Phylogenetic inference of inter-population transmission rates for infectious diseases.

Estimating transmission rates is a challenging yet essential aspect of comprehending and controlling the spread of infectious diseases. Various methods exist for estimating transmission rates, each with distinct assumptions, data needs, and constraints. This study introduces a novel phylogenetic approach called transRate, which integrates genetic information with traditional epidemiological approaches to estimate inter-population transmission rates. The phylogenetic method is statistically consistent as the sample size (i.e. the number of pathogen genomes) approaches infinity under the multi-population susceptible-infected-recovered model. Simulation analyses indicate that transRate can accurately estimate the transmission rate with a sample size of 200 ~ 400 pathogen genomes. Using transRate, we analyzed 40,028 high-quality sequences of SARS-CoV-2 in human hosts during the early pandemic. Our analysis uncovered significant transmission between populations even before widespread travel restrictions were implemented. The development of transRate provides valuable insights for scientists and public health officials to enhance their understanding of the pandemic's progression and aiding in preparedness for future viral outbreaks. As public databases for genomic sequences continue to expand, transRate is increasingly vital for tracking and mitigating the spread of infectious diseases.

Metatranscriptomic response of deep ocean microbial populations to infusions of oil and/or synthetic chemical dispersant.

Oil spills are a frequent perturbation to the marine environment that has rapid and significant impacts on the local microbiome. Previous studies have shown that exposure to synthetic dispersant alone did not enhance heterotrophic microbial activity or oxidation rates of specific hydrocarbon components but increased the abundance of some taxa (e.g., Colwellia). In contrast, exposure to oil, but not dispersants, increased the abundance of other taxa (e.g., Marinobacter) and stimulated hydrocarbon oxidation rates. Here, we advance these findings by interpreting metatranscriptomic data from this experiment to explore how and why specific components of the microbial community responded to distinct organic carbon exposure regimes. Dispersant alone was selected for a unique community and for dominant organisms that reflected treatment- and time-dependent responses. Dispersant amendment also led to diverging functional profiles among the different treatments. Similarly, oil alone was selected for a community that was distinct from treatments amended with dispersants. The presence of oil and dispersants with added nutrients led to substantial differences in microbial responses, likely suggesting increased fitness driven by the presence of additional inorganic nutrients. The oil-only additions led to a marked increase in the expression of phages, prophages, transposable elements, and plasmids (PPTEPs), suggesting that aspects of microbial community response to oil are driven by the "mobilome," potentially through viral-associated regulation of metabolic pathways in ciliates and flagellates that would otherwise throttle the microbial community through grazing.IMPORTANCEMicrocosm experiments simulated the April 2010 Deepwater Horizon oil spill by applying oil and synthetic dispersants (Corexit EC9500A and EC9527A) to deep ocean water samples. The exposure regime revealed severe negative alterations in the treatments' heterotrophic microbial activity and hydrocarbon oxidation rates. We expanded these findings by exploring metatranscriptomic signatures of the microbial communities during the chemical amendments in the microcosm experiments. Here we report how dominant organisms were uniquely associated with treatment- and time-dependent trajectories during the exposure regimes; nutrient availability was a significant factor in driving changes in metatranscriptomic responses. Remarkable signals associated with PPTEPs showed the potential role of mobilome and viral-associated survival responses. These insights underscore the time-dependent environmental perturbations of fragile marine environments under oil and anthropogenic stress.

Differences in COVID-19 Outpatient Antiviral Treatment Among Adults Aged ≥65 Years by Age Group - National Patient-Centered Clinical Research Network, United States, April 2022-September 2023.

Adults aged ≥65 years experience the highest risk for COVID-19-related hospitalization and death, with risk increasing with increasing age; outpatient antiviral treatment reduces the risk for these severe outcomes. Despite the proven benefit of COVID-19 antiviral treatment, information on differences in use among older adults with COVID-19 by age group is limited. Nonhospitalized patients aged ≥65 years with COVID-19 during April 2022-September 2023 were identified from the National Patient-Centered Clinical Research Network. Differences in use of antiviral treatment among patients aged 65-74, 75-89, and ≥90 years were assessed. Multivariable logistic regression was used to estimate the association between age and nonreceipt of antiviral treatment. Among 393,390 persons aged ≥65 years, 45.9% received outpatient COVID-19 antivirals, including 48.4%, 43.5%, and 35.2% among those aged 65-75, 76-89, and ≥90 years, respectively. Patients aged 75-89 and ≥90 years had 1.17 (95% CI = 1.15-1.19) and 1.54 (95% CI = 1.49-1.61) times the adjusted odds of being untreated, respectively, compared with those aged 65-74 years. Among 12,543 patients with severe outcomes, 2,648 (21.1%) had received an outpatient COVID-19 antiviral medication, compared with 177,874 (46.7%) of 380,847 patients without severe outcomes. Antiviral use is underutilized among adults ≥65 years; the oldest adults are least likely to receive treatment. To prevent COVID-19-associated morbidity and mortality, increased use of COVID-19 antiviral medications among older adults is needed.

External validity in distributed data networks.

PURPOSE: While much has been written about how distributed networks address internal validity, external validity is rarely discussed. We aimed to define key terms related to external validity, discuss how they relate to distributed networks, and identify how three networks (the US Food and Drug Administration's Sentinel System, the Canadian Network for Observational Drug Effect Studies [CNODES], and the National Patient Centered Clinical Research Network [PCORnet]) deal with external validity. METHODS: We define external validity, target populations, target validity, generalizability, and transportability and describe how each relates to distributed networks. We then describe Sentinel, CNODES, and PCORnet and how each approaches these concepts, including a sample case study. RESULTS: Each network approaches external validity differently. As its target population is US citizens and it includes only US data, Sentinel primarily worries about lack of external validity by not including some segments of the population. The fact that CNODES includes Canadian, United States, and United Kingdom data forces them to seriously consider whether the United States and United Kingdom data will be transportable to Canadian citizens when they meta-analyze database-specific estimates. PCORnet, with its focus on study-specific cohorts and pragmatic trials, conducts more case-by-case explorations of external validity for each new analytic data set it generates. CONCLUSIONS: There is no one-size-fits-all approach to external validity within distributed networks. With these networks and comparisons between their findings becoming a key part of pharmacoepidemiology, there is a need to adapt tools for improving external validity to the distributed network setting.

RTExtract: time-series NMR spectra quantification based on 3D surface ridge tracking.

MOTIVATION: Time-series nuclear magnetic resonance (NMR) has advanced our knowledge about metabolic dynamics. Before analyzing compounds through modeling or statistical methods, chemical features need to be tracked and quantified. However, because of peak overlap and peak shifting, the available protocols are time consuming at best or even impossible for some regions in NMR spectra. RESULTS: We introduce Ridge Tracking-based Extract (RTExtract), a computer vision-based algorithm, to quantify time-series NMR spectra. The NMR spectra of multiple time points were formulated as a 3D surface. Candidate points were first filtered using local curvature and optima, then connected into ridges by a greedy algorithm. Interactive steps were implemented to refine results. Among 173 simulated ridges, 115 can be tracked (RMSD < 0.001). For reproducing previous results, RTExtract took less than 2 h instead of ∼48 h, and two instead of seven parameters need tuning. Multiple regions with overlapping and changing chemical shifts are accurately tracked. AVAILABILITY AND IMPLEMENTATION: Source code is freely available within Metabolomics toolbox GitHub repository (https://github.com/artedison/Edison_Lab_Shared_Metabolomics_UGA/tree/master/metabolomics_toolbox/code/ridge_tracking) and is implemented in MATLAB and R. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

An Interrupted Time-series Evaluation of the Association Between State Laws Mandating Prescriber Use of Prescription Drug Monitoring Programs and Discontinuation of Chronic Opioid Therapy in US Veterans.

BACKGROUND: Most states have recently passed laws requiring prescribers to use prescription drug monitoring programs (PDMPs) before prescribing opioid medications. The impact of these mandates on discontinuing chronic opioid therapy among Veterans managed in the Veterans Health Administration (VA) is unknown. We assess the association between the earliest of these laws and discontinuation of chronic opioid therapy in Veterans receiving VA health care. METHODS: We conducted a comparative interrupted time-series study in the 5 states mandating PDMP use before August 2013 (Ohio, West Virginia, Kentucky, New Mexico, and Tennessee), adjusting for trends in the 17 neighboring control states without such mandates. We modeled 25 months of prescribing for each state centered on the month the mandate became effective. We included Veterans prescribed long-term outpatient opioid therapy (305 of the preceding 365 d). Our outcomes were discontinuation of chronic opioid therapy (primary outcome) and the average daily quantity of opioids per Veteran over the following 6 months (secondary outcome). RESULTS: We included 250 monthly cohorts with 225,665 unique Veterans and 3.4 million Veteran-months. Baseline discontinuation rates before the PDMP mandates were 0.4%-2.7% per month. Kentucky saw a discontinuation increase of 1 absolute percentage point following its PDMP mandate which decreased over time. The other 4 states had no significant association between their mandates and change in opioid discontinuation. There was no evidence of decreasing opioid quantities following PDMP mandates. CONCLUSION: We did not find consistent evidence that state laws mandating provider PDMP use were associated with the discontinuation of chronic opioid therapy within the VA for the time period studied.

Effect of Electronic Health Record-Based Coaching on Weight Maintenance: A Randomized Trial.

Background: Weight regain after intentional loss is common. Most evidence-based weight management programs focus on short-term loss rather than long-term maintenance. Objective: To evaluate the benefit of coaching in an electronic health record (EHR)-based weight maintenance intervention. Design: Randomized controlled trial. (ClinicalTrials.gov: NCT01946191). Setting: Practices affiliated with an academic medical center. Participants: Adult outpatients with body mass index (BMI) of 25 kg/m2 or higher, intentional weight loss of at least 5% in the previous 2 years, and no bariatric procedures in the previous 5 years. Intervention: Participants were randomly assigned to EHR tools (tracking group) versus EHR tools plus coaching (coaching group). The EHR tools included weight, diet, and physical activity tracking flow sheets; standardized surveys; and reminders. The coaching group received 24 months of personalized coaching through the EHR patient portal, with 24 scheduled contacts. Measurements: The primary outcome was weight change at 24 months. Secondary outcomes included 5% weight loss maintenance and changes in BMI, waist circumference, number of steps per day, health-related quality of life, physical function, blood pressure, and satisfaction. Results: Among 194 randomly assigned participants (mean age, 53.4 years [SD, 12.2]; 143 [74%] women; 171 [88%] white), 157 (81%) completed the trial. Mean baseline weight and BMI were 85.8 kg (SD, 19.1) and 30.4 kg/m2 (SD, 5.9). At 24 months, mean weight regain (± SE) was 2.1 ± 0.62 kg and 4.9 ± 0.63 kg in the coaching and tracking groups, respectively. The between-group difference in weight change at 24 months was significant (-2.86 kg [95% CI, -4.60 to -1.11 kg]) in the linear mixed model. At 24 months, 65% of participants in the coaching group and 50% in the tracking group maintained weight loss of at least 5%. Limitation: Single-site trial, which limits generalizability. Conclusion: Among adults with intentional weight loss of at least 5%, use of EHR tools plus coaching resulted in less weight regain than EHR tools alone. Primary Funding Source: Agency for Healthcare Research and Quality and National Institutes of Health.

Visualization of angiogenesis and vasculogenesis in a late tissue radiation injury of the chest wall treated with adjuvant hyperbaric oxygen therapy using fluorescence angiography.

Adjuvant radiation therapy for breast cancer treatment often involves high doses of radiation, making patients more susceptible to late radiation tissue injury (LRTI), severe complications of which involve necrosis and ulceration. Treatment of such wounds is challenging. One modality that can be utilized is hyperbaric oxygen (HBO2) therapy. However, an optimal dose and the objective evidence of its benefit in use as an adjunctive treatment modality is limited. Presented here is a case of a non-surgical candidate in which serial indocyanine green fluorescence angiography (ICGFA) was utilized to determine if it could detect changes in tissue perfusion over the course of treatment. Serial ICGFA allowed for visualization of the current phase of wound healing, angiogenesis and vasculogenesis. Future large studies should be employed to better determine the utility of serial ICGFA to improve HBO2 utilization in patients who are undergoing HBO2 as part of their course of treatment for LRTI.

What is Phase in Cellular Clocks?

Four inter-related measures of phase are described to study the phase synchronization of cellular oscillators, and computation of these measures is described and illustrated on single cell fluorescence data from the model filamentous fungus, Neurospora crassa. One of these four measures is the phase shift ϕ in a sinusoid of the form x(t) = A(cos(ωt + ϕ), where t is time. The other measures arise by creating a replica of the periodic process x(t) called the Hilbert transform x̃(t), which is 90 degrees out of phase with the original process x(t). The second phase measure is the phase angle FH(t) between the replica x̃(t) and x(t), taking values between -π and π. At extreme values the Hilbert Phase is discontinuous, and a continuous form FC(t) of the Hilbert Phase is used, measuring time on the nonnegative real axis (t). The continuous Hilbert Phase FC(t) is used to define the phase MC(t1,t0) for an experiment beginning at time t0 and ending at time t1. In that phase differences at time t0 are often of ancillary interest, the Hilbert Phase FC(t0) is subtracted from FC(t1). This difference is divided by 2π to obtain the phase MC(t1,t0) in cycles. Both the Hilbert Phase FC(t) and the phase MC(t1,t0) are functions of time and useful in studying when oscillators phase-synchronize in time in signal processing and circadian rhythms in particular. The phase of cellular clocks is fundamentally different from circadian clocks at the macroscopic scale because there is an hourly cycle superimposed on the circadian cycle.

Charcot Foot: Clinical Clues, Diagnostic Strategies, and Treatment Principles.

Acute Charcot neuroarthropathy of the foot and ankle is often difficult to diagnose because of limited findings in the patient history, physical examination, imaging, and laboratory studies. Delay in treatment results in the development of rigid foot and ankle deformities, increasing the risk of ulceration, infection, and major lower extremity amputation. Acute Charcot neuroarthropathy should be suspected in any patient 40 years or older with obesity and peripheral neuropathy who presents with an acutely swollen foot following minimal or no recalled trauma and who reports minimal to no pain, particularly if radiography and laboratory markers of infection are normal. Magnetic resonance imaging or computed tomography should be performed in these cases. If changes consistent with acute Charcot neuroarthropathy are observed, prompt immobilization and/or referral to a foot and ankle subspecialist is needed to minimize sequelae. Immobilization should continue until lower extremity edema and warmth resolve, and serial radiography shows evidence of osseous consolidation. Intranasal calcitonin salmon may have a role as adjunctive therapy. Although controversial, surgery may be indicated if there is severe dislocation or instability, concern for skin breakdown, or failure of conservative treatment to obtain a stable, plantigrade foot.

The EXPLORE Trial: A Feasibility Study Using Fluorescence Angiography to Evaluate Perfusion in the Oxygen-Rich Environment.

INTRODUCTION: Hyperbaric oxygen therapy (HBOT) is defined as breathing 100% oxygen at a pressure ≥1.4 atmospheres absolute (ATA). Adjunct HBOT is one modality used for treatment of certain complex wounds. The resulting increase in oxygen delivery to wounded tissue has been associated with reduced edema, reduced inflammation, improved infection control, increased collagen deposition, and increased angiogenesis. However, there remains a relative paucity of evidence supporting the use of HBOT in the treatment of certain acute and chronic, non-healing wounds. This feasibility study was undertaken to evaluate the ability of fluorescence angiography to provide real-time visualization and objective assessment of changes in local tissue perfusion over a standard course of HBOT. MATERIALS AND METHODS: This single-center, prospective, feasibility study included a total of 34 subjects with wounds of various etiologies deemed eligible for treatment with adjunct HBOT. Fluorescence angiography was performed pre- and post-HBOT sessions 1, 5, 10, 15, and 20. The imaging sequences were analyzed to determine the effects of HBOT on local tissue perfusion to the wounds. RESULTS: A total of 22 subjects received a minimum of 10 HBO sessions with associated pre- and post-fluorescence angiography performed and analyzed. Fluorescence angiography was able to provide both real-time visualization and objective assessment of changes in tissue perfusion over the course of adjunct HBOT. CONCLUSION: The results of this feasibility study suggest that serial fluorescence angiography can detect short- and long-term changes in wound area tissue perfusion associated with HBOT. These findings may assist in the selection and monitoring of patients undergoing HBOT.

Secondary structural entropy in RNA switch (Riboswitch) identification.

BACKGROUND: RNA regulatory elements play a significant role in gene regulation. Riboswitches, a widespread group of regulatory RNAs, are vital components of many bacterial genomes. These regulatory elements generally function by forming a ligand-induced alternative fold that controls access to ribosome binding sites or other regulatory sites in RNA. Riboswitch-mediated mechanisms are ubiquitous across bacterial genomes. A typical class of riboswitch has its own unique structural and biological complexity, making de novo riboswitch identification a formidable task. Traditionally, riboswitches have been identified through comparative genomics based on sequence and structural homology. The limitations of structural-homology-based approaches, coupled with the assumption that there is a great diversity of undiscovered riboswitches, suggests the need for alternative methods for riboswitch identification, possibly based on features intrinsic to their structure. As of yet, no such reliable method has been proposed. RESULTS: We used structural entropy of riboswitch sequences as a measure of their secondary structural dynamics. Entropy values of a diverse set of riboswitches were compared to that of their mutants, their dinucleotide shuffles, and their reverse complement sequences under different stochastic context-free grammar folding models. Significance of our results was evaluated by comparison to other approaches, such as the base-pairing entropy and energy landscapes dynamics. Classifiers based on structural entropy optimized via sequence and structural features were devised as riboswitch identifiers and tested on Bacillus subtilis, Escherichia coli, and Synechococcus elongatus as an exploration of structural entropy based approaches. The unusually long untranslated region of the cotH in Bacillus subtilis, as well as upstream regions of certain genes, such as the sucC genes were associated with significant structural entropy values in genome-wide examinations. CONCLUSIONS: Various tests show that there is in fact a relationship between higher structural entropy and the potential for the RNA sequence to have alternative structures, within the limitations of our methodology. This relationship, though modest, is consistent across various tests. Understanding the behavior of structural entropy as a fairly new feature for RNA conformational dynamics, however, may require extensive exploratory investigation both across RNA sequences and folding models.

APOE ϵ4, rated life experiences, and affect among centenarians.

OBJECTIVES: The purpose of this study was to assess the relationship between apolipoprotein E (APOE), life events and engagement, and subjective well-being (as measured by positive and negative affect) among centenarians. Based on the life stress paradigm, we predicted that higher levels of stress would allow APOE to influence positive and negative affect. METHOD: 196 centenarians and near-centenarians (98 years and older) of the Georgia Centenarian Study participated in this research. The APOE, positive and negative affect, the number of recent (last 2 years) and lifelong (more than 20 years prior to testing) events, as well as a number of life engagement tasks were assessed. RESULTS: Results suggested that centenarians carrying the APOE ϵ4 allele rated lower in positive affect, the number of lifelong events, and in engaged lifestyle, when compared to centenarians without the APOE ϵ4 allele (t = 3.43, p < .01; t = 3.19, p < .01; and t = 2.33, p < .05, respectively). Blockwise multiple regressions indicated that the APOE ϵ4 predicted positive but not negative affect after controlling for demographics. Gene-environment interactions were obtained for the APOE ϵ4 and lifelong events, suggesting that carriers of the APOE ϵ4 allele had higher scores of negative affect after having experienced more events, whereas noncarriers had reduced negative affect levels after having experienced more events. CONCLUSION: APOE ϵ4 is directly related to positive affect and is related to negative affect in interaction with life events.

The clock in growing hyphae and their synchronization in Neurospora crassa.

Utilizing a microfluidic chip with serpentine channels, we inoculated the chip with an agar plug with Neurospora crassa mycelium and successfully captured individual hyphae in channels. For the first time, we report the presence of an autonomous clock in hyphae. Fluorescence of a mCherry reporter gene driven by a clock-controlled gene-2 promoter (ccg-2p) was measured simultaneously along hyphae every half an hour for at least 6 days. We entrained single hyphae to light over a wide range of day lengths, including 6,12, 24, and 36 h days. Hyphae tracked in individual serpentine channels were highly synchronized (K = 0.60-0.78). Furthermore, hyphae also displayed temperature compensation properties, where the oscillation period was stable over a physiological range of temperatures from 24 °C to 30 °C (Q10 = 1.00-1.10). A Clock Tube Model developed could mimic hyphal growth observed in the serpentine chip and provides a mechanism for the stable banding patterns seen in race tubes at the macroscopic scale and synchronization through molecules riding the growth wave in the device.

Computer vision models enable mixed linear modeling to predict arbuscular mycorrhizal fungal colonization using fungal morphology.

The presence of Arbuscular Mycorrhizal Fungi (AMF) in vascular land plant roots is one of the most ancient of symbioses supporting nitrogen and phosphorus exchange for photosynthetically derived carbon. Here we provide a multi-scale modeling approach to predict AMF colonization of a worldwide crop from a Recombinant Inbred Line (RIL) population derived from Sorghum bicolor and S. propinquum. The high-throughput phenotyping methods of fungal structures here rely on a Mask Region-based Convolutional Neural Network (Mask R-CNN) in computer vision for pixel-wise fungal structure segmentations and mixed linear models to explore the relations of AMF colonization, root niche, and fungal structure allocation. Models proposed capture over 95% of the variation in AMF colonization as a function of root niche and relative abundance of fungal structures in each plant. Arbuscule allocation is a significant predictor of AMF colonization among sibling plants. Arbuscules and extraradical hyphae implicated in nutrient exchange predict highest AMF colonization in the top root section. Our work demonstrates that deep learning can be used by the community for the high-throughput phenotyping of AMF in plant roots. Mixed linear modeling provides a framework for testing hypotheses about AMF colonization phenotypes as a function of root niche and fungal structure allocations.

Electronic Health Record-Based Nudge Intervention and Axillary Surgery in Older Women With Breast Cancer: A Nonrandomized Controlled Trial.

Importance: Choosing Wisely recommendations advocate against routine use of axillary staging in older women with early-stage, clinically node-negative (cN0), hormone receptor-positive (HR+), and HER2-negative breast cancer. However, rates of sentinel lymph node biopsy (SLNB) in this population remain persistently high. Objective: To evaluate whether an electronic health record (EHR)-based nudge intervention targeting surgeons in their first outpatient visit with patients meeting Choosing Wisely criteria decreases rates of SLNB. Design, Setting, and Participants: This nonrandomized controlled trial was a hybrid type 1 effectiveness-implementation study with subsequent postintervention semistructured interviews and lasted from October 2021 to October 2023. Data came from EHRs at 8 outpatient clinics within an integrated health care system; participants included 7 breast surgical oncologists. Data were collected for female patients meeting Choosing Wisely criteria for omission of SLNB (aged ≥70 years with cT1 and cT2, cN0, HR+/HER2- breast cancer). The study included a 12-month preintervention control period; baseline surveys assessing perceived acceptability, appropriateness, and feasibility of the designed intervention; and a 12-month intervention period. Intervention: A column nudge was embedded into the surgeon's schedule in the EHR identifying patients meeting Choosing Wisely criteria for potential SLNB omission. Main Outcomes and Measures: The primary outcome was rate of SLNB following nudge deployment into the EHR. Results: Similar baseline demographic and tumor characteristics were observed before (control period, n = 194) and after (intervention period, n = 193) nudge deployment. Patients in both the control and intervention period had a median (IQR) age of 75 (72-79) years. Compared with the control period, unadjusted rates of SLNB decreased by 23.1 percentage points (46.9% SLNB rate prenudge to 23.8% after; 95% CI, -32.9 to -13.8) in the intervention period. An interrupted time series model showed a reduction in the rate of SLNB following nudge deployment (adjusted odds ratio, 0.26; 95% CI, 0.07 to 0.90; P = .03). The participating surgeons scored the intervention highly on acceptability, appropriateness, and feasibility. Dominant themes from semistructured interviews indicated that the intervention helped remind the surgeons of potential Choosing Wisely applicability without the need for additional clicks or actions on the day of the patient visit, which facilitated use. Conclusions and Relevance: This study showed that a nudge intervention in the EHR significantly decreased low-value axillary surgery in older women with early-stage, cN0, HR+/HER2- breast cancer. This user-friendly and easily implementable EHR-based intervention could be a beneficial approach for decreasing low-value care in other practice settings or patient populations. Trial Registration: ClinicalTrials.gov Identifier: NCT06006910.

Prevalent Metformin Use in Adults With Diabetes and the Incidence of Long COVID: An EHR-Based Cohort Study From the RECOVER Program.

OBJECTIVE: Studies show metformin use before and during SARS-CoV-2 infection reduces severe COVID-19 and postacute sequelae of SARS-CoV-2 (PASC) in adults. Our objective was to describe the incidence of PASC and possible associations with prevalent metformin use in adults with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: This is a retrospective cohort analysis using the National COVID Cohort Collaborative (N3C) and Patient-Centered Clinical Research Network (PCORnet) electronic health record (EHR) databases with an active comparator design that examined metformin-exposed individuals versus nonmetformin-exposed individuals who were taking other diabetes medications. T2DM was defined by HbA1C ≥6.5 or T2DM EHR diagnosis code. The outcome was death or PASC within 6 months, defined by EHR code or computable phenotype. RESULTS: In the N3C, the hazard ratio (HR) for death or PASC with a U09.9 diagnosis code (PASC-U09.0) was 0.79 (95% CI 0.71-0.88; P < 0.001), and for death or N3C computable phenotype PASC (PASC-N3C) was 0.85 (95% CI 0.78-0.92; P < 0.001). In PCORnet, the HR for death or PASC-U09.9 was 0.87 (95% CI 0.66-1.14; P = 0.08), and for death or PCORnet computable phenotype PASC (PASC-PCORnet) was 1.04 (95% CI 0.97-1.11; P = 0.58). Incident PASC by diagnosis code was 1.6% metformin vs. 2.0% comparator in the N3C, and 2.1% metformin vs. 2.5% comparator in PCORnet. By computable phenotype, incidence was 4.8% metformin and 5.2% comparator in the N3C and 24.7% metformin vs. 26.1% comparator in PCORnet. CONCLUSIONS: Prevalent metformin use is associated with a slightly lower incidence of death or PASC after SARS-CoV-2 infection. PASC incidence by computable phenotype is higher than by EHR code, especially in PCORnet. These data are consistent with other observational analyses showing prevalent metformin is associated with favorable outcomes after SARS-CoV-2 infection in adults with T2DM.

Pediatric Gastrointestinal Outcomes During the Post-Acute Phase of COVID-19: Findings from RECOVER Initiative from 29 Hospitals in the US.

Importance: The profile of gastrointestinal (GI) outcomes that may affect children in post-acute and chronic phases of COVID-19 remains unclear. Objective: To investigate the risks of GI symptoms and disorders during the post-acute phase (28 days to 179 days after SARS-CoV-2 infection) and the chronic phase (180 days to 729 days after SARS-CoV-2 infection) in the pediatric population. Design: We used a retrospective cohort design from March 2020 to Sept 2023. Setting: twenty-nine healthcare institutions. Participants: A total of 413,455 patients aged not above 18 with SARS-CoV-2 infection and 1,163,478 patients without SARS-CoV-2 infection. Exposures: Documented SARS-CoV-2 infection, including positive polymerase chain reaction (PCR), serology, or antigen tests for SARS-CoV-2, or diagnoses of COVID-19 and COVID-related conditions. Main Outcomes and Measures: Prespecified GI symptoms and disorders during two intervals: post-acute phase and chronic phase following the documented SARS-CoV-2 infection. The adjusted risk ratio (aRR) was determined using a stratified Poisson regression model, with strata computed based on the propensity score. Results: Our cohort comprised 1,576,933 patients, with females representing 48.0% of the sample. The analysis revealed that children with SARS-CoV-2 infection had an increased risk of developing at least one GI symptom or disorder in both the post-acute (8.64% vs. 6.85%; aRR 1.25, 95% CI 1.24-1.27) and chronic phases (12.60% vs. 9.47%; aRR 1.28, 95% CI 1.26-1.30) compared to uninfected peers. Specifically, the risk of abdominal pain was higher in COVID-19 positive patients during the post-acute phase (2.54% vs. 2.06%; aRR 1.14, 95% CI 1.11-1.17) and chronic phase (4.57% vs. 3.40%; aRR 1.24, 95% CI 1.22-1.27). Conclusions and Relevance: In the post-acute phase or chronic phase of COVID-19, the risk of GI symptoms and disorders was increased for COVID-positive patients in the pediatric population.

Long COVID incidence in adults and children between 2020 and 2023: a real-world data study from the RECOVER Initiative.

Estimates of post-acute sequelae of SARS-CoV-2 infection (PASC) incidence, also known as Long COVID, have varied across studies and changed over time. We estimated PASC incidence among adult and pediatric populations in three nationwide research networks of electronic health records (EHR) participating in the RECOVER Initiative using different classification algorithms (computable phenotypes). Overall, 7% of children and 8.5%-26.4% of adults developed PASC, depending on computable phenotype used. Excess incidence among SARS-CoV-2 patients was 4% in children and ranged from 4-7% among adults, representing a lower-bound incidence estimation based on two control groups - contemporary COVID-19 negative and historical patients (2019). Temporal patterns were consistent across networks, with peaks associated with introduction of new viral variants. Our findings indicate that preventing and mitigating Long COVID remains a public health priority. Examining temporal patterns and risk factors of PASC incidence informs our understanding of etiology and can improve prevention and management.

Post-acute and Chronic Kidney Function Outcomes of COVID-19 in Children and Adolescents: An EHR Cohort Study from the RECOVER Initiative.

We investigated the risks of post-acute and chronic adverse kidney outcomes of SARS-CoV-2 infection in the pediatric population via a retrospective cohort study using data from the RECOVER program. We included 1,864,637 children and adolescents under 21 from 19 children's hospitals and health institutions in the US with at least six months of follow-up time between March 2020 and May 2023. We divided the patients into three strata: patients with pre-existing chronic kidney disease (CKD), patients with acute kidney injury (AKI) during the acute phase (within 28 days) of SARS-CoV-2 infection, and patients without pre-existing CKD or AKI. We defined a set of adverse kidney outcomes for each stratum and examined the outcomes within the post-acute and chronic phases after SARS-CoV-2 infection. In each stratum, compared with the non-infected group, patients with COVID-19 had a higher risk of adverse kidney outcomes. For patients without pre-existing CKD, there were increased risks of CKD stage 2+ (HR 1.20; 95% CI: 1.13-1.28) and CKD stage 3+ (HR 1.35; 95% CI: 1.15-1.59) during the post-acute phase (28 days to 365 days) after SARS-CoV-2 infection. Within the post-acute phase of SARS-CoV-2 infection, children and adolescents with pre-existing CKD and those who experienced AKI were at increased risk of progression to a composite outcome defined by at least 50% decline in estimated glomerular filtration rate (eGFR), eGFR <15 mL/min/1.73m2, End Stage Kidney Disease diagnosis, dialysis, or transplant.