Predicting Early and Late Readmissions Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Postoperative readmissions not only burden the healthcare system but may also affect clinical outcomes of cancer patients. Despite this, little is known about readmissions after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), or their impact on survival outcomes. PATIENTS AND METHODS: A single-institution retrospective cohort study of CRS-HIPEC procedures from April 2001 and September 2019 was performed. Early readmission (ERA) was defined as hospitalization within 30 days of discharge post-CRS/HIPEC, while late readmission (LRA) was defined as hospitalization between day 31 and 90 after discharge. Patient demographic, oncological, and perioperative factors were analyzed to identify predictors of readmission, and comparison of survival outcomes was performed. RESULTS: Overall, 342 patients who underwent CRS-HIPEC were included in the study. The incidence of ERA and LRA was 18.5% and 7.4%, respectively. High-grade postoperative complication was the only independent predictor of ERA (HR 3.64, 95% CI 1.47-9.02), while comorbid hypertension (HR 2.71, 95% CI 1.17-6.28) and stoma creation (HR 2.83, 95% CI 1.23-6.50) were independent predictors for LRA. Patients with readmission had significantly worse disease-free survival than patients who had no readmission (NRA) (LRA 1.1 years, ERA 1.2 years, NRA 1.8 years, p = 0.002), and patients with LRA had worse median overall survival (2.1 years) than ERA patients (3.3 years) or patients without readmission (4.4 years) (p < 0.001). CONCLUSIONS: Readmission following CRS-HIPEC is associated with adverse survival outcomes. In particular, LRA may portend worse prognosis than ERA.

The Use of Wireless, Smartphone App-Assisted Home Blood Pressure Monitoring Among Hypertensive Patients in Singapore: Pilot Randomized Controlled Trial.

BACKGROUND: Reliable home blood pressure monitoring (HBPM) is essential to effective hypertension management; however, manual recording is subject to underreporting and inaccuracies. Mobile health technologies hold great potential as HBPM tools, but the fidelity of a smartphone app in HBPM has not been adequately assessed. OBJECTIVE: The primary aim of the trial was to compare the fidelity of a smartphone app to that of a handwritten logbook in making HBPM data available to clinicians at follow-up visits. Fidelity was defined as the percentage of scheduled blood pressure (BP) recordings over a 3-week period that were properly recorded and reported to the clinic. The secondary aims were to investigate patient factors associated with HBPM fidelity and to explore the effect of time on the fidelity. METHODS: A 2-arm, parallel, unblinded, randomized controlled pilot trial was conducted in a government polyclinic in Singapore. Hypertensive adults, aged 40 to 70 years, who were on antihypertensive medication and owned a smartphone were recruited and randomized by a computer-generated randomization schedule to 3 weeks of either semiautomated HBPM utilizing a Bluetooth-enabled BP monitor and a smartphone app or a fully manual process utilizing a conventional handwritten logbook. The primary outcome was home BP recording fidelity. RESULTS: Of the 80 patients randomized, 79 (smartphone app: 38 and logbook: 41) were included in the final analysis. Although fidelity was higher among the app users, it did not differ significantly between study arms (smartphone app: 66.7% and logbook: 52.4%; P=.21). Chinese and Indian ethnicities were associated with higher fidelity (absolute percent and 95% CI) by 35.6% (4.27 to 66.9) and 45.0% (8.69 to 81.3), respectively, in comparison with other ethnicities (P=.03); longer smartphone ownership increased fidelity on an average of 10.5% (0.83 to 20.2) per year (P=.03); the number of apps on the smartphone decreased fidelity at a rate of -0.32% (-0.58 to -0.05) per app (P=.02); years of hypertension morbidity increased fidelity at a rate of 1.56% (0.03 to 3.09) per year (P=.046); and the number of people working in the household decreased fidelity at a rate of -8.18% (-16.3 to -0.08) per additional working person (P=.048). The fidelity of the app was significantly higher in the first week (64.4%) than the second (55.1%, P=.001) and third (58.2%, P=.03) weeks of monitoring. CONCLUSIONS: Amid the increasing integration of health technologies into clinical practice, our study demonstrates the feasibility of smartphone app-assisted HBPM in hypertensive adults of Singapore. Our pilot study found no statistically significant difference in mean BP recording fidelity between a smartphone app and conventional handwritten logbook. However, the small sample size precludes definitive conclusions and highlights the need for a larger, adequately powered trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03209024; https://clinicaltrials.gov/ct2/show/NCT03209024 (Archived by WebCite at http://www.webcitation.org/78EVWBg0T).

Mutations of PKA cyclic nucleotide-binding domains reveal novel aspects of cyclic nucleotide selectivity.

Cyclic AMP and cyclic GMP are ubiquitous second messengers that regulate the activity of effector proteins in all forms of life. The main effector proteins, the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) and the 3',5'-cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG), are preferentially activated by cAMP and cGMP, respectively. However, the molecular basis of this cyclic nucleotide selectivity is still not fully understood. Analysis of isolated cyclic nucleotide-binding (CNB) domains of PKA regulatory subunit type Iα (RIα) reveals that the C-terminal CNB-B has a higher cAMP affinity and selectivity than the N-terminal CNB-A. Here, we show that introducing cGMP-specific residues using site-directed mutagenesis reduces the selectivity of CNB-B, while the combination of two mutations (G316R/A336T) results in a cGMP-selective binding domain. Furthermore, introducing the corresponding mutations (T192R/A212T) into the PKA RIα CNB-A turns this domain into a highly cGMP-selective domain, underlining the importance of these contacts for achieving cGMP specificity. Binding data with the generic purine nucleotide 3',5'-cyclic inosine monophosphate (cIMP) reveal that introduced arginine residues interact with the position 6 oxygen of the nucleobase. Co-crystal structures of an isolated CNB-B G316R/A336T double mutant with either cAMP or cGMP reveal that the introduced threonine and arginine residues maintain their conserved contacts as seen in PKG I CNB-B. These results improve our understanding of cyclic nucleotide binding and the molecular basis of cyclic nucleotide specificity.

Structural basis for cyclic-nucleotide selectivity and cGMP-selective activation of PKG I.

Cyclic guanosine monophosphate (cGMP) and cyclic AMP (cAMP)-dependent protein kinases (PKG and PKA) are closely related homologs, and the cyclic nucleotide specificity of each kinase is crucial for keeping the two signaling pathways segregated, but the molecular mechanism of cyclic nucleotide selectivity is unknown. Here, we report that the PKG Iß C-terminal cyclic nucleotide binding domain (CNB-B) is highly selective for cGMP binding, and we have solved crystal structures of CNB-B with and without bound cGMP. These structures, combined with a comprehensive mutagenic analysis, allowed us to identify Leu296 and Arg297 as key residues that mediate cGMP selectivity. In addition, by comparing the cGMP bound and unbound structures, we observed large conformational changes in the C-terminal helices in response to cGMP binding, which were stabilized by recruitment of Tyr351 as a "capping residue" for cGMP. The observed rearrangements of the C-terminal helices provide a mechanical insight into release of the catalytic domain and kinase activation.