Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Factors associated with intraoperative conversion during robotic sacrocolpopexy

Objective To evaluate for potential predictors of intraoperative conversion from robotic sacrocolpopexy (RSC) to open abdominal sacrocolpopexy. Patients and Methods We identified 83 consecutive patients from 2002-2012 with symptomatic high-grade post-hysterectomy vaginal vault prolapse that underwent RSC. Multiple clinical variables including patient age, comorbidities (body-mass index [BMI], hypertension, diabetes mellitus, tobacco use), prior intra-abdominal surgery and year of surgery were evaluated for potential association with conversion. Results Overall, 14/83 cases (17%) required conversion to an open sacrocolpopexy. Patients requiring conversion were found to have a significantly higher BMI compared to those who did not (median 30.2kg/m2 versus 25.8kg/m2; p=0.003). Other medical and surgical factors evaluated were similar between the cohorts. When stratified by increasing BMI, conversion remained associated with an increased BMI. That is, conversion occurred in 3.8% (1/26) of patients with BMI &#8804;25 kg/m2, 14.7% (5/34) with BMI 25-29.9 kg/m2 and 34.7% (8/23) with BMI &#8805;30 kg/m2 (p=0.004). When evaluated as a continuous variable, BMI was also associated with a significantly increased risk of conversion to an open procedure (OR 1.18, p=0.004). Conclusions Higher BMI was the only clinical factor associated with a significantly increased risk of intra-operative conversion during robotic sacrocolpopexy. Recognition of this may aid in pre-operative counseling and surgical patient selection

Risk Factors for Postoperative Fever and Systemic Inflammatory Response Syndrome after Ureteroscopy for Stone Disease

Introduction: Infectious complications after ureteroscopy (URS) for stone disease lead to emergency department visits, hospitalizations, and other costly health care utilization. The objective of our study was to identify risk factors for postoperative fever (POF) and systemic inflammatory response syndrome (SIRS) after URS for stone disease. Materials and Methods: We performed a retrospective cohort study on 2746 patients who underwent 3298 URS for stone disease at Geisinger from 2008 to 2016. A univariate analysis tested the associations between candidate demographic, preoperative, and intraoperative predictors and the primary outcome of POF (temperature \u3e100.4°F) or SIRS. Variables with a p-value of \u3c0.05 on univariate comparisons were entered into a random-effects logistic regression model. The final model used backward elimination random-effects logistic regression to identify predictors most predictive of POF/SIRS. Results: Overall, 229 (6.9%) of 3298 URS had POF/SIRS. On univariate analysis, individuals with POF/SIRS were older, had higher mean body mass index, higher Charlson Comorbidity Index (CCI), bilateral and larger stones, stone location in the kidney, positive preoperative urine culture, pre-stented, and longer surgical times. In the final model, female gender (adjusted odds ratio [OR] 1.6, 95% confidence interval [CI] 1.19-2.15), surgical time (adjusted OR 1.01, 95% CI 1.0-1.01), CCI ≥2 (adjusted OR 1.86, 95% CI 1.29-2.67), and positive preoperative urine culture (adjusted OR 1.53, 95% CI 1.06-2.22) were the most significant predictors of POF/SIRS. Conclusions: Female gender, longer surgical time, medical complexity, and positive preoperative urine culture are associated with POF/SIRS after URS. These data may be used to identify and counsel high-risk individuals

Rate and risk factors for sacral nerve stimulator lead breakage at the time of lead revision or explantation

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