Patients avoided important care during the early weeks of the coronavirus pandemic: diverticulitis patients were more likely to present with an abscess on CT

PURPOSE: To evaluate the frequency with which patients with an urgent health concern, specifically diverticulitis, avoided appropriate medical care during the early weeks of the coronavirus pandemic of 2020 and to study the consequences of the resultant delay in care, the incidence of an associated abscess. METHODS: This study was institutional review board approved. Reports for CT studies with findings of newly diagnosed diverticulitis within Henry Ford Health System during the early weeks of the coronavirus pandemic of 2020 were reviewed and compared with the same time period in 2019. Total cases of diverticulitis on CT were compared, as well as the prevalence of an associated abscess. A chi-squared analysis was performed to determine the statistical significance of the percentage of patients presenting with an abscess in each year. RESULTS: During the early weeks of the coronavirus pandemic, 120 patients were identified with CT findings of newly diagnosed diverticulitis with 11.7% of those patients (14 patients) presenting with an associated abscess. During the same time period in 2019, many more CT studies with newly diagnosed diverticulitis were obtained (339), and, compared to 2020, less than half the percentage of those patients had an associated abscess (4.4% or 15 patients). CONCLUSION: Patients with urgent health concerns avoided appropriate and necessary care during the early weeks of the coronavirus pandemic. While non-COVID-19 emergency visits were diminished, patients who did present with diverticulitis were more likely to present with greater disease severity as manifested by an associated abscess. Patients must be encouraged to seek care when appropriate and need reassurance that hospitals and their emergency departments are safe to visit. Furthermore, emergency physicians and radiologists in particular should be vigilant during times when emergency volumes are low, such as a future surge in coronavirus patients, other pandemics, snow storms, and holidays as the patients who do present for care are more likely to present at later stages and with serious complications

Modeling Conformational Ensembles of Slow Functional Motions in Pin1-WW

Protein-protein interactions are often mediated by flexible loops that experience conformational dynamics on the microsecond to millisecond time scales. NMR relaxation studies can map these dynamics. However, defining the network of inter-converting conformers that underlie the relaxation data remains generally challenging. Here, we combine NMR relaxation experiments with simulation to visualize networks of inter-converting conformers. We demonstrate our approach with the apo Pin1-WW domain, for which NMR has revealed conformational dynamics of a flexible loop in the millisecond range. We sample and cluster the free energy landscape using Markov State Models (MSM) with major and minor exchange states with high correlation with the NMR relaxation data and low NOE violations. These MSM are hierarchical ensembles of slowly interconverting, metastable macrostates and rapidly interconverting microstates. We found a low population state that consists primarily of holo-like conformations and is a “hub” visited by most pathways between macrostates. These results suggest that conformational equilibria between holo-like and alternative conformers pre-exist in the intrinsic dynamics of apo Pin1-WW. Analysis using MutInf, a mutual information method for quantifying correlated motions, reveals that WW dynamics not only play a role in substrate recognition, but also may help couple the substrate binding site on the WW domain to the one on the catalytic domain. Our work represents an important step towards building networks of inter-converting conformational states and is generally applicable

Negative Regulation of Peptidyl-Prolyl Isomerase Activity by Interdomain Contact in Human Pin1

SummaryPin1 is a modular peptidyl-prolyl isomerase specific for phosphorylated Ser/Thr-Pro (pS/T-P) motifs, typically within intrinsically disordered regions of signaling proteins. Pin1 consists of two flexibly linked domains: an N-terminal WW domain for substrate binding and a larger C-terminal peptidyl-prolyl isomerase (PPIase) domain. Previous studies showed that binding of phosphopeptide substrates to Pin1 could alter Pin1 interdomain contact, strengthening or weakening it depending on the substrate sequence. Thus, substrate-induced changes in interdomain contact may act as a trigger within the Pin1 mechanism. Here, we investigate this possibility via nuclear magnetic resonance studies of several Pin1 mutants. Our findings provide new mechanistic insights for those substrates that reduce interdomain contact. Specifically, the reduced interdomain contact can allosterically enhance PPIase activity relative to that when the contact is sustained. These findings suggest Pin1 interdomain contact can negatively regulate its activity