FDA-authorized mRNA COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system.

BACKGROUND: Two US Food and Drug Administration (FDA)-authorized coronavirus disease 2019 (COVID-19) mRNA vaccines, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna), have demonstrated high efficacy in large phase 3 randomized clinical trials. It is important to assess their effectiveness in a real-world setting. METHODS: This is a retrospective analysis of 136,532 individuals in the Mayo Clinic health system (Arizona, Florida, Iowa, Minnesota, and Wisconsin) with PCR testing data between December 1, 2020 and April 20, 2021. We compared clinical outcomes for a vaccinated cohort of 68,266 individuals who received at least one dose of either vaccine (nBNT162b2 = 51,795; nmRNA-1273 = 16,471) and an unvaccinated control cohort of 68,266 individuals propensity matched based on relevant demographic, clinical, and geographic features. We estimated real-world vaccine effectiveness by comparing incidence rates of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR testing and COVID-19-associated hospitalization and intensive care unit (ICU) admission starting 7 days after the second vaccine dose. FINDINGS: The real-world vaccine effectiveness of preventing SARS-CoV-2 infection was 86.1% (95% confidence interval [CI]: 82.4%-89.1%) for BNT162b2 and 93.3% (95% CI: 85.7%-97.4%) for mRNA-1273. BNT162b2 and mRNA-1273 were 88.8% (95% CI: 75.5%-95.7%) and 86.0% (95% CI: 71.6%-93.9%) effective in preventing COVID-19-associated hospitalization. Both vaccines were 100% effective (95% CIBNT162b2: 51.4%-100%; 95% CImRNA-1273: 43.3%-100%) in preventing COVID-19-associated ICU admission. CONCLUSIONS: BNT162b2 and mRNA-1273 are effective in a real-world setting and are associated with reduced rates of SARS-CoV-2 infection and decreased burden of COVID-19 on the healthcare system. FUNDING: This study was funded by nference.

Real-time analysis of a mass vaccination effort confirms the safety of FDA-authorized mRNA COVID-19 vaccines.

BACKGROUND: As the coronavirus disease 2019 (COVID-19) vaccination campaign unfolds, it is important to continuously assess the real-world safety of Food and Drug Administration (FDA)-authorized vaccines. Curation of large-scale electronic health records (EHRs) enables near-real-time safety evaluations that were not previously possible. METHODS: In this retrospective study, we deployed deep neural networks over a large EHR system to automatically curate the adverse effects mentioned by physicians in over 1.2 million clinical notes between December 1, 2020 and April 20, 2021. We compared notes from 68,266 individuals who received at least one dose of BNT162b2 (n = 51,795) or mRNA-1273 (n = 16,471) to notes from 68,266 unvaccinated individuals who were matched by demographic, geographic, and clinical features. FINDINGS: Individuals vaccinated with BNT162b2 or mRNA-1273 had a higher rate of return to the clinic, but not the emergency department, after both doses compared to unvaccinated controls. The most frequently documented adverse effects within 7 days of each vaccine dose included myalgia, headache, and fatigue, but the rates of EHR documentation for each side effect were remarkably low compared to those derived from active solicitation during clinical trials. Severe events, including anaphylaxis, facial paralysis, and cerebral venous sinus thrombosis, were rare and occurred at similar frequencies in vaccinated and unvaccinated individuals. CONCLUSIONS: This analysis of vaccine-related adverse effects from over 1.2 million EHR notes of more than 130,000 individuals reaffirms the safety and tolerability of the FDA-authorized mRNA COVID-19 vaccines in practice. FUNDING: This study was funded by nference.

Building a best-in-class automated de-identification tool for electronic health records through ensemble learning.

The presence of personally identifiable information (PII) in natural language portions of electronic health records (EHRs) constrains their broad reuse. Despite continuous improvements in automated detection of PII, residual identifiers require manual validation and correction. Here, we describe an automated de-identification system that employs an ensemble architecture, incorporating attention-based deep-learning models and rule-based methods, supported by heuristics for detecting PII in EHR data. Detected identifiers are then transformed into plausible, though fictional, surrogates to further obfuscate any leaked identifier. Our approach outperforms existing tools, with a recall of 0.992 and precision of 0.979 on the i2b2 2014 dataset and a recall of 0.994 and precision of 0.967 on a dataset of 10,000 notes from the Mayo Clinic. The de-identification system presented here enables the generation of de-identified patient data at the scale required for modern machine-learning applications to help accelerate medical discoveries.

Plasma IL-6 levels following corticosteroid therapy as an indicator of ICU length of stay in critically ill COVID-19 patients.

Intensive care unit (ICU) admissions and mortality in severe COVID-19 patients are driven by "cytokine storms" and acute respiratory distress syndrome (ARDS). Interim clinical trial results suggest that the corticosteroid dexamethasone displays better 28-day survival in severe COVID-19 patients requiring ventilation or oxygen. In this study, 10 out of 16 patients (62.5%) that had an average plasma IL-6 value over 10 pg/mL post administration of corticosteroids also had worse outcomes (i.e., ICU stay >15 days or death), compared to 8 out of 41 patients (19.5%) who did not receive corticosteroids (p-value = 0.0024). Given this potential association between post-corticosteroid IL-6 levels and COVID-19 severity, we hypothesized that the glucocorticoid receptor (GR or NR3C1) may be coupled to IL-6 expression in specific cell types that govern cytokine release syndrome (CRS). Examining single-cell RNA-seq data from BALF of severe COVID-19 patients and nearly 2 million cells from a pan-tissue scan shows that alveolar macrophages, smooth muscle cells, and endothelial cells co-express NR3C1 and IL-6, motivating future studies on the links between the regulation of NR3C1 function and IL-6 levels.

Exploratory analysis of immunization records highlights decreased SARS-CoV-2 rates in individuals with recent non-COVID-19 vaccinations.

Clinical studies are ongoing to assess whether existing vaccines may afford protection against SARS-CoV-2 infection through trained immunity. In this exploratory study, we analyze immunization records from 137,037 individuals who received SARS-CoV-2 PCR tests. We find that polio, Haemophilus influenzae type-B (HIB), measles-mumps-rubella (MMR), Varicella, pneumococcal conjugate (PCV13), Geriatric Flu, and hepatitis A/hepatitis B (HepA-HepB) vaccines administered in the past 1, 2, and 5 years are associated with decreased SARS-CoV-2 infection rates, even after adjusting for geographic SARS-CoV-2 incidence and testing rates, demographics, comorbidities, and number of other vaccinations. Furthermore, age, race/ethnicity, and blood group stratified analyses reveal significantly lower SARS-CoV-2 rate among black individuals who have taken the PCV13 vaccine, with relative risk of 0.45 at the 5 year time horizon (n: 653, 95% CI (0.32, 0.64), p-value: 6.9e-05). Overall, this study identifies existing approved vaccines which can be promising candidates for pre-clinical research and Randomized Clinical Trials towards combating COVID-19.

Long-term SARS-CoV-2 RNA shedding and its temporal association to IgG seropositivity.

Longitudinal characterization of SARS-CoV-2 PCR testing from COVID-19 patient's nasopharynx and its juxtaposition with blood-based IgG-seroconversion diagnostic assays is critical to understanding SARS-CoV-2 infection durations. Here, we retrospectively analyze 851 SARS-CoV-2-positive patients with at least two positive PCR tests and find that 99 of these patients remain SARS-CoV-2-positive after 4 weeks from their initial diagnosis date. For the 851-patient cohort, the mean lower bound of viral RNA shedding was 17.3 days (SD: 7.8), and the mean upper bound of viral RNA shedding from 668 patients transitioning to confirmed PCR-negative status was 22.7 days (SD: 11.8). Among 104 patients with an IgG test result, 90 patients were seropositive to date, with mean upper bound of time to seropositivity from initial diagnosis being 37.8 days (95% CI: 34.3-41.3). Our findings from juxtaposing IgG and PCR tests thus reveal that some SARS-CoV-2-positive patients are non-hospitalized and seropositive, yet actively shed viral RNA (14 of 90 patients). This study emphasizes the need for monitoring viral loads and neutralizing antibody titers in long-term non-hospitalized shedders as a means of characterizing the SARS-CoV-2 infection lifecycle.

Outcomes of loco-regional anaesthesia in ureteroscopy for stone disease: a systematic review.

PURPOSE OF REVIEW: Routine ureteroscopy (URS) for stone disease is performed under a general anaesthesia. However, controversy exists on the role of loco-regional anaesthesia and the outcomes associated with it. Here we review the challenges, outcomes and complications of loco-regional anaesthesia for URS. A Cochrane style review was performed in accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines to evaluate the outcomes of loco-reginal anaesthesia for URS in stone disease, including all English language articles from January 1980 and December 2019. RECENT FINDINGS: Twenty-one studies (1843 procedures) with a mean age of 46 years and a male : female ratio of 1.2 : 1 underwent URS under loco-regional anaesthesia. The mean stone size was 9 mm (range:4-21 mm) and except five papers, all other papers included stones in the ureter of which the majority were in the distal ureter. The conversion to general anaesthesia was needed in 2.7% patients (range 1-21%) across studies, with a stone free rate of 48-100%. The complication rate varied from 1.4 to 36%. Although the intraoperative complications included ureteric injury (n = 21) or perforation (n = 4), the postoperative complications included fever (n = 37), urinary tract infection (n = 20), haematuria (n = 4), urosepsis (n = 4) and others (n = 7). SUMMARY: The present systematic review shows that local anaesthetic URS is a potential alternative to general anaesthetic URS in carefully selected patients. Randomised controlled trials with subgroup analysis are required to further assess whether loco-regional anaesthesia URS is noninferior to general anaesthesia URS and might help determine if the former approach should become more widespread.

Long-term SARS-CoV-2 RNA Shedding and its Temporal Association to IgG Seropositivity.

Analysis of 851 COVID-19 patients with a SARS-CoV-2-positive PCR at follow-up shows 99 patients remained SARS-CoV-2-positive after four weeks from initial diagnosis. Surprisingly, a majority of these long-term viral RNA shedders were not hospitalized (61 of 99), with variable PCR Crossing point values over the month post diagnosis. For the 851-patient cohort, the mean lower bound of viral RNA shedding was 17.3 days (SD: 7.8), and the mean upper bound of viral RNA shedding from 668 patients transitioning to confirmed PCR-negative status was 22.7 days (SD: 11.8). Among 104 patients with an IgG test result, 90 patients were seropositive to date, with mean upper bound of time to seropositivity from initial diagnosis being 37.8 days (95%CI: 34.3-41.3). Juxtaposing IgG/PCR tests revealed that 14 of 90 patients are non-hospitalized and seropositive yet shed viral RNA. This study emphasizes the need for monitoring viral loads and neutralizing antibody titers in long-term shedders.

Donor and post-transplant ureteroscopy for stone disease in patients with renal transplant: evidence from a systematic review.

PURPOSE OF REVIEW: Renal transplant is needed for end-stage renal disease. Although treatment of donor stones may be needed pretransplant and increases the pool available for renal transplant, posttransplant stone disease may also need treatment to maintain the allograft function. A Cochrane style review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to evaluate the outcomes of donor and posttransplant ureteroscopy (URS) for stone disease, including all English language articles between January 1996 and December 2018. RECENT FINDINGS: Eighteen articles (167 patients), seven ex-vivo or donor URS and 11 posttransplant URS met inclusion criteria and were included in the review. A pretransplant URS showed a stone-free rate (SFR) of 100% with an overall complication rate of 7.5% (four Clavien I and one Clavien ≥3), where as a posttransplant URS showed SFR of 100% in five studies and 60-91% in four studies with an overall complication rate of 12.9% (10 Clavien I and three Clavien ≥3). SUMMARY: Advancements in endourological technique has made URS for donor and posttransplant urolithiasis a safe and effective procedure. Although data were based on small retrospective caser series, it shows that in experienced centres it can be performed with low morbidity and a high SFR.

Finite element simulation of Reference Point Indentation on bone.

Reference Point Indentation (RPI) is a novel technique aimed to assess bone quality. Measurements are recorded by the BioDent instrument that applies multiple indents to the same location of cortical bone. Ten RPI parameters are obtained from the resulting force-displacement curves. Using the commercial finite element analysis software Abaqus, we assess the significance of the RPI parameters. We create an axisymmetric model and employ an isotropic viscoelastic-plastic constitutive relation with damage to simulate indentations on a human cortical bone. Fracture of bone tissue is not simulated for simplicity. The RPI outputs are computed for different simulated test cases and then compared with experimental results, measured using the BioDent, found in literature. The number of cycles, maximum indentation load, indenter tip radius, and the mechanical properties of bone: Young׳s modulus, compressive yield stress, and viscosity and damage constants, are varied. The trends in the RPI parameters are then investigated. We find that the RPI parameters are sensitive to the mechanical properties of bone. An increase in Young׳s modulus of bone causes the force-displacement loading and unloading slopes to increase and the total indentation distance (TID) to decrease. The compressive yield stress is inversely proportional to a creep indentation distance (CID1) and the TID. The viscosity constant is proportional to the CID1 and an average of the energy dissipated (AvED). The maximum indentation load is proportional to the TID, CID1, loading and unloading slopes, and AvED. The damage parameter is proportional to the TID, but it is inversely proportional to both the loading and unloading slopes and the AvED. The value of an indenter tip radius is proportional to the CID1 and inversely proportional to the TID. The number of load cycles is inversely proportional to an average of a creep indentation depth (AvCID) and the AvED. The indentation distance increase (IDI) is strongly inversely proportional to the compressive yield stress, and strongly proportional to the viscosity constant and maximum applied load, but has weak relation with the damage parameter, indenter tip radius, and elastic modulus. This computational study advances our understanding of the RPI outputs and provides a starting point for more comprehensive computational studies of the RPI technique.

Recurrent migratory sympathetically maintained pain syndrome in a child: a case report.

A 10-year-old boy presented with pain and swelling of short duration in his right hand. A traumatic cause was ruled out. He had clinical features suggestive of sympathetic overactivity in the form of hyperesthesia, edema and dry skin. The results of a few baseline investigations performed at this stage were all within normal limits. A provisional diagnosis of sympathetically maintained pain syndrome (SMPS) was made. He responded dramatically to a stellate ganglion block. His symptoms recurred within 3 weeks, though now in the lower limb. Again the clinical features were consistent with SMPS. His response to a lumbar sympathetic block was again dramatic. This case illustrates that the diagnosis of SMPS is essentially clinical and that prompt diagnosis and treatment with sympathetic blocks can be very rewarding.

Non-union in osteogenesis imperfecta.

A retrospective study of 44 patients with osteogenesis imperfecta treated over a 14-year period was undertaken to determine the frequency and pattern of non-unions of long bones in these patients. Nine non-unions were encountered in eight patients. Four of these non-unions developed at sites of osteotomies performed at the time of intramedullary rodding. These children have remained asymptomatic, however, without appreciable limitations in spite of the non-union. Five atrophic or gap non-unions that occurred in the humerus were following inadequately treated fractures. These children were disabled on account of the non-unions. In three patients all attempts at obtaining union failed. The other two patients were braced. We conclude that non-union in osteogenesis imperfecta is not a very rare phenomenon. We also recommend that all fractures in children with osteogenesis imperfecta must be treated with appropriate immobilization to prevent a gap non-union developing, since gap non-unions are exceedingly difficult to treat.