Impact of clinical frailty on surgical and non-surgical complications after major emergency abdominal surgery.

BACKGROUND: Major emergency abdominal surgery is associated with a high risk of morbidity and mortality. Given the ageing and increasingly frail population, understanding the impact of frailty on complication patterns after surgery is crucial. The aim of this study was to evaluate the association between clinical frailty and organ-specific postoperative complications after major emergency abdominal surgery. METHODS: A prospective cohort study including all patients undergoing major emergency abdominal surgery at Copenhagen University Hospital Herlev, Denmark, from 1 October 2020 to 1 August 2022, was performed. Clinical frailty scale scores were determined for all patients upon admission and patients were then analysed according to clinical frailty scale groups (scores of 1-3, 4-6, or 7-9). Postoperative complications were registered until discharge. RESULTS: A total of 520 patients were identified. Patients with a low clinical frailty scale score (1-3) experienced fewer total complications (120 complications per 100 patients) compared with patients with clinical frailty scale scores of 4-6 (250 complications per 100 patients) and 7-9 (277 complications per 100 patients) (P < 0.001). A high clinical frailty scale score was associated with a high risk of pneumonia (P = 0.009), delirium (P < 0.001), atrial fibrillation (P = 0.020), and infectious complications in general (P < 0.001). Patients with severe frailty (clinical frailty scale score of 7-9) suffered from more surgical complications (P = 0.001) compared with the rest of the cohort. Severe frailty was associated with a high risk of 30-day mortality (33% for patients with a clinical frailty scale score of 7-9 versus 3.6% for patients with a clinical frailty scale score of 1-3, P < 0.001). In a multivariate analysis, an increasing degree of clinical frailty was found to be significantly associated with developing at least one complication. CONCLUSION: Patients with frailty have a significantly increased risk of postoperative complications after major emergency abdominal surgery, especially atrial fibrillation, delirium, and pneumonia. Likewise, patients with frailty have an increased risk of mortality within 90 days. Thus, frailty is a significant predictor for adverse events after major emergency abdominal surgery and should be considered in all patients undergoing major emergency abdominal surgery.

Effect of oral semaglutide on the pharmacokinetics of thyroxine after dosing of levothyroxine and the influence of co-administered tablets on the pharmacokinetics of oral semaglutide in healthy subjects: an open-label, one-sequence crossover, single-center, multiple-dose, two-part trial.

BACKGROUND: Oral semaglutide comprises the glucagon-like peptide-1 analog, semaglutide, and sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Levothyroxine has similar dosing conditions to oral semaglutide. This trial investigated if oral semaglutide co-administered with levothyroxine affects thyroxine (T4) exposure and if multiple placebo tablets co-administered with oral semaglutide affect semaglutide exposure. RESEARCH DESIGN AND METHODS: In this one-sequence crossover trial, 45 healthy subjects received levothyroxine (600 µg single-dose) alone, or with concomitant SNAC 300 mg or concomitant oral semaglutide 14 mg at steady-state. Subjects also received oral semaglutide 14 mg at steady-state alone or with five placebo tablets once-daily for 5 weeks. RESULTS: A 33% increase in total T4 exposure was observed with levothyroxine/oral semaglutide vs levothyroxine alone, but baseline-corrected maximum concentration (Cmax) was unaffected. SNAC alone did not affect total T4 exposure, whereas Cmax was slightly decreased. A 34% decrease in semaglutide exposure was observed when oral semaglutide was co-administered with placebo tablets, and Cmax also decreased. CONCLUSIONS: Levothyroxine pharmacokinetics were influenced by co-administration with oral semaglutide. Monitoring of thyroid parameters should be considered when treating patients with both oral semaglutide and levothyroxine. Oral semaglutide exposure was influenced by co-administration with multiple tablets, which is addressed in the dosing guidance.

[Heterotopic ossification in a midline incision].

Heterotopic ossification (HO) is the formation of bone outside the skeletal system. It is a well-known complication in orthopaedic surgery but is infrequently reported in abdominal surgery. HO can be asymptomatic or cause chronic pain but can also cause complications during later surgery. In this case report we present a 54-year-old male with an HO in a midline incision following surgery 20 years earlier.

Randomized Clinical Trial of Preoperative High-Dose Methylprednisolone on Postoperative Pain at Rest After Laparoscopic Appendectomy.

BACKGROUND: Methylprednisolone administered intravenously preoperatively has been shown to reduce pain, nausea, and fatigue after elective surgery. We aimed to show that 125 mg of methylprednisolone given intravenously 30 minutes before laparoscopic surgery for suspected appendicitis would reduce pain at rest during the first 3 postoperative days. METHODS: A multicenter, parallel-group, double-blind, placebo-controlled study was conducted including patients 18 years of age and older with an American Society of Anesthesiologist class of I-III undergoing laparoscopic surgery for suspected appendicitis. The primary outcome was pain at rest measured on the 11-point numerical rating scale 5 times during the first 3 days after surgery. The effect of 125 mg of methylprednisolone on postoperative pain at rest during the first 3 days was assessed using a mixed-effects model with time and intervention as main effects. RESULTS: From April 2016 to August 2016, 78 patients were included, and all were eligible for analysis of the primary outcome. The estimated effect of 125 mg of methylprednisolone on pain at rest during the first 3 days after surgery was a nonsignificant increase of 0.2 (95% confidence interval, -0.5 to 0.9; P = .571) on the 11-point numerical rating scale. There was no difference between the 2 groups regarding the need for opioid agonists during hospital stay on the first postoperative day (P = .381). CONCLUSIONS: A 125-mg dose of methylprednisolone given intravenously 30 minutes before laparoscopic surgery for appendicitis seemed no better than placebo at providing a clinical meaningful reduction in postoperative pain at rest.

Up to 89% of neonates received antibiotics in cross-sectional Indian study including those with no infections and unclear diagnoses.

AIM: There is a global lack of data on antibiotic prescribing for neonates. This study compared antibiotic prescribing practices in the neonatal intensive care units (NICUs) of two private-sector, tertiary-level hospitals. METHODS: A three-year, cross-sectional study was conducted from 2008 to 2011 in the NICUs of a teaching and nonteaching hospital in the Ujjain district of India. The data were analysed using methods recommended by the World Health Organization. RESULTS: Of the 1789 inpatients, 89% (1399/1572) in the nonteaching hospital and 71% (154/217) in the teaching hospital were prescribed antibiotics and 123 patients died. All the antibiotics were prescribed empirically and cephalosporins and aminoglycosides were the most commonly prescribed subclasses. Fixed-dose combinations of cephalosporins were commonly prescribed in the nonteaching hospital. Neonatal sepsis was the most common diagnosis, in more than 30% of patients, and more than 93% neonates with sepsis were prescribed antibiotics. In addition, 40% of neonates in the nonteaching hospital were admitted for observation and were frequently prescribed antibiotics. CONCLUSION: These two Indian NICUs prescribed antibiotics for noninfectious or unclear diagnoses in addition to prescribing combinations of broad-spectrum antibiotics. Such practices increase the global risk of treatment failure, neonatal mortality rates and antibiotic resistance.

Fast and sensitive detection of indels induced by precise gene targeting.

The nuclease-based gene editing tools are rapidly transforming capabilities for altering the genome of cells and organisms with great precision and in high throughput studies. A major limitation in application of precise gene editing lies in lack of sensitive and fast methods to detect and characterize the induced DNA changes. Precise gene editing induces double-stranded DNA breaks that are repaired by error-prone non-homologous end joining leading to introduction of insertions and deletions (indels) at the target site. These indels are often small and difficult and laborious to detect by traditional methods. Here we present a method for fast, sensitive and simple indel detection that accurately defines indel sizes down to ±1 bp. The method coined IDAA for Indel Detection by Amplicon Analysis is based on tri-primer amplicon labelling and DNA capillary electrophoresis detection, and IDAA is amenable for high throughput analysis.

[Sportman's hernia]. / Sportshernie.

Sportman's hernia is a disease with insidious groin pain that primarily affects young males undertaking sports activities with frequent kicking and twisting. Pathophysiological theories include: 1) a weakening of the posterior inguinal potential or 2) injuries of the fascias of the muscles and insertions of tendons at the pubic bone. The diagnosis requires exclusion of differential diagnoses. Patients rarely respond to conservative treatment, whereas uncontrolled studies suggest improvement after surgery. However, there is a lack of randomized trials with a long follow-up to define the role of surgery in the treatment.

RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells.

The RAS-stimulated RAF-MEK-ERK pathway confers epithelial cells with critical motile and invasive capacities during development, tissue regeneration, and carcinoma progression, often via promoting the epithelial-mesenchymal transition (EMT). Many mechanisms by which ERK exerts this control remain elusive. We demonstrate that the ERK-activated kinase RSK is necessary to induce mesenchymal motility and invasive capacities in nontransformed epithelial and carcinoma cells. RSK is sufficient to induce certain motile responses. Expression profiling analysis revealed that a primary role of RSK is to induce transcription of a potent promotile/invasive gene program by FRA1-dependent and -independent mechanisms. The program enables RSK to coordinately modulate the extracellular environment, the intracellular motility apparatus, and receptors mediating communication between these compartments to stimulate motility and invasion. These findings uncover a mechanism whereby the RAS-ERK pathway controls epithelial cell motility by identifying RSK as a key effector, from which emanate multiple highly coordinate transcription-dependent mechanisms for stimulation of motility and invasive properties.

Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation.

The growth factor/insulin-stimulated AGC kinases share an activation mechanism based on three phosphorylation sites. Of these, only the role of the activation loop phosphate in the kinase domain and the hydrophobic motif (HM) phosphate in a C-terminal tail region are well characterized. We investigated the role of the third, so-called turn motif phosphate, also located in the tail, in the AGC kinases PKB, S6K, RSK, MSK, PRK and PKC. We report cooperative action of the HM phosphate and the turn motif phosphate, because it binds a phosphoSer/Thr-binding site above the glycine-rich loop within the kinase domain, promoting zipper-like association of the tail with the kinase domain, serving to stabilize the HM in its kinase-activating binding site. We present a molecular model for allosteric activation of AGC kinases by the turn motif phosphate via HM-mediated stabilization of the alphaC helix. In S6K and MSK, the turn motif phosphate thereby also protects the HM from dephosphorylation. Our results suggest that the mechanism described is a key feature in activation of upto 26 human AGC kinases.

Functional characterization of human RSK4, a new 90-kDa ribosomal S6 kinase, reveals constitutive activation in most cell types.

The 90-kDa ribosomal S6 kinases (RSK1-3) are important mediators of growth factor stimulation of cellular proliferation, survival, and differentiation and are activated via coordinated phosphorylation by ERK and 3-phosphoinositide-dependent protein kinase-1 (PDK1). Here we performed the functional characterization of a predicted new human RSK homologue, RSK4. We showed that RSK4 is a predominantly cytosolic protein with very low expression and several characteristics of the RSK family kinases, including the presence of two functional kinase domains and a C-terminal docking site for ERK. Surprisingly, however, in all cell types analyzed, endogenous RSK4 was maximally (constitutively) activated under serum-starved conditions where other RSKs are inactive due to their requirement for growth factor stimulation. Constitutive activation appeared to result from constitutive phosphorylation of Ser232, Ser372, and Ser389, and the low basal ERK activity in serum-starved cells appeared to be sufficient for induction of approximately 50% of the constitutive RSK4 activity. Finally experiments in mouse embryonic stem cells with targeted deletion of the PDK1 gene suggested that PDK1 was not required for phosphorylation of Ser232, a key regulatory site in the activation loop of the N-terminal kinase domain, that in other RSKs is phosphorylated by PDK1. The unusual regulation and growth factor-independent kinase activity indicate that RSK4 is functionally distinct from other RSKs and may help explain recent findings suggesting that RSK4 can participate in non-growth factor signaling as for instance p53-induced growth arrest.