Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or “long COVID”), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies. The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19. We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies. Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID. U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411 .

Background: Primary care visits can serve many purposes and potentially influence health behaviors. Although previous studies suggest that increasing primary care provider numbers may be beneficial, the mechanism responsible for the association is unclear, and have not linked primary care access to specific preventative interventions. We investigated the association between the number of times patients accessed their primary care provider team and the likelihood they received selected preventative health interventions. Methods: Patients with complete data sets from Sanford Health were categorized based on the number of primary care visits they received in a specified time period and the preventative health interventions they received. Patient characteristics were used in a propensity analysis to control for variables. Relative risks and 95% confidence intervals were calculated to estimate the likelihood of obtaining preventative measures based on number of primary care visits compared with patients who had no primary care visits during the specified time period. Results: The likelihood of a patient receiving three specified preventative interventions was increased by 127% for vaccination, 122% for colonoscopy, and 75% for mammography if the patient had ≥ 1 primary care visit per year. More primary care visits correlated with increasing frequency of vaccinations, but increased primary care visits beyond one did not correlate with increasing frequency of mammography or colonoscopy. Conclusions: One or more primary care visits per year is associated with increased likelihood of specific evidence-based preventative care interventions that improve longitudinal health outcomes and decrease healthcare costs. Increasing efforts to track and increase the number of primary care visits by clinics and health systems may improve patient compliance with select preventative measures.

Background/Aims: Human enterocytic differentiation is altered during development, fasting, adaptation, and bariatric surgery, but its intracellular control remains unclear. We hypothesized that Schlafen 12 (SLFN12) regulates enterocyte differentiation. Methods: We used laser capture dissection of epithelium, qRT-PCR, and immunohistochemistry to evaluate SLFN12 expression in biopsies of control and fasting human duodenal mucosa, and viral overexpression and siRNA to trace the SLFN12 pathway in human Caco-2 and HIEC6 intestinal epithelial cells. Results: Fasting human duodenal mucosa expressed less SLFN12 mRNA and protein, accompanied by decreases in enterocytic markers like sucrase-isomaltase. SLFN12 overexpression increased Caco-2 sucrase-isomaltase promoter activity, mRNA, and protein independently of proliferation, and activated the SLFN12 putative promoter. SLFN12 coprecipitated Serpin B12 (SERPB12). An inactivating SLFN12 point mutation prevented both SERPB12 binding and sucrase-isomaltase induction. SERPB12 overexpression also induced sucrase-isomaltase, while reducing SERPB12 prevented the SLFN12 effect on sucrase-isomaltase. Sucrase-isomaltase induction by both SLFN12 and SERPB12 was attenuated by reducing UCHL5 or USP14, and blocked by reducing both. SERPB12 stimulated USP14 but not UCHL5 activity. SERPB12 coprecipitated USP14 but not UCHL5. Moreover, SLFN12 increased protein levels of the sucrase-isomaltase-promoter-binding transcription factor cdx2 without altering Cdx2 mRNA. This was prevented by reducing UCHL5 and USP14. We further validated this pathway in vitro and in vivo. SLFN12 or SERPB12 overexpression induced sucrase-isomaltase in human non-malignant HIEC-6 enterocytes. Conclusions: SLFN12 regulates human enterocytic differentiation by a pathway involving SERPB12, the deubiquitylases, and Cdx2. This pathway may be targeted to manipulate human enterocytic differentiation in mucosal atrophy, short gut or obesity.

Importance Studies have compared surgical with nonsurgical therapy for acute uncomplicated appendicitis, but none of these studies have a patient-centered perspective. Objectives To evaluate how patients might choose between surgical and nonsurgical therapy for acute uncomplicated appendicitis and to identify targets to make antibiotic treatment more appealing. Design, Setting, and Participants This study comprised an online survey and an in-person sensitivity analysis survey. For the web survey, a convenience sample of 1728 respondents were asked to imagine that they or their child had acute uncomplicated appendicitis, provided information about laparoscopic and open appendectomy and antibiotic treatment alone, and asked which treatment they might choose. The web survey was open from April 17, 2016, through June 16, 2016, and was disseminated via email link, a poster with a Quick Response code, and social media. For the sensitivity analysis, 220 respondents were given the same scenario and options. Those who chose surgery were asked whether certain factors influenced their decision; each factor was incrementally improved during questioning about whether respondents would consider switching to antibiotics. These participants were recruited at public venues from June 3, 2016, to July 31, 2016. Web survey data were analyzed from June 17, 2016, to September 21, 2017. Sensitivity analysis data were analyzed from August 1, 2016, to September 21, 2017. Main Outcomes and Measures Treatment preferences. Results Among the 1728 web survey respondents, 1225 (70.9%) were female and 500 (28.9%) were male (3 [0.2%] either did not answer or responded as “gender fluid” within the comments section of the survey), and most self-reported being between 50 and 59 years of age (391 [22.6%]) and being non-Hispanic white (1563 [90.5%]). For themselves, 1482 respondents (85.8%) chose laparoscopic appendectomy, 84 (4.9%) chose open appendectomy, and 162 (9.4%) chose antibiotics alone. For their child, 1372 respondents (79.4%) chose laparoscopic appendectomy, 106 (6.1%) open appendectomy, and 250 (14.5%) antibiotics alone. Respondents were somewhat more likely to choose antibiotics for themselves if they had education beyond college (105 [12.6%];P < .001), identified as other than non-Hispanic white (24 [14.9%];P < .001), or did not know anyone who had previously been hospitalized (12 [15.8%];P = .02), but they were less likely to choose antibiotics if they were surgeons (11 [5.4%];P = .008). Of the 220 participants interviewed for the sensitivity analysis, 120 (54.5%) were female and 100 (45.5%) were male, and most self-reported being between 18 and 24 years of age (53 [24.1%]) and being non-Hispanic white (204 [92.7%]). Their responses suggested that improvements in the short- and long-term failure rate of antibiotic treatment—rather than reductions in the duration of hospitalization or antibiotic treatment—were more likely to increase the desirability of choosing antibiotics. Conclusions and Relevance Most patients may choose surgical intervention over antibiotics alone in treatment of acute uncomplicated appendicitis, but a meaningful number may choose nonoperative management. Therefore, from a patient-centered perspective, this option should be discussed with patients, and future research could be directed at reducing the failure and recurrence rates of antibiotic treatment for appendicitis.

Self-renewal and differentiation are essential for intestinal epithelium absorptive functioning and adaptation to pathological states such as short gut syndrome, ulcers, and inflammatory bowel disease. The rodent Slfn3 and its human analog Slfn12 are critical in regulating intestinal epithelial differentiation. We sought to characterize intestinal function in Slfn3 knockout (KO) mice. Male and female pair-fed Slfn3KO mice gained less weight with decreased food efficiency than wild type (WT) mice, with more pronounced effects in females. RNA sequencing performed on intestinal mucosa of Slfn3KO and WT mice showed gene ontology decreases in cell adhesion molecule signaling, tumor necrosis factor receptor binding, and adaptive immune cell proliferation/functioning genes in Slfn3KO mice, with greater effects in females. qPCR analysis of fatty acid metabolism genes, Pla2g4c, Pla2g2f, and Cyp3c55 revealed an increase in Pla2g4c, and a decrease in Pla2g2f in Slfn3KO females. Additionally, adipogenesis genes, Fabp4 and Lpl were decreased and ketogenesis gene Hmgcs2 was increased in female Slfn3KO mice. Sequencing did not reveal significant changes in differentiation markers, so qPCR was utilized. Slfn3KO tended to have decreased expression of intestinal differentiation markers sucrase isomaltase, dipeptidyl peptidase 4, villin 1, and glucose transporter 1 (Glut1) vs. WT males, although these trends did not achieve statistical significance unless data from several markers was pooled. Differentiation markers, Glut2 and sodium-glucose transporter 1 (SGLT1), did show statistically significant sex-dependent differences. Glut2 mRNA was reduced in Slfn3KO females, while SGLT1 increased in Slfn3KO males. Notch2 and Cdx2 were only increased in female Slfn3KO mice. Although Slfn3KO mice gain less weight and decreased food efficiency, their biochemical phenotype is more subtle and suggests a complex interplay between gender effects, Slfn3, and another regulatory pathway yet to be identified that compensates for the chronic loss of Slfn3.

Gut homeostasis, injury, and healing: New therapeutic targets