Association between appendiceal stump closure method and post-operative bowel obstruction after laparoscopic appendectomy.

BACKGROUND: Laparoscopic appendectomy is one of the most common urgent pediatric surgical operations. Endoscopic surgical staplers and pre-tied endoloop ligatures are both routinely used for closure of the appendiceal stump in children. Practice patterns vary for a number of reasons, including cost, size, and ease of use. While stapling is standard for some pediatric surgeons, others believe that staples can act as a nidus for small bowel obstruction (SBO). However, studies comparing closure methods have been conflicting in their results and limited in size. Therefore, we aim to determine if there is an association between appendiceal stump closure method and SBO using a national comparative pediatric database. METHODS: We queried the Pediatric Health Information System (PHIS) for patients ages 3-18 years who underwent laparoscopic appendectomy for appendicitis between 1/1/2016 - 12/31/2020. We included hospitals that had greater than 50 patients with billing data and excluded patients with inflammatory bowel disease and simultaneous abdominal operations. We used billing data for the patient's appendectomy to determine if a stapler or a suture ligature was used during the case. Our primary outcome of interest was post-operative SBO or reoperation for lysis of adhesion or intestinal surgery within the first 30 post-operative days. Multivariable regression analyses were used to estimate the association between stump closure method and post-operative SBO or reoperation in addition to cost while adjusting for patient demographics and appendiceal perforation. RESULTS: In total, 49,191 patients from 37 hospitals were included, of which, 29,733 (60.44%) were male, 21,403 (43.51%) were non-Hispanic white, and 18,291 (37.18%) had a diagnosis of complicated appendicitis. The median [IQR] age of the cohort was 11 [8-14] years. A surgical stapler was used during laparoscopic appendectomy in 35,788 (72.75%) patients, and early SBO or reoperation occurred in 653 (1.33%) patients. In adjusted analysis controlling for demographics and complicated appendicitis there was no statistically significant difference in the odds of SBO or reoperation between the two groups. (OR 1.17; 99% CI 0.86 - 1.6). Complicated appendicitis was the factor most associated with post-operative SBO or reoperation (OR 4.4; 99% CI 3.01 - 6.44). Median cumulative cost was slightly higher on unadjusted analysis in the stapler group ($10,329.3 vs $9,569.2). However, there was no significant difference on adjusted analysis. CONCLUSION: SBO or reoperation following laparoscopic appendectomy for appendicitis is uncommon. Complicated appendicitis is the most predictive factor of this outcome. Adjusting for available patient, disease, and hospital characteristics, use of a surgical stapler does not appear to be meaningfully associated with the development of acute SBO or reoperation. Surgeon preference remains the mainstay for safe appendiceal stump closure method. LEVEL OF EVIDENCE: Level III. STUDY TYPE: Retrospective Comparative Study.

Use of Functional MRI in Deep Brain Stimulation in Parkinson's Diseases: A Systematic Review.

Deep brain stimulation (DBS) has been used to modulate aberrant circuits associated with Parkinson's disease (PD) for decades and has shown robust therapeutic benefits. However, the mechanism of action of DBS remains incompletely understood. With technological advances, there is an emerging use of functional magnetic resonance imaging (fMRI) after DBS implantation to explore the effects of stimulation on brain networks in PD. This systematic review was designed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to summarize peer-reviewed articles published within the past 10 years in which fMRI was employed on patients with PD-DBS. Search in PubMed database provided 353 references, and screenings resulted in a total of 19 studies for qualitative synthesis regarding study designs (fMRI scan timepoints and paradigm), methodology, and PD subtypes. This review concluded that fMRI may be used in patients with PD-DBS after proper safety test; resting-state and block-based fMRI designs have been employed to explore the effects of DBS on brain networks and the mechanism of action of the DBS, respectively. With further validation of safety use of fMRI and advances in imaging techniques, fMRI may play an increasingly important role in better understanding of the mechanism of stimulation as well as in improving clinical care to provide subject-specific neuromodulation treatments.

Correlation between Cyclin Dependent Kinases and Artemisinin-Induced Dormancy in Plasmodium falciparum In Vitro.

BACKGROUND: Artemisinin-induced dormancy provides a plausible explanation for recrudescence following artemisinin monotherapy. This phenomenon shares similarities with cell cycle arrest where cyclin dependent kinases (CDKs) and cyclins play an important role. METHODS: Transcription profiles of Plasmodium falciparum CDKs and cyclins before and after dihydroartemisinin (DHA) treatment in three parasite lines, and the effect of CDK inhibitors on parasite recovery from DHA-induced dormancy were investigated. RESULTS: After DHA treatment, parasites enter a dormancy phase followed by a recovery phase. During the dormancy phase parasites up-regulate pfcrk1, pfcrk4, pfcyc2 and pfcyc4, and down-regulate pfmrk, pfpk5, pfpk6, pfcrk3, pfcyc1 and pfcyc3. When entering the recovery phase parasites immediately up-regulate all CDK and cyclin genes. Three CDK inhibitors, olomoucine, WR636638 and roscovitine, produced distinct effects on different phases of DHA-induced dormancy, blocking parasites recovery. CONCLUSIONS: The up-regulation of PfCRK1 and PfCRK4, and down regulation of other CDKs and cyclins correlate with parasite survival in the dormant state. Changes in CDK expression are likely to negatively regulate parasite progression from G1 to S phase. These findings provide new insights into the mechanism of artemisinin-induced dormancy and cell cycle regulation of P. falciparum, opening new opportunities for preventing recrudescence following artemisinin treatment.

Cyclization of the antimicrobial peptide gomesin with native chemical ligation: influences on stability and bioactivity.

Gomesin is an 18-residue peptide originally isolated from the hemocytes of the Brazilian spider Acanthoscurria gomesiana. A broad spectrum of bioactivities have been attributed to gomesin, including in vivo and in vitro cytotoxicity against tumour cells, antimicrobial, antifungal, anti-Leishmania and antimalarial effects. Given the potential therapeutic applications of gomesin, it was of interest to determine if an engineered version with a cyclic backbone has improved stability and bioactivity. Cyclization has been shown to confer enhanced stability and activity to a range of bioactive peptides and, in the case of a cone snail venom peptide, confer oral activity in a pain model. The current study demonstrates that cyclization improves the in vitro stability of gomesin over a 24 hour time period and enhances cytotoxicity against a cancer cell line without being toxic to a noncancerous cell line. In addition, antimalarial activity is enhanced upon cyclization. These findings provide additional insight into the influences of backbone cyclization on the therapeutic potential of peptides.

Targeting protein kinases in the malaria parasite: update of an antimalarial drug target.

Millions of deaths each year are attributed to malaria worldwide. Transmitted through the bite of an Anopheles mosquito, infection and subsequent death from the Plasmodium species, most notably P. falciparum, can readily spread through a susceptible population. A malaria vaccine does not exist and resistance to virtually every antimalarial drug predicts that mortality and morbidity associated with this disease will increase. With only a few antimalarial drugs currently in the pipeline, new therapeutic options and novel chemotypes are desperately needed. Hit-to-Lead diversity may successfully provide novel inhibitory scaffolds when essential enzymes are targeted, for example, the plasmodial protein kinases. Throughout the entire life cycle of the malaria parasite, protein kinases are essential for growth and development. Ongoing efforts continue to characterize these kinases, while simultaneously pursuing them as antimalarial drug targets. A collection of structural data, inhibitory profiles and target validation has set the foundation and support for targeting the malarial kinome. Pursuing protein kinases as cancer drug targets has generated a wealth of information on the inhibitory strategies that can be useful for antimalarial drug discovery. In this review, progress on selected protein kinases is described. As the search for novel antimalarials continues, an understanding of the phosphor-regulatory pathways will not only validate protein kinase targets, but also will identify novel chemotypes to thwart malaria drug resistance.