Factors Associated with Post-Acute Sequelae of SARS-CoV-2 (PASC) After Diagnosis of Symptomatic COVID-19 in the Inpatient and Outpatient Setting in a Diverse Cohort.

BACKGROUND: The incidence of persistent clinical symptoms and risk factors in Post-Acute Sequelae of SARS-CoV-2 (PASC) in diverse US cohorts is unclear. While there are a disproportionate share of COVID-19 deaths in older patients, ethnic minorities, and socially disadvantaged populations in the USA, little information is available on the association of these factors and PASC. OBJECTIVE: To evaluate the association of demographic and clinical characteristics with development of PASC. DESIGN: Prospective observational cohort of hospitalized and high-risk outpatients, April 2020 to February 2021. PARTICIPANTS: One thousand thirty-eight adults with laboratory-confirmed symptomatic COVID-19 infection. MAIN MEASURES: Development of PASC determined by patient report of persistent symptoms on questionnaires conducted 60 or 90 days after COVID-19 infection or hospital discharge. Demographic and clinical factors associated with PASC. KEY RESULTS: Of 1,038 patients with longitudinal follow-up, 309 patients (29.8%) developed PASC. The most common persistent symptom was fatigue (31.4%) followed by shortness of breath (15.4%) in hospitalized patients and anosmia (15.9%) in outpatients. Hospitalization for COVID-19 (odds ratio [OR] 1.49, 95% [CI] 1.04-2.14), having diabetes (OR, 1.39; 95% CI 1.02-1.88), and higher BMI (OR, 1.02; 95% CI 1-1.04) were independently associated with PASC. Medicaid compared to commercial insurance (OR, 0.49; 95% CI 0.31-0.77) and having had an organ transplant (OR 0.44, 95% CI, 0.26-0.76) were inversely associated with PASC. Age, race/ethnicity, Social Vulnerability Index, and baseline functional status were not associated with developing PASC. CONCLUSIONS: Three in ten survivors with COVID-19 developed a subset of symptoms associated with PASC in our cohort. While ethnic minorities, older age, and social disadvantage are associated with worse acute COVID-19 infection and greater risk of death, our study found no association between these factors and PASC.

Coexisting Systemic Infections in Patients Hospitalized Because of a Fall: Prevalence and Risk Factors.

BACKGROUND: Infectious disease-related factors that may contribute to or complicate falls have received relatively little attention in the literature. OBJECTIVE: Our aim was to determine the prevalence of, and risk factors for, coexisting systemic infections (CSIs) in patients admitted to the hospital because of a fall or its complications. METHODS: We conducted a retrospective cohort study of adult patients seen at a tertiary care hospital emergency department and subsequently hospitalized because of a fall or its complications. RESULTS: Of 1,456 evaluable cases, 775 patients (53.2%) were female. Mean age was 71.6 years (range 18-104 years). CSI was diagnosed in 303 patients (20.8%), of which 166 (54.8%) were urinary tract infections and 108 (35.6%) were pneumonia cases; 14 patients (4.6%) were bacteremic. CSI was not initially suspected by providers in 98 (32.5%) subsequently diagnosed cases. Age ≥50 years (odds ratio [OR] 5.6; 95% confidence interval [CI] 1.2-24.9), inability to get up on own after the index fall (OR 2.1; 95% CI 1.2-3.6), preexisting symptom(s) (OR 3.0; 95% CI 1.8-5.2), and systemic inflammatory response syndrome (SIRS) (OR 2.9; 95% CI 1.5-5.4), or confusion at presentation (OR 3.0; 95% CI 1.5-6.0) were independently associated with CSI. In-hospital mortality rate was significantly higher among patients with CSI (6.9% vs. 3.8 %, OR 1.9; 95% CI 1.1-3.3). CONCLUSIONS: CSIs are common among patients admitted to the hospital after a fall or its complications. Age ≥ 50 years, inability to get up on own, preexisting symptom(s), and the presence of SIRS or confusion at presentation are potential predictors of CSI in this patient population.

Complete pathologic response of HER2-positive breast cancer liver metastasis with dual anti-HER2 antagonism.

BACKGROUND: Although breast cancer frequently metastasizes to the bones and brain, rarely breast cancer patients may develop isolated liver metastasis. There is increasing data that anti-HER2 targeted therapy in conjunction with systemic chemotherapy may lead to increased rates of pathologic complete response in the primary breast cancer. However, little is known about its effects on metastatic liver disease. CASE PRESENTATION: We report the treatment of a 54-year-old female who was diagnosed with HER2-positive invasive ductal carcinoma and synchronous breast cancer liver metastasis (BCLM). The patient underwent eight cycles of standard docetaxel with two anti-HER2 targeted agents, trastuzumab and pertuzumab. Subsequent radiographic imaging demonstrated complete radiographic response in the primary lesion with an approximate 75% decrease in the liver metastasis. After informed consent the patient underwent modified radical mastectomy that revealed pathologic complete response. Re-staging demonstrated no new disease outside the liver and a left hepatectomy was performed for resection of BCLM. Final pathologic examination revealed no residual malignant cells in the liver specimen, indicating pathologic complete response. Herein, we discuss the anti-HER2 targeted agents trastuzumab and pertuzumab and review the data on dual HER2 antagonism for HER2-positive breast cancer and the role of surgical resection of BCLM. CONCLUSIONS: The role of targeted agents for metastatic HER2-positive breast cancer is under active clinical trial investigation and we await the maturation of trial results and long-term survival data. Our results suggest that these agents may also be effective for producing considerable pathologic response in patients with BCLM.

A Practical and Analytical Comparative Study of Gel-Based Top-Down and Gel-Free Bottom-Up Proteomics Including Unbiased Proteoform Detection.

Proteomics is an indispensable analytical technique to study the dynamic functioning of biological systems via different proteins and their proteoforms. In recent years, bottom-up shotgun has become more popular than gel-based top-down proteomics. The current study examined the qualitative and quantitative performance of these two fundamentally different methodologies by the parallel measurement of six technical and three biological replicates of the human prostate carcinoma cell line DU145 using its two most common standard techniques, label-free shotgun and two-dimensional differential gel electrophoresis (2D-DIGE). The analytical strengths and limitations were explored, finally focusing on the unbiased detection of proteoforms, exemplified by discovering a prostate cancer-related cleavage product of pyruvate kinase M2. Label-free shotgun proteomics quickly yields an annotated proteome but with reduced robustness, as determined by three times higher technical variation compared to 2D-DIGE. At a glance, only 2D-DIGE top-down analysis provided valuable, direct stoichiometric qualitative and quantitative information from proteins to their proteoforms, even with unexpected post-translational modifications, such as proteolytic cleavage and phosphorylation. However, the 2D-DIGE technology required almost 20 times as much time per protein/proteoform characterization with more manual work. Ultimately, this work should expose both techniques' orthogonality with their different contents of data output to elucidate biological questions.

Writing to learn on the wards: scholarly blog posts by medical students and housestaff at a teaching hospital.

BACKGROUND: Informative writing is a valuable tool for learning and fostering the scientific process. Pearls4Peers (P4P) is an educational open-access website dedicated to scholarly blog posts in hospital medicine based on questions raised during ward teaching rounds. A goal of P4P is to enhance the learning experience of medical students and housestaff (i.e., interns and upper-level residents) by inviting them to write blog posts for a worldwide audience. OBJECTIVE: To describe our experience with inviting medical students and housestaff to contribute blog posts to a clinically oriented educational website with the aim of promoting concise evidence-based informative medical writing. DESIGN: Medical students and housestaff assigned to the hospital ward team of an attending physician (FM) on the medical service were routinely invited to submit one or more posts or 'pearls' based on clinical questions raised during patient rounds. Selected features of submissions during the first 2 years of P4P (27 June 2015 through 26 June 2017) were then retrospectively reviewed and analyzed. RESULTS: Of 156 pearls posted during the study period, 25 (16%) were contributed by medical students and 16 (10.3%) by housestaff. Medical students were significantly more likely to contribute than housestaff (19[70.4%] vs. 11 (9.6%], p < 0.01). Superfluous information was noted in 12 (29.3%) submissions. Word count exceeded the suggested limit of 200 words in 12 (29.3%) cases. An inverted pyramid structure, a widely recognized web writing format with the most important information presented at the outset, was noted in only 17 (41.5%) of entries. Unsolicited comments by contributors suggested a positive learning experience in writing the posts. CONCLUSIONS: Writing clinically oriented concise blog posts appears feasible and may be an effective tool in enhancing the ward-based learning experience of medical students and housestaff. More formal instructions on the proper content and structure of blog posts seem warranted.

iRGD-guided Tumor-penetrating Nanocomplexes for Therapeutic siRNA Delivery to Pancreatic Cancer.

Pancreatic cancer is one of the leading causes of cancer-related death, with 5-year survival of 8.5%. The lack of significant progress in improving therapy reflects our inability to overcome the desmoplastic stromal barrier in pancreatic ductal adenocarcinoma (PDAC) as well as a paucity of new approaches targeting its genetic underpinnings. RNA interference holds promise in targeting key mutations driving PDAC; however, a nucleic acid delivery vehicle that homes to PDAC and breaches the stroma does not yet exist. Noting that the cyclic peptide iRGD mediates tumor targeting and penetration through interactions with αvß3/5 integrins and neuropilin-1, we hypothesized that "tandem" peptides combining a cell-penetrating peptide and iRGD can encapsulate siRNA to form tumor-penetrating nanocomplexes (TPN) capable of delivering siRNA to PDAC. The use of directly conjugated iRGD is justified by receptor expression patterns in human PDAC biopsies. In this work, we optimize iRGD TPNs with polyethylene glycol (PEG)-peptide conjugates for systemic delivery to sites of disease. We show that TPNs effectively knockdown siRNA targets in PDAC cell lines and in an immunocompetent genetically engineered mouse model of PDAC. Furthermore, we validate their tumor-penetrating ability in three-dimensional organoids and autochthonous tumors. In murine therapeutic trials, TPNs delivering anti-Kras siRNA significantly delay tumor growth. Thus, iRGD TPNs hold promise in treating PDAC by not only overcoming physical barriers to therapy, but by leveraging the stroma to achieve knockdown of the gold-standard genetic target. Moreover, the modular construction of this delivery platform allows for facile adaptation to future genetic target candidates in pancreatic cancer. Mol Cancer Ther; 17(11); 2377-88. ©2018 AACR.