Longitudinal analysis of caloric requirements in critically ill trauma patients: a retrospective cohort study.

PURPOSE Nutrition is of paramount importance in critically ill trauma patients. However, adequate supply is difficult to achieve, as caloric requirements are unknown. This study investigated caloric requirements over time, based on indirect calorimetry, in critically ill trauma patients. METHODS Retrospective cohort study at a tertiary trauma center including critically ill trauma patients who underwent indirect calorimetry 2012-2019. Caloric requirements were assessed as resting energy expenditure (REE) during the intensive care unit stay up to 28 days and analyzed in patient-clustered linear regression analysis. RESULTS A total of 129 patients were included. Median REE per day was 2376 kcal. The caloric intake did not meet REE at any time with a median daily deficit of 1167 kcal. In univariable analysis, ISS was not significantly associated with REE over time (RC 0.03, p = 0.600). Multivariable analysis revealed a significant REE increase (RC 0.62, p < 0.001) and subsequent decrease (RC - 0.03, p < 0.001) over time. Age < 65 years (RC 2.07, p = 0.018), male sex (RC 4.38, p < 0.001), and BMI ≥ 35 kg/m2 (RC 6.94, p < 0.001) were identified as independent predictors for higher REE over time. Severe head trauma was associated with lower REE over time (RC - 2.10, p = 0.030). CONCLUSION In critically ill trauma patients, caloric requirements significantly increased and subsequently decreased over time. Younger age, male sex and higher BMI were identified as independent predictors for higher caloric requirements, whereas severe head trauma was associated with lower caloric requirements over time. These results support the use of IC and will help to adjust nutritional support in critically ill trauma patients

Heat shock protein 90 (HSP90) inhibitors in gastrointestinal cancer: where do we currently stand?-A systematic review.

PURPOSE Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target in oncology, including the treatment of gastrointestinal cancers. METHODS We carried out a systematic review of data extracted from clinicaltrials.gov and pubmed.gov, which included all studies available until January 1st, 2022. The published data was evaluated using primary and secondary endpoints, particularly with focus on overall survival, progression-free survival, and rate of stable disease. RESULTS Twenty trials used HSP90 inhibitors in GI cancers, ranging from phase I to III clinical trials. Most studies assessed HSP90 inhibitors as a second line treatment. Seventeen of the 20 studies were performed prior to 2015 and only few studies have results pending. Several studies were terminated prematurely, due to insufficient efficacy or toxicity. Thus far, the data suggests that HSP90 inhibitor NVP-AUY922 might improve outcome for colorectal cancer and gastrointestinal stromal tumors. CONCLUSION It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade

Gastroesophageal Junction and Pylorus Distensibility Before and After Sleeve Gastrectomy-pilot Study with EndoFlipTM.

Sleeve gastrectomy (SG) is the most frequently performed bariatric surgical intervention worldwide. Gastroesophageal reflux disease (GERD) is frequently observed after SG and is a relevant clinical problem. This prospective study investigated the gastroesophageal junction (GEJ) and pyloric sphincter by impedance planimetry (EndoFlipTM) and their association with GERD at a tertiary university hospital center. Between January and December 2018, patients undergoing routine laparoscopic SG had pre-, intra-, and postoperative assessments of the GEJ and pyloric sphincter by EndoFlipTM. The distensibility index (DI) was measured at different volumes and correlated with GERD (in accordance with the Lyon consensus guidelines). Nine patients were included (median age 48 years, preoperative BMI 45.1 kg/m2, 55.6% female). GERD (de novo or stable) was observed in 44.4% of patients one year postoperatively. At a 40-ml filling volume, DI increased significantly pre- vs. post-SG of the GEJ (1.4 mm2/mmHg [IQR 1.1-2.6] vs. 2.9 mm2/mmHg [2.6-5.3], p VALUE=0.046) and of the pylorus (6.0 mm2/mmHg [4.1-10.7] vs. 13.1 mm2/mmHg [7.6-19.2], p VALUE=0.046). Patients with postoperative de novo or stable GERD had a significantly increased preoperative DI at 40 ml of the GEJ (2.6 mm2/mmHg [1.9-3.5] vs. 0.5 mm2/mmHg [0.5-1.1], p VALUE=0.031). There was no significant difference in DI at 40 mL filling in the preoperative pylorus and postoperative GEJ or pylorus. In this prospective study, the DI of the GEJ and the pylorus significantly increased after SG. Postoperative GERD was associated with a significantly higher preoperative DI of the GEJ but not of the pylorus

Orally Available Selective Melanocortin-4 Receptor Antagonists Stimulate Food Intake and Reduce Cancer-Induced Cachexia in Mice

BACKGROUND: Cachexia is among the most debilitating and life-threatening aspects of cancer. It represents a metabolic syndrome affecting essential functional circuits involved in the regulation of homeostasis, and includes anorexia, fat and muscle tissue wasting. The anorexigenic peptide alpha-MSH is believed to be crucially involved in the normal and pathologic regulation of food intake. It was speculated that blockade of its central physiological target, the melanocortin (MC)-4 receptor, might provide a promising anti-cachexia treatment strategy. This idea is supported by the fact that in animal studies, agouti-related protein (AgRP), the endogenous inverse agonist at the MC-4 receptor, was found to affect two hallmark features of cachexia, i.e. to increase food intake and to reduce energy expenditure. METHODOLOGY/PRINCIPAL FINDINGS: SNT207707 and SNT209858 are two recently discovered, non peptidic, chemically unrelated, orally active MC-4 receptor antagonists penetrating the blood brain barrier. Both compounds were found to distinctly increase food intake in healthy mice. Moreover, in mice subcutaneously implanted with C26 adenocarcinoma cells, repeated oral administration (starting the day after tumor implantation) of each of the two compounds almost completely prevented tumor induced weight loss, and diminished loss of lean body mass and fat mass. CONCLUSIONS/SIGNIFICANCE: In contrast to the previously reported peptidic and small molecule MC-4 antagonists, the compounds described here work by the oral administration route. Orally active compounds might offer a considerable advantage for the treatment of cachexia patients

Key Learning Outcomes for Clinical Pharmacology and Therapeutics Education in Europe: A Modified Delphi Study.

Harmonizing clinical pharmacology and therapeutics (CPT) education in Europe is necessary to ensure that the prescribing competency of future doctors is of a uniform high standard. As there are currently no uniform requirements, our aim was to achieve consensus on key learning outcomes for undergraduate CPT education in Europe. We used a modified Delphi method consisting of three questionnaire rounds and a panel meeting. A total of 129 experts from 27 European countries were asked to rate 307 learning outcomes. In all, 92 experts (71%) completed all three questionnaire rounds, and 33 experts (26%) attended the meeting. 232 learning outcomes from the original list, 15 newly suggested and 5 rephrased outcomes were included. These 252 learning outcomes should be included in undergraduate CPT curricula to ensure that European graduates are able to prescribe safely and effectively. We provide a blueprint of a European core curriculum describing when and how the learning outcomes might be acquired

Distal axonopathy in peripheral nerves of PMP22-mutant mice

A partial duplication of chromosome 17 is associated with Charcot-Marie-Tooth disease type 1A (CMT1A), a demyelinating peripheral neuropathy that causes progressive distal muscle atrophy and sensory impairment. Trisomic expression of peripheral myelin protein 22 (PMP22) whose gene is contained within the duplicated region is considered to be responsible for the disease. By using recombinant gene technology in rodents, we had demonstrated previously that PMP22 is sensitive to gene dosage. Homozygous PMP22 knockout (PMP220/0) mice and transgenic animals carrying additional copies of the PMP22 gene develop distinct peripheral polyneuropathies. We have now performed a detailed morphometrical analysis of the L3 roots, quadriceps and saphenous nerves of these PMP22-mutant mice to study whether the myelin and potential axonal deficits are evenly distributed. The L3 roots and the peripheral nerves were chosen as representatives of the proximal and distal segments of the peripheral nervous system. When the roots were compared with the peripheral nerves, myelin deficiencies appeared more severe at the radicular levels, in particular the ventral roots. Decreased numbers of large calibre axons were a prominent feature in the motor branches of both strains of PMP22-mutant mice, and these axonal deficits were more severe distally. Active axonal damage was only observed in the nerves of PMP220/0 mice. Despite the distinct effects on myelination and the Schwann cell phenotype that characterize the neuropathies of PMP22-mutant mice, both strains develop a distally accentuated axonopathy as a common disease mechanism which is likely to be responsible for the neurological deficit