticosteroids. However, randomized controlled trials are necessary to evaluate the use in clinical practices in all stages of HAM.

Screen for New Antimicrobial Natural Products from the NCI Program for Natural Product Discovery Prefractionated Extract Library.

The continuing emergence of antibiotic-resistant microbes highlights the need for the identification of new chemotypes with antimicrobial activity. One of the most prolific sources of antimicrobial molecules has been the systematic screening of natural product samples. The National Institute of Allergy and Infectious Diseases and the National Cancer Institute here report a large screen of 326,656 partially purified natural product fractions against a panel of four microbial pathogens, resulting in the identification of >3000 fractions with antifungal and/or antibacterial activity. A small sample of these active fractions was further purified and the chemical structures responsible for the antimicrobial activity were elucidated. The proof-of-concept study identified many different chemotypes, several of which have not previously been reported to have antimicrobial activity. The results show that there remain many unidentified antibiotic compounds from nature.