Minimally Invasive transCervical oEsophagectomy (MICE) for oesophageal cancer: prospective cohort study (IDEAL stage 2A).

BACKGROUND: Minimally invasive transcervical oesophagectomy is a surgical technique that offers radical oesophagectomy without the need for transthoracic access. The aim of this study was to evaluate the safety and feasibility of the minimally invasive transcervical oesophagectomy procedure and to report the refinement of this technique in a Western cohort. METHODS: A single-centre prospective cohort study was designed as an IDEAL stage 2A study. Patients with oesophageal cancer (cT1b-4a N0-3 M0) who were scheduled for oesophagectomy with curative intent were eligible for inclusion in the study. The main outcome parameter was the postoperative pulmonary complication rate and the secondary outcomes were the anastomotic leakage, recurrent laryngeal nerve palsy, and R0 resection rates, as well as the lymph node yield. RESULTS: In total, 75 patients underwent minimally invasive transcervical oesophagectomy between January 2021 and November 2023. Several modifications to the surgical technique were registered, evaluated, and implemented in the context of IDEAL stage 2A. A total of 12 patients (16%) had postoperative pulmonary complications, including pneumonia (4 patients) and pleural effusion with drainage or aspiration (8 patients). Recurrent laryngeal nerve palsy was observed in 33 of 75 patients (44%), with recovery in 30 of 33 patients (91%). A total of 5 of 75 patients (7%) had anastomotic leakage. The median number of resected lymph nodes was 29 (interquartile range 22-37) and the R0 resection rate was 96% (72 patients). CONCLUSION: Introducing minimally invasive transcervical oesophagectomy for oesophageal cancer in a Dutch institution is associated with a low rate of postoperative pulmonary complications and a high rate of temporary recurrent laryngeal nerve palsy.

E-Health-based, trans-sectoral, geriatric health service - Geriatric Network (GerNe).

Currently, exchange of information between the geriatric clinic and the attending general practitioner (GP) occurs primarily through the doctor's letter after discharging from the clinic. The aim of our study was to reduce readmissions of multimorbid, geriatric patients to the clinic by establishing a new form of care via an electronic case file (ECF) and a consultation service (CS). The discharging geriatric clinic filled out an online ECF. The patient's GP should document quarterly follow-ups in the ECF. The case file was monitored by the discharging clinic due to a consultation service. The primary efficacy endpoint was the rehospitalization rate within one year. The hospitalization rate for patients managed in the project was 83.1/100 person years (PY), while the control group from insurance data had a rate of 69.0/100 PY. The primary endpoint did not show a statistically significant difference (p = 0.15). A total of 195 contacts were documented via CS for 171 participants, mostly initiated by the clinics. The clinical queries primarily concerned drug therapy. The Covid pandemic had an overall impact on hospitalizations. There are many approaches to reducing hospital readmissions after discharge of older patients. Supporting the transition from inpatient to outpatient care by different professional groups or care systems has been shown to have a positive effect. Furthermore, the utilisation of an ECF can also be beneficial in this regard.

Trabecular, but not cortical, bone tissue protein synthesis rates are lower in the femoral head when compared to the proximal femur following an intracapsular hip fracture.

BACKGROUND: All musculoskeletal tissues are in a constant state of turnover, with a dynamic equilibrium between tissue protein synthesis and breakdown rates. The synthesis of protein allows musculoskeletal tissues to heal following injury. Yet, impaired tissue healing is observed following certain injuries, such as geriatric hip fractures. It is assumed that the regenerative properties of femoral head bone tissue are compromised following an intracapsular hip fracture and therefore hip replacement surgery is normally performed. However, the actual impact on in vivo bone protein synthesis rates has never been determined. DESIGN: In the present study, 10 patients (age: 79 ± 10 y, BMI: 24 ± 4 kg/m2) with an acute (<24 h) intracapsular hip fracture received a primed continuous intravenous infusion of L-[ring-13C6]-phenylalanine before and throughout their hip replacement surgery. Trabecular and cortical bone tissue from both the femoral head and proximal femur were sampled during surgery to assess protein synthesis rates of affected (femoral head) and unaffected (proximal femur) bone tissue, respectively. In addition, tissue samples of gluteus maximus muscle, synovium, ligamentum teres, and femoral head cartilage were collected. Tissue-specific protein synthesis rates were assessed by measuring L-[ring-13C6]-phenylalanine incorporation in tissue protein. RESULTS: Femoral head trabecular bone protein synthesis rates (0.056 [0.024-0.086] %/h) were lower when compared to proximal femur trabecular bone protein synthesis rates (0.081 [0.056-0.118] %/h; P = 0.043). Cortical bone protein synthesis rates did not differ between the femoral head and proximal femur (0.041 [0.021-0.078] and 0.045 [0.028-0.073] %/h, respectively; P > 0.05). Skeletal muscle, synovium, ligamentum teres, and femoral head cartilage protein synthesis rates averaged 0.080 [0.048-0.089], 0.093 [0.051-0.130], 0.121 [0.110-0.167], and 0.023 [0.015-0.039] %/h, respectively. CONCLUSION: In contrast to the general assumption that the femoral head is avital after an intracapsular displaced hip fracture in the elderly, our data show that bone protein synthesis is still ongoing in femoral head bone tissue during the early stages following an intracapsular hip fracture in older patients. Nonetheless, trabecular bone protein synthesis rates are lower in the femoral head when compared to the proximal femur in older patients following an acute intracapsular hip fracture. Trial register no: NL9036.

Viability of selected microorganisms in parenteral preparations for novel systemic anti-cancer therapy.

BACKGROUND: Risk factors for aseptic preparation of parenteral medicines encompass the growth-promoting nature of the preparation. Although many aqueous parenteral preparations do not have growth-promoting properties, inadvertently introduced microorganisms may remain viable. Knowledge about the viability of microorganisms in parenteral preparations can add useful information for assigning shelf life to preparations used to treat cancer patients. AIM: The aim of the study was to assess the viability of four different facultative pathogenic microorganisms in 20 ready-to-administer parenteral preparations aseptically prepared in hospital pharmacies. METHODS: Samples of 20 different biologics and small molecules for systemic anti-cancer therapy were inoculated either with different bacteria (i.e., Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium) or with Candida albicans suspension. The resulting test concentrations were 104-105 microorganisms per mL. Aliquots of inoculated test solutions were transferred in duplicate to tryptic soy agar plates at the time points 0, 4, 24, 48, 144 h. The plates were incubated for 24 h (bacterial strains) and 72 h (C. albicans) at 37 °C and colony forming units (CFUs) were counted. RESULTS: In most test solutions, especially in monoclonal antibody solutions, increased CFU counts of P. aeruginosa and unchanged or increased CFU counts of E. faecium and S. aureus were registered. Pronounced nutritive properties of monoclonal antibodies and filgrastim were not registered. Azacitidine, pixantrone and vinflunine containing test solutions revealed species-specific bacteriostatic and even bactericidal activity. All test solutions, except nivolumab and pixantrone containing solutions, showed constant or increasing CFU counts of C. albicans after incubation. CONCLUSION: Viability of the selected pathogenic microorganisms was retained in most of the tested biological and small molecule preparations used to treat cancer patients. Therefore, in pharmacy departments strict aseptic conditions should be regarded and the lack of antimicrobial activity should be considered when assigning shelf life to RTA parenteral preparations.

Good handling practice of parenterally administered medicines in neonatal intensive care units - position paper of an interdisciplinary working group.

This position paper, developed by an interdisciplinary expert group of neonatologists, paediatric infectious disease physicians, clinical pharmacists and specialists for the prevention and control of nosocomial infections, describes the "Good handling practice of medicines parenterally administered to patients on NICUs". It takes equal account of patient safety and the specialties of neonatal intensive care regarding feasibility and proportionality. The overall concept is perceived as a "learning system", in which open communication within the health-care team relating to medication errors and critical incidents enables continuous development and improvement to ensure patient safety. In our opinion, pharmacists, who are responsible for the supply of ready-to-administer parenteral medicinal products for neonatal intensive care patients, as well as the hygiene staff responsible on site are integral parts of the interdisciplinary treatment team. Risks of the current clinical practice of parenteral treatment of NICU patients are discussed in detail and recommendations for safety-relevant procedures are given.

A Novel Monoclonal Antibody Degrades the Thyrotropin Receptor Autoantibodies in Graves' Disease.

OBJECTIVE: Autoantibodies against the thyrotropin receptor (TSH-R-Ab) are key mediators for the pathogenesis of Graves' disease (GD). TSH-R-Ab degradation was evaluated using several immunoassays within an exploratory, controlled trial in patients with GD receiving a monoclonal antibody (mAb) targeting the neonatal crystallizable fragment receptor (FcRn). METHODS: Serial measurements of TSH-R-Ab serum levels were performed using 3 different binding and cell-based assays in patients with GD either on medication or on placebo. RESULTS: In contrast to the placebo group, in which no changes were observed, a 12-week mAb therapy led to an early and significant decrease (>60%) in the serum TSH-R-Ab levels in patients with thyroidal and extrathyroidal GD, as unanimously shown in all 3 assays. These marked changes were noted already at week 7 post baseline (P <.0001 for the binding immunoassay and for the luciferase (readout) bioassay). The 3 TSH-R-Ab binding and bioassays were highly correlated in the samples of both study groups (binding immunoassay vs luciferase bioassay, r =.91, P <.001, binding vs cyclic adenosine monophosphate (cAMP) bioassay, r = 0.86, P <.001, and luciferase vs cAMP bioassay, r = 0.71, P =.006). The serological results correlated with the course of the extrathyroidal clinical parameters of GD, that is, clinical activity score and proptosis. CONCLUSION: Targeting the FcRn markedly reduces the disease-specific TSH-R-Ab in patients with GD. The novel and rapid TSH-R-Ab bioassay improves diagnosis and management of patients with GD.

Physicochemical Stability of Generic Thiotepa Concentrate and Ready-to-Administer Infusion Solutions for Conditioning Treatment.

The objective of this study was to determine the physicochemical in-use stability of recently approved Thiotepa Riemser concentrate in the original vial and diluted ready-to-administer (RTA) infusion solutions in prefilled glucose 5% and 0.9% NaCl polyolefin bags. Thiotepa Riemser 10 mg/mL concentrates and infusion solutions (1 mg/mL, 2 mg/mL, 3 mg/mL) were prepared in triplicate and stored at 2-8 °C or 25 °C for 14 days. Thiotepa concentrations were determined using a stability-indicating RP-HPLC assay. In parallel, pH and osmolality were measured. Sub-visible particles were counted on day 0 and 14. Thiotepa Riemser concentrate was revealed to be stable for 14 days when stored at 2-8 °C, or for 24 h when stored at 25 °C. Thiotepa concentrations in infusion solutions stored at 2-8 °C remained above 95% of the initial concentrations for at least 14 days, regardless of the type of vehicle solution. When stored at 25 °C, thiotepa infusion solutions in glucose 5% proved to be physicochemically stable for 3 days (1 mg/mL), 5 days (2 mg/mL) or 7 days (3 mg/mL). Thiotepa infusion solutions in 0.9% NaCl remained physicochemically stable for 5 days (1 mg/mL) or 7 days (2 mg/mL, 3 mg/mL). At these points in time, the specification limit of ≤0.6% monochloro-adduct was fulfilled. In parallel, an elevation of the pH values was registered. Thiotepa concentrates and infusion solutions should be stored at 2-8 °C due to temperature-dependent physicochemical stability, and for microbiological reasons. Glucose 5% infusion solution is recommended as a diluent, and stability-improving nominal 2 mg/mL to 3 mg/mL thiotepa concentrations should be obtained.

[Standardized concentrations for continuous infusion-results of a nationwide survey in German intensive care units]. / Standardkonzentrationen für Dauerinfusionen ­ Ergebnisse einer bundesweiten Befragung auf deutschen Erwachsenenintensivstationen.

BACKGROUND: Continuous infusion of numerous parenteral medications is common practice in intensive care units (ICU). In contrast to some countries, there is a lack of clearly defined standardized concentrations in Germany, especially for high-risk medications designated for infusion therapy. OBJECTIVES: The goal was to collect representative data of standardized concentrations commonly used for continuous infusion in German ICUs. Results should be used to draft nationwide recommendations for standardized continuous infusions. MATERIALS AND METHODS: To determine the nationwide acceptance and preference for medications designated for continuous infusion, a questionnaire was developed and sent to the directors of 1816 ICUs in Germany. The questionnaire comprised suggestions of 59 medicinal products with 73 concentrations. In addition, participants could make their own proposals on medications and concentrations preferably used. Evaluation was performed with SurveyMonkey® and Microsoft® Excel®. RESULTS: A total of 312 (17%) ICUs answered the survey. Data analyses indicate a very high acceptance rate for rate-controlled continuous infusion with standardized concentrations. More than 90% (50%) of participating physicians routinely use the top 10 (top 25) medicines listed for continuous infusion. For most medicines, one concentration could be identified. CONCLUSIONS: Our survey results generate a suitable basis for a nationwide list with standardized concentrations of medicines intended for continuous infusion (usually 50 mL). Publication of such a list by the corresponding expert committees is likely to be met with broad acceptance and implementation into clinical practice can be expected.

Drug safety in thyroid eye disease - a systematic review.

INTRODUCTION: The autoimmune-induced thyroid eye disease (TED) is a frequent extrathyroidal manifestation of Graves' disease and less frequently of Hashimoto's thyroiditis. Pathognomonic clinical signs, i.e. exophthalmos, double vision, and inflammation of the orbital tissue cause physical, ophthalmic, and socio-psychological limitations. AREAS COVERED: PubMed and MeSH database were searched for specific guidelines, randomized controlled trials, prospective clinical studies, systematic reviews, and meta-analyses pertaining to the safety profile of currently administered immunosuppressive agents for the treatment of TED. Occurred adverse events (AE), severe AE (SAE), side effects (SE), and severe SE (SSE) were classified according to the standardized medical dictionary for regulatory activities (MedDRA). EXPERT OPINION: This novel systematic analysis offers an overview of potential AE, SAE, and SE for currently recommended immunosuppressive drugs for the treatment of TED. Nonspecific, anti-inflammatory drugs and more specific, targeted biologicals are treatment options for active and severe TED. Critical evaluation of the pertinent literature confirms an evidence-based, beneficial efficacy/risk ratio of the current first-line and second-line treatment recommendations endorsed by the European Society of Endocrinology. However, further large, well-conceived trials are mandatory to enhance our knowledge and experience with novel specific small molecules and/or monoclonal antibodies targeting the key autoantigens in TED.

In-use stability of diluted thiamazole (methimazole) infusion solutions in prefilled 0.9% sodium chloride infusion bags for continuous infusion.

OBJECTIVE: In patients with severe hyperthyroidism unable to tolerate oral antithyroid therapy, diluted thiamazole infusion solutions (dose 120-240 mg) are administered by continuous infusion over 24 hours. Information about the type of diluent and compatibility/stability of the ready-to-administer thiamazole preparation is missing in the summary of product characteristics of the injection concentrate marketed in Germany. We studied the in-use stability of diluted infusion solutions over 24 hours. METHODS: Thiamazol 40 mg inject. Henning was diluted in prefilled polyolefin infusion bags containing 250 mL 0.9% sodium chloride (NaCl) infusion solution and kept for 24 hours at room temperature and diffuse room light. Content of the diluted infusion solutions (0.48 and 0.96 mg/mL) was analysed every 4 hours over the course of 24 hours by reversed-phase high-performance liquid chromatography. pH was measured after 0, 12 and 24 hours. The infusion bags were regularly inspected for visible particles. Subvisible particles were measured by particle counting. RESULTS: Thiamazole infusion solutions of the nominal concentrations 0.48 and 0.96 mg/mL in 0.9% NaCl diluent, kept at room temperature under diffuse room light, are physicochemically stable over a period of at least 24 hours. No evidence of colour change, particle formation or pH change was observed throughout the observation period. CONCLUSION: Dilution of 120 or 240 mg doses of licensed thiamazole injection concentrate with 0.9% NaCl infusion solution in prefilled polyolefin containers is recommendable for continuous infusion over 24 hours in the treatment of thyrotoxicosis.

Significant interaction between high-dose methotrexate and high-dose piperacillin-tazobactam causing reversible neurotoxicity and renal failure in an osteosarcoma patient.

INTRODUCTION: Pharmacokinetic interaction of high-dose methotrexate (MTX) and other concomitantly administered renally secreted medicinal products may lead to insufficient methotrexate serum level decrease and significant MTX toxicity. CASE REPORT: We report the case of an 18-year-old male patient treated with high-dose MTX for an osteosarcoma and with high-dose piperacillin-tazobactam at the same time. MTX serum levels were severely elevated 24 hours after the MTX infusion and did not decrease in accordance with the specific calcium folinate rescue protocol. The patient experienced renal failure accompanied by neurological symptoms, most consistent with MTX-related renal and CNS toxicity.Management and outcome: After discontinuation of piperacillin-tazobactam, intensified calcium folinate rescue therapy, and IV hydration, the MTX serum levels decreased appropriately, and toxicity symptoms resolved. DISCUSSION: Severe MTX-related toxicity, caused by drug-drug interaction, suggests that the concomitant use of high-dose MTX and high-dose piperacillin-tazobactam should be avoided generally.

Multi-center observational study on the adherence, quality of life, and adverse events in lung cancer patients treated with tyrosine kinase inhibitors.

INTRODUCTION: Cancer patients tend to prefer oral instead of parenteral chemotherapy. To date, there is little evidence on the medication adherence in cancer patients. We investigated medication adherence to tyrosine kinase inhibitors in patients suffering from non-small cell lung cancer. METHODS: Tyrosine kinase inhibitor adherence was measured electronically by MEMS® (medication event monitoring system) over at least six months. Adherence rates were calculated in terms of Dosing Compliance, Timing Compliance, Taking Compliance, and Drug Holidays. Patients were dichotomized as adherent when Dosing Compliance and Timing Compliance were ≥80%, Taking Compliance ranged between 90 and 110%, and <1 Drug Holiday was registered. Quality of life was assessed by two questionnaires (EORTC QLQ-C30 version 3.0, EORTC QLQ-LC13) at three time points. Adverse drug events were reported via patient diaries. RESULTS: Out of 32 patients enrolled, data from 23 patients were evaluable. Median Dosing Compliance, Taking Compliance, and Timing Compliance adherence rates of tyrosine kinase inhibitor intake amounted to 100%, 98%, and 99%, respectively; Drug Holidays were observed in three patients. Four patients were dichotomized as non-adherent. Three of them had a twice-daily tyrosine kinase inhibitor regimen. Median quality of life scores amounted to 67 (max. 100) and remained unchanged over the study period. Fatigue and rash were the most frequently reported adverse drug events. CONCLUSION: Medication adherence of non-small cell lung cancer patients treated with tyrosine kinase inhibitors was extraordinarily high and is likely to support the effectiveness of tyrosine kinase inhibitor treatment and a good quality of life over a long period of time. Adherence facilitating information and education is especially relevant for patients taking tyrosine kinase inhibitors in a twice-daily regimen.

Formulation and Administration of Biological Medicinal Products".

Monoclonal antibody (Mabs) containing medicinal products are widely used in clinical practice. Prior to parenteral administration, licensed Mab containing medicinal products are transferred to the ready-to-administer (RTA) forms. Reconstitution and/or preparation should follow the guidelines for Good Reconstitution/Good Preparation Practice. Preparation in the pharmacy must take place within the framework of a suitable quality management system. The responsible pharmacist must apply a risk assessment on the process to ensure the appropriate quality of the RTA preparation, especially because the extent of quality testing is limited by batch size (often one single unit) and time restraints. In these cases, appropriate quality is to be assured by means of qualification activities, environmental monitoring, process validation with growth medium and in-process controls. Correct labelling of the Mab containing RTA preparations includes a suitable storage advice and a defined shelf life. Physicochemical stability of a given Mab preparation can be assessed based on a specific stability study (supplied by the manufacturer in the SmPC or scientific journals, study published by an expert in a peer-reviewed scientific journal). Physicochemical stability studies require the use of various orthogonal physicochemical methods to detect accurately the degradation changes that may result from the deamidation, oxidation, disulfide formation, aggregation or fragmentation during storage. Complementary, biological activity can be measured. Compatibility studies of Mabs and devices used for preparation and administration are still scarce. Microbiological stability of Mab preparations is related to the complexity of the preparation process, the growth supporting nature of the preparation and the integrity of the container or container/closure combination. In use viability tests revealed that the potential of Mab preparations to support microbial growth was similar to that of the pure vehicle solutions used as control solutions. The enumerated microbial counts varied according to the species utilized and the type of Mab preparation. If sterility testing of the individual preparation is impossible, maximum permitted shelf life can be assessed empirically with regard to the maximum shelf lives defined in the USP <797> monograph. Finally, microbiological and physicochemical stability are to be considered concurrently when determining the shelf life of an individual Mab preparation. In each case, shelf life should be limited according to the shorter period of proven stability, either derived from the microbiological or physicochemical stability data.

Implementation and microbiological stability of dose-banded ganciclovir infusion bags prepared in series by a robotic system.

OBJECTIVES: The implementation of dose-banding (DB) in centralised, pharmacy-based cytotoxic drug preparation units allows the preparation of standardised doses in series. The aim of this study was to evaluate the feasibility of DB for the prescribing of ganciclovir (GV) infusion solutions and to investigate the microbiological stability of dose-banded, automatically prepared ready-to-administer GV infusion bags by media-fill simulation tests and sterility tests. METHODS: The frequency of prescription of GV doses was retrospectively analysed before and after implementing the DB scheme. Four dose-ranges or 'bands' and the corresponding standard doses (250, 300, 350, 400 mg) were identified. The maximum variance was set at ±10% of the individually prescribed dose. The aseptic preparation of a series of GV infusion bags was simulated with double strength tryptic soy broth as growth medium and prefilled 0.9% NaCl polyolefin infusion bags as primary packaging materials. The simulation process was performed with the APOTECAchemo robot on five consecutive days. In total, 50 infusion bags were filled, incubated and stored for 12 weeks at room temperature. The media-filled bags were visually inspected for turbidity after 2, 4, 8, 10 and 12 weeks. Following incubation, growth promotion tests were performed. During the simulation tests, airborne contamination was monitored with settle plates and microbial surface contamination with contact plates. Pooled sterility tests were performed for a series of 10 standard GV infusion bags after a 12-week storage period under refrigeration (2 °C-8 °C). RESULTS: After implementation of the DB scheme, about 60% of the prescribed GV doses were prepared as standard preparations by the robotic system. The number of different GV doses was reduced by 61.8% (76 vs 29). None of the 50 media-filled bags showed turbidity after a storage period of 12 weeks, indicating the absence of microorganisms. The environmental monitoring with settle/contact plates matched the recommended limits set for cleanroom Grade A zones, except in the loading area of the robot. Media fills used for the sterility tests remained clear during the incubation period, thereby revealing sterility. Positive growth promotion tests proved the process's reliability. CONCLUSIONS: A DB scheme for prescribing and preparation of standard GV infusion bags was successfully implemented. Microbiological tests of aseptic preparation of infusion bags in series by the APOTECAchemo robot revealed an adequate level of sterility and a well-controlled aseptic procedure. The sterility was maintained over extended storage periods, thereby encouraging extended beyond-use dating.

Glucocorticoids in Graves' orbitopathy: mechanisms of action and clinical application.

BACKGROUND: Graves' orbitopathy (GO) is the most frequent extrathyroidal manifestation of the autoimmune Graves' disease. GO significantly impacts quality of life and has a psycho-social morbidity. Inflammation and swelling of the orbital tissue often leads to proptosis, diplopia, and decrease of visual acuity. Due to the inflammatory background of the disease, glucocorticoids (GC) have been used as a first-line treatment for decades. METHODS: PubMed and MeSH database were searched for original articles, clinical trials, reviews, and meta-analyses published between 1 January 2000 and 31 March 2020 and pertaining to both the mechanism of action and immunological effects of GC as well as to the treatment of GO by GC. The publications were evaluated according to their setting and study design. RESULTS: GC act through genomic (trans-activation and trans-repression) and rapid non-genomic mechanisms. GC in general, and the intravenous (IV) administration of GC in particular, markedly decrease the activity and number of the most potent antigen-presenting dendritic cells. According to the internationally acknowledged European Thyroid Association Guidelines for the management of GO, weekly IVGC application over 12 weeks is recommended as first-line treatment for patients with active and severe GO. The daily and cumulative dose should be tailored according to clinical severity, for example, 4.5 g of IV methylprednisolone for the inflammatory component versus 7.5 g in the presence of diplopia and severe proptosis. Fast and significant improvements in orbital symptoms and signs are noted in 65-70% of patients. Long-term experience over decades, and worldwide availability at low cost, underline the clinical and therapeutic relevance of GC. Adverse events are rarely severe, dose-dependent, and usually reversible, hence easy to handle by medical investigators. Oral GC application on a daily basis is characterized by high bioavailability but reduced efficacy and increased toxicity. CONCLUSION: IVGC still represents the standard of care in active/severe GO. Innovative biologicals, like monoclonal antibodies targeting the thyrotropin/Insulin-like growth factor-1 receptors or pro-inflammatory cytokines (e.g., Interleukin-6) should be compared with standard GC treatment with respect to short- and long-term efficacy, safety, costs, and global availability.

Aerosolization Performance of Jet Nebulizers and Biopharmaceutical Aspects.

In this work, 13 jet nebulizers, some of which in different configurations, were investigated in order to identify the biopharmaceutical constraints related to the quality attributes of the medicinal products, which affect their safety, efficiency, compliance, and effectiveness. The aerosolization parameters, including the aerosol output, aerosol output rate, mass median aerodynamic diameter, and fine particle fraction, were determined according to the European Standard EN 13544-1, using sodium fluoride as a reference formulation. A comparison between the aerosol output nebulization time and the fine particle fraction displayed a correlation between the aerosol quality and the nebulization rate. Indeed, the quality of the nebulization significantly increased when the rate of aerosol emission was reduced. Moreover, the performance of the nebulizers was analyzed in terms of respirable delivered dose and respirable dose delivery rate, which characterize nebulization as the rate and amount of respirable product that could be deposited into the lungs. Depending on which of these two latter parameters was used, the nebulizers showed different performances. The differences, in terms of the rate and amount of delivered aerosol, could provide relevant information for the appropriate choice of nebulizer as a function of drug product, therapy, and patient characteristics.

Basal and Postprandial Myofibrillar Protein Synthesis Rates Do Not Differ between Lean and Obese Middle-Aged Men.

BACKGROUND: Excess lipid availability has been associated with the development of anabolic resistance. As such, obesity may be accompanied by impairments in muscle protein metabolism. OBJECTIVE: We hypothesized that basal and postprandial muscle protein synthesis rates are lower in obese than in lean men. METHODS: Twelve obese men [mean ± SEM age: 48 ± 2 y; BMI (in kg/m2): 37.0 ± 1.5; body fat: 32 ± 2%] and 12 age-matched lean controls (age: 43 ± 3 y; BMI: 23.4 ± 0.4; body fat: 21 ± 1%) received primed continuous L-[ring-2H5]-phenylalanine and L-[ring-3,5-2H2]-tyrosine infusions and ingested 25 g intrinsically L-[1-13C]-phenylalanine labeled whey protein. Repeated blood and muscle samples were obtained to assess protein digestion and amino acid absorption kinetics, and basal and postprandial myofibrillar protein synthesis rates. RESULTS: Exogenous phenylalanine appearance rates increased after protein ingestion in both groups (P < 0.001), with a total of 53 ± 1% and 53 ± 2% of dietary protein-derived phenylalanine appearing in the circulation over the 5-h postprandial period in lean and obese men, respectively (P = 0.82). After protein ingestion, whole-body protein synthesis and oxidation rates increased to a greater extent in lean men than in the obese (P-interaction < 0.05), resulting in a higher whole-body protein net balance in the lean than in the obese (7.1 ± 0.2 and 4.6 ± 0.4 µmol phenylalanine · h-1 · kg-1, respectively; P-interaction < 0.001). Myofibrillar protein synthesis rates increased from 0.030 ± 0.002 and 0.028 ± 0.003%/h in the postabsorptive period to 0.034 ± 0.002 and 0.035 ± 0.003%.h-1 in the 5-h postprandial period (P = 0.03) in lean and obese men, respectively, with no differences between groups (P-interaction = 0.58). CONCLUSIONS: Basal, postabsorptive myofibrillar protein synthesis rates do not differ between lean and obese middle-aged men. Postprandial protein handling, including protein digestion and amino acid absorption, and the postprandial muscle protein synthetic response after the ingestion of 25 g whey protein are not impaired in obese men. This trial was registered at www.trialregister.nl as NTR4060.

Leucine coingestion augments the muscle protein synthetic response to the ingestion of 15 g of protein following resistance exercise in older men.

Older adults have shown an attenuated postexercise increase in muscle protein synthesis rates following ingestion of smaller amounts of protein compared with younger adults. Consequently, it has been suggested that older adults require the ingestion of more protein to increase postexercise muscle protein synthesis rates compared with younger adults. We investigated whether coingestion of 1.5 g of free leucine with a single 15-g bolus of protein further augments the postprandial muscle protein synthetic response during recovery from resistance-type exercise in older men. Twenty-four healthy older men (67 ± 1 yr) were randomly assigned to ingest 15 g of milk protein concentrate (MPC80) with (15G+LEU; n = 12) or without (15G; n = 12) 1.5 g of free leucine after performing a single bout of resistance-type exercise. Postprandial protein digestion and amino acid absorption kinetics, whole body protein metabolism, and postprandial myofibrillar protein synthesis rates were assessed using primed, continuous infusions with l-[ring-2H5]phenylalanine, l-[ring-2H2]tyrosine, and l-[1-13C]leucine combined with ingestion of intrinsically l-[1-13C]phenylalanine-labeled milk protein. A total of 70 ± 1% (10.5 ±0.2 g) and 75 ± 2% (11.2 ± 0.3 g) of the protein-derived amino acids were released in the circulation during the 6-h postexercise recovery phase in 15G+LEU and 15G, respectively (P < 0.05). Postexercise myofibrillar protein synthesis rates were 16% (0.058 ± 0.003 vs. 0.049 ± 0.002%/h, P < 0.05; based on l-[ring-2H5]phenylalanine) and 19% (0.071 ± 0.003 vs. 0.060 ± 0.003%/h, P < 0.05; based on l-[1-13C]leucine) greater in 15G+LEU compared with 15G. Leucine coingestion further augments the postexercise muscle protein synthetic response to the ingestion of a single 15-g bolus of protein in older men.

Dose-Dependent Increases in Whole-Body Net Protein Balance and Dietary Protein-Derived Amino Acid Incorporation into Myofibrillar Protein During Recovery from Resistance Exercise in Older Men.

BACKGROUND: Age-related decline in skeletal muscle mass is at least partly attributed to anabolic resistance to food intake. Resistance exercise sensitizes skeletal muscle tissue to the anabolic properties of amino acids. OBJECTIVE: The present study assessed protein digestion and amino acid absorption kinetics, whole-body protein balance, and the myofibrillar protein synthetic response to ingestion of different amounts of protein during recovery from resistance exercise in older men. METHODS: Forty-eight healthy older men [mean ± SEM age: 66 ± 1 y; body mass index (kg/m2): 25.4 ± 0.3] were randomly assigned to ingest 0, 15, 30, or 45 g milk protein concentrate after a single bout of resistance exercise consisting of 4 sets of 10 repetitions of leg press and leg extension and 2 sets of 10 repetitions of lateral pulldown and chest press performed at 75-80% 1-repetition maximum. Postprandial protein digestion and amino acid absorption kinetics, whole-body protein metabolism, and myofibrillar protein synthesis rates were assessed using primed, continuous infusions of l-[ring-2H5]-phenylalanine, l-[ring-2H2]-tyrosine, and l-[1-13C]-leucine combined with ingestion of intrinsically l-[1-13C]-phenylalanine and l-[1-13C]-leucine labeled protein. RESULTS: Whole-body net protein balance showed a dose-dependent increase after ingestion of 0, 15, 30, or 45 g of protein (0.015 ± 0.002, 0.108 ± 0.004, 0.162 ± 0.008, and 0.215 ± 0.009 µmol Phe · kg-1 · min-1, respectively; P < 0.001). Myofibrillar protein synthesis rates were higher after ingesting 30 (0.0951% ± 0.0062%/h, P = 0.07) or 45 g of protein (0.0970% ± 0.0062%/h, P < 0.05) than after 0 g (0.0746% ± 0.0051%/h). Incorporation of dietary protein-derived amino acids (l-[1-13C]-phenylalanine) into de novo myofibrillar protein showed a dose-dependent increase after ingestion of 15, 30, or 45 g protein (0.0171 ± 0.0017, 0.0296 ± 0.0030, and 0.0397 ± 0.0026 mole percentage excess, respectively; P < 0.05). CONCLUSIONS: Dietary protein ingested during recovery from resistance exercise is rapidly digested and absorbed. Whole-body net protein balance and dietary protein-derived amino acid incorporation into myofibrillar protein show dose-dependent increases. Ingestion of ≥30 g protein increases postexercise myofibrillar protein synthesis rates in older men. This trial was registered at Nederlands Trial Register as NTR4492.

Perioperative nutritional supplementation and skeletal muscle mass in older hip-fracture patients.

Older people with hip fractures are often malnourished at the time of fracture, which can have substantial influence on mortality and clinical outcomes, as well as functional outcome and quality of life. A close relationship between protein intake and muscle maintenance has been demonstrated. Skeletal muscle weakness is an independent risk factor for falls and fall-related injuries in the elderly and is an independent marker of prognosis. However, the effect of perioperative nutritional interventions on outcomes in elderly hip-fracture patients remains controversial. In this narrative review, an overview is presented of the existing literature on nutritional status and sarcopenia in elderly hip-fracture patients, clinical outcomes, and the effects of nutritional intervention on outcome and rehabilitation in this patient group.