Impact of 18FFDG-PET/CT and Laparoscopy in Staging of Locally Advanced Gastric Cancer: A Cost Analysis in the Prospective Multicenter PLASTIC-Study.

BACKGROUND: Unnecessary D2-gastrectomy and associated costs can be prevented after detecting non-curable gastric cancer, but impact of staging on treatment costs is unclear. This study determined the cost impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FFDG-PET/CT) and staging laparoscopy (SL) in gastric cancer staging. MATERIALS AND METHODS: In this cost analysis, four staging strategies were modeled in a decision tree: (1) 18FFDG-PET/CT first, then SL, (2) SL only, (3) 18FFDG-PET/CT only, and (4) neither SL nor 18FFDG-PET/CT. Costs were assessed on the basis of the prospective PLASTIC-study, which evaluated adding 18FFDG-PET/CT and SL to staging advanced gastric cancer (cT3-4 and/or cN+) in 18 Dutch hospitals. The Dutch Healthcare Authority provided 18FFDG-PET/CT unit costs. SL unit costs were calculated bottom-up. Gastrectomy-associated costs were collected with hospital claim data until 30 days postoperatively. Uncertainty was assessed in a probabilistic sensitivity analysis (1000 iterations). RESULTS: 18FFDG-PET/CT costs were €1104 including biopsy/cytology. Bottom-up calculations totaled €1537 per SL. D2-gastrectomy costs were €19,308. Total costs per patient were €18,137 for strategy 1, €17,079 for strategy 2, and €19,805 for strategy 3. If all patients undergo gastrectomy, total costs were €18,959 per patient (strategy 4). Performing SL only reduced costs by €1880 per patient. Adding 18FFDG-PET/CT to SL increased costs by €1058 per patient; IQR €870-1253 in the sensitivity analysis. CONCLUSIONS: For advanced gastric cancer, performing SL resulted in substantial cost savings by reducing unnecessary gastrectomies. In contrast, routine 18FFDG-PET/CT increased costs without substantially reducing unnecessary gastrectomies, and is not recommended due to limited impact with major costs. TRIAL REGISTRATION: NCT03208621. This trial was registered prospectively on 30-06-2017.

Understanding the Risk of Sexual Reoffending in Adult Men: A Network-Based Model.

The predominant approach to understand dynamic risk factors of sexual reoffending has been referred to as the Propensities Model (Thornton, 2016). According to this model, dynamic risk factors can be conceptualized as latent constructs whose change alters the risk of sexual reoffending. Despite its strengths and contributions to research, this model does not offer answers to the question of how dynamic risk factors contribute to the risk of sexual reoffending, or of how sustained change in risk might take place. In this paper we introduce the Network-Based Model of Risk of Sexual Reoffending (NBM-RSR), which addresses several limitations and constraints of the Propensities Model and offers empirically testable propositions regarding the nature and development of the risk of sexual reoffending. The NBM-RSR considers risk of sexual reoffending to involve a self-sustaining network of causally connected dynamic risk factors. Consistent with this, an increased risk of sexual reoffending is characterized through a network that contains more and stronger interconnected dynamic risk factors with a higher strength. Sustained change in risk of sexual reoffending occurs when activity in the network exceeds a critical point resulting in a new self-sustaining network. Propositions based on the NBM-RSR are introduced and translated into testable hypotheses. These propositions revolve around (a) risk of sexual reoffending resulting from the construction of a network of causally connected dynamic risk factors, (b) network stability, sudden changes, and critical transitions, and (c) dynamic risk factors' relative influence on risk of sexual reoffending.

Budesonide/formoterol maintenance and reliever therapy versus fluticasone/salmeterol fixed-dose treatment in patients with COPD.

BACKGROUND: Maintenance and reliever therapy (MART) with inhaled corticosteroid (ICS)/formoterol effectively reduces exacerbations in asthma. We aimed to investigate its efficacy compared with fixed-dose fluticasone/salmeterol in chronic obstructive pulmonary disease (COPD). METHODS: Patients with COPD and ≥1 exacerbation in the previous 2 years were randomly assigned to open-label MART (Spiromax budesonide/formoterol 160/4.5 µg 2 inhalations twice daily+1 prn) or fixed-dose therapy (Diskus fluticasone propionate/salmeterol combination (FSC) 500/50 µg 1 inhalation twice daily+salbutamol 100 µg prn) for 1 year. The primary outcome was rate of moderate/severe exacerbations, defined by treatment with oral prednisolone and/or antibiotics. RESULTS: In total, 195 patients were randomised (MART Bud/Form n=103; fixed-dose FSC n=92). No significant difference was seen between MART and FSC therapy in exacerbation rates (1.32 vs 1.32 /year, respectively, rate ratio 1.05 (95% CI 0.79 to 1.39); p=0.741). No differences in lung function parameters or health status were observed. Total ICS dose was significantly lower with MART than FSC therapy (budesonide-equivalent 928 µg/day vs 1747 µg/day, respectively, p<0.05). Similar proportions of patients reported adverse events (MART Bud/Form: 73% vs fixed-dose FSC: 68%, p=0.408) and pneumonias (MART: 5% vs FSC: 1%, p=0.216). CONCLUSIONS: This first study of MART in COPD found that budesonide/formoterol MART might be similarly effective to fluticasone/salmeterol fixed-dose therapy in moderate to severe patients with COPD, at a lower daily ICS dosage. Further evidence is needed about long-term safety.

Gastrointestinal Symptoms After Resection of Esophagogastric Cancer: A Longitudinal Study on Their Incidence and Impact on Patient-Reported Outcomes.

BACKGROUND: This study assesses the incidence of gastrointestinal symptoms in the first year after resection of esophageal or gastric cancer and its association with health-related quality of life (HRQoL), functioning, work productivity, and daily activities. PATIENTS AND METHODS: Patients diagnosed with esophageal or gastric cancer between 2015 and 2021, who underwent a resection, and completed ≥ 2 questionnaires from the time intervals prior to resection and 0-3, 3-6, 6-9, and 9-12 months after resection were included. Multivariable generalized linear mixed models were used to assess changes in gastrointestinal symptoms over time and the impact of the number of gastrointestinal symptoms on HRQoL, functioning, work productivity, and daily activities for patients who underwent an esophagectomy or gastrectomy separately. RESULTS: The study population consisted of 961 (78.8%) and 259 (21.2%) patients who underwent an esophagectomy and gastrectomy, respectively. For both groups, the majority of gastrointestinal symptoms changed significantly over time. Most clinically relevant differences were observed 0-3 after resection compared with prior to resection and included increased diarrhea, appetite loss, and eating restrictions, and specifically after esophagectomy dry mouth, trouble with coughing, and trouble talking. At 9-12 after resection one or more severe gastrointestinal symptoms were reported by 38.9% after esophagectomy and 33.7% after gastrectomy. A higher number of gastrointestinal symptoms was associated with poorer functioning, lower HRQoL, higher impairment in daily activities, and lower work productivity. CONCLUSIONS: This study shows that gastrointestinal symptoms are frequently observed and burdensome after esophagectomy or gastrectomy, highlighting the importance to address these sequelae for high quality survivorship.

The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial.

BACKGROUND: P2X3 receptor antagonists seem to have a promising potential for treating patients with refractory chronic cough. In this double-blind, randomized, placebo-controlled study, we investigated the efficacy, safety, and tolerability of the novel selective P2X3 receptor antagonist filapixant (BAY1902607) in patients with refractory chronic cough. METHODS: Following a crossover design, 23 patients with refractory chronic cough (age: 60.4 ± 9.1 years) received ascending doses of filapixant in one period (20, 80, 150, and 250 mg, twice daily, 4-days-on/3-days-off) and placebo in the other. The primary efficacy endpoint was the 24-h cough frequency on Day 4 of each dosing step. Further, subjective cough severity and health-related quality of life were assessed. RESULTS: Filapixant at doses ≥ 80 mg significantly reduced cough frequency and severity and improved cough health-related quality of life. Reductions in 24-h cough frequency over placebo ranged from 17% (80 mg dose) to 37% (250 mg dose), reductions over baseline from 23% (80 mg) to 41% (250 mg) (placebo: 6%). Reductions in cough severity ratings on a 100-mm visual analog scale ranged from 8 mm (80 mg) to 21 mm (250 mg). No serious or severe adverse events or adverse events leading to discontinuation of treatment were reported. Taste-related adverse events occurred in 4%, 13%, 43%, and 57% of patients treated with filapixant 20, 80, 150, and 250 mg, respectively, and in 12% treated with placebo. CONCLUSIONS: Filapixant proved to be efficacious, safe, and-apart from the occurrence of taste disturbances, especially at higher dosages-well tolerated during the short therapeutic intervention. Clinical trial registration EudraCT, eudract.ema.europa.eu, 2018-000129-29; ClinicalTrials.gov, NCT03535168.

Management of anastomotic leakage after robot-assisted minimally invasive esophagectomy with an intrathoracic anastomosis.

Anastomotic leakage is a feared complication after esophagectomy and associated with increased post-operative morbidity and mrotality. The aim of this study was to evaluate the management of leakage after robot-assisted minimally invasive esophagectomy (RAMIE) with intrathoracic anastomosis. From a single center prospectively maintained database, all patients with anastomotic leakages defined by the Esophageal Complications Consensus Group between 2016 and 2021 were included. Contained leakage was defined as presence of air or fluid at level of the anastomosis without the involvement of the mediastinum or thorax. Non-contained leakage was defined as mediastinitis and/or mediastinal/pleural fluid collections. The primary outcome was 90-day mortality and the secondary outcome was successful recovery. In this study, 40 patients with anastomotic leakage were included. The 90-day mortality rate was 3% (n = 1). Leakage was considered contained in 29 patients (73%) and non-contained in 11 patients (27%). In the contained group, the majority of the patients were treated non-surgically (n = 27, 93%) and management was successful in 22 patients (76%). In the non-contained group, all patients required a reoperation with thoracic drainage and management was successful in seven patients (64%). Management failed in 11 patients (28%) of whom 7 developed an esophagobronchial fistula, 3 had a disconnection of the anastomosis and 1 died of a septic bleeding. In conclusion, this study demonstrates that the management anastomotic leakage in patients who underwent RAMIE with an intrathoracic anastomosis was successful in 73% of the patients with a 90-day mortality rate of 3%. A differentiated approach for the management of intrathoracic anastomotic leakage is proposed.

Opioids in patients with COPD and refractory dyspnea: literature review and design of a multicenter double blind study of low dosed morphine and fentanyl (MoreFoRCOPD).

BACKGROUND: Refractory dyspnea or breathlessness is a common symptom in patients with advanced chronic obstructive pulmonary disease (COPD), with a high negative impact on quality of life (QoL). Low dosed opioids have been investigated for refractory dyspnea in COPD and other life-limiting conditions, and some positive effects were demonstrated. However, upon first assessment of the literature, the quality of evidence in COPD seemed low or inconclusive, and focused mainly on morphine which may have more side effects than other opioids such as fentanyl. For the current publication we performed a systematic literature search. We searched for placebo-controlled randomized clinical trials investigating opioids for refractory dyspnea caused by COPD. We included trials reporting on dyspnea, health status and/or QoL. Three of fifteen trials demonstrated a significant positive effect of opioids on dyspnea. Only one of four trials reporting on QoL or health status, demonstrated a significant positive effect. Two-thirds of included trials investigated morphine. We found no placebo-controlled RCT on transdermal fentanyl. Subsequently, we hypothesized that both fentanyl and morphine provide a greater reduction of dyspnea than placebo, and that fentanyl has less side effects than morphine. METHODS: We describe the design of a robust, multi-center, double blind, double-dummy, cross-over, randomized, placebo-controlled clinical trial with three study arms investigating transdermal fentanyl 12 mcg/h and morphine sustained-release 10 mg b.i.d. The primary endpoint is change in daily mean dyspnea sensation measured on a numeric rating scale. Secondary endpoints are change in daily worst dyspnea, QoL, anxiety, sleep quality, hypercapnia, side effects, patient preference, and continued opioid use. Sixty patients with severe stable COPD and refractory dyspnea (FEV1 < 50%, mMRC ≥ 3, on optimal standard therapy) will be included. DISCUSSION: Evidence for opioids for refractory dyspnea in COPD is not as robust as usually appreciated. We designed a study comparing both the more commonly used opioid morphine, and transdermal fentanyl to placebo. The cross-over design will help to get a better impression of patient preferences. We believe our study design to investigate both sustained-release morphine and transdermal fentanyl for refractory dyspnea will provide valuable information for better treatment of refractory dyspnea in COPD. Trial registration NCT03834363 (ClinicalTrials.gov), registred at 7 Feb 2019, https://clinicaltrials.gov/ct2/show/NCT03834363 .

Chemotherapy and Tyrosine Kinase Inhibitors in the last month of life in patients with metastatic lung cancer: A patient file study in the Netherlands.

OBJECTIVE: Chemotherapy in the last month of life for patients with metastatic lung cancer is often considered as aggressive end-of-life care. Targeted therapy with Tyrosine Kinase Inhibitors (TKIs) is a relatively new treatment of which not much is known yet about use in the last month of life. We examined what percentage of patients received chemotherapy or TKIs in the last month of life in the Netherlands. METHODS: Patient files were drawn from 10 hospitals across the Netherlands. Patients had to meet the following eligibility criteria: metastatic lung cancer; died between June 1, 2013 and July 31, 2015. RESULTS: From the included 1,322 patients, 39% received no treatment for metastatic lung cancer, 52% received chemotherapy and 9% received TKIs. A total of 232 patients (18%) received treatment in the last month of life (11% chemotherapy, 7% TKIs). From the patients who received chemotherapy, 145 (21%) received this in the last month of life and 79 (11%) started this treatment in the last month of life. TKIs were given and started more often in the last month of life: from the patients who received TKIs, 87 (72%) received this treatment in the last month of life and 15 (12%) started this treatment in the last month of life. CONCLUSION: A substantial percentage of patient received and even started chemotherapy or TKIs in the last month of life. For chemotherapy, this might be seen as aggressive care. TKIs are said to have less side effects, do not lead to many hospital visits and due to the rapid response, are considered good palliation. However, it is not known, yet possible that, when patients still receiving treatment until shortly before death, this might influence preparing for death in a negative way.

Current trends in the management of Gastro-oEsophageal cancers: Updates to the ESSO core curriculum (ESSO-ETC-UGI-WG initiative).

Gastro-oEsophageal Cancers (GECs) are severe diseases whose management is rapidly evolving. The European Society of Surgical Oncology (ESSO) is committed to the generation and spread of knowledge, and promotes the multidisciplinary management of cancer patients through its core curriculum. The present work discusses the approach to GECs, including the management of oligometastatic oesophagogastric cancers (OMEC), the diagnosis and management of peritoneal metastases from gastric cancer (GC), the management of Siewert Type II tumors, the importance of mesogastric excision, the role of robotic surgery, textbook outcomes, organ preserving options, the use of molecular markers and immune check-point inhibitors in the management of patients with GECs, as well as the improvement of current clinical practice guidelines for the management of patients with GECs. The aim of the present review is to provide a concise overview of the state-of-the-art on the management of patients with GECs and, at the same time, to share the latest advancements in the field and to foster the debate between surgical oncologists treating GECs worldwide. We are sure that our work will, at the same time, give an update to the advanced surgical oncologists and help the training surgical oncologists to settle down the foundations for their future practice.

Tailored anticoagulant treatment after a first venous thromboembolism: protocol of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study - cohort-based randomised controlled trial.

INTRODUCTION: Patients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain whether patients with an intermediate recurrence risk or with a high recurrence and high bleeding risk will benefit from extended anticoagulant treatment, and whether a strategy where anticoagulant duration is tailored on the predicted risks of rVTE and bleeding can improve outcomes. The aim of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study is to evaluate the outcomes of tailored duration of long-term anticoagulant treatment based on individualised assessment of rVTE and major bleeding risks. METHODS AND ANALYSIS: The L-TRRiP study is a multicentre, open-label, cohort-based, randomised controlled trial, including patients with a first VTE. We classify the risk of rVTE and major bleeding using the L-TRRiP and VTE-BLEED scores, respectively. After 3 months of anticoagulant therapy, patients with a low rVTE risk will discontinue anticoagulant treatment, patients with a high rVTE and low bleeding risk will continue anticoagulant treatment, whereas all other patients will be randomised to continue or discontinue anticoagulant treatment. All patients will be followed up for at least 2 years. Inclusion will continue until the randomised group consists of 608 patients; we estimate to include 1600 patients in total. The primary outcome is the combined incidence of rVTE and major bleeding in the randomised group after 2 years of follow-up. Secondary outcomes include the incidence of rVTE and major bleeding, functional outcomes, quality of life and cost-effectiveness in all patients. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft. Results are expected in 2028 and will be disseminated through peer-reviewed journals and during (inter)national conferences. TRIAL REGISTRATION NUMBER: NCT06087952.

Sonographic follow-up of diaphragm function in COVID-19: an exploratory study.

Introduction: Survivors of COVID-19 frequently endure chronic disabilities. We hypothesise that diaphragm function has a long recovery time after COVID-19 hospitalisation and may play a role in post-COVID-19 syndrome. The aim of this study was to assess diaphragm function during COVID-19 hospitalisation and during recovery. Methods: We conducted a prospective single-centre cohort study in 49 enrolled patients, of which 28 completed 1-year follow-up. Participants were evaluated for diaphragm function. Diaphragm function was assessed using ultrasound measuring of diaphragm thickening fraction (TF) within 24 h after admission, after 7 days of admission or at discharge, whichever came first, and 3 and 12 months after hospital admission. Results: Estimated mean TF increased from 0.56 (95% CI 0.46-0.66) on admission to 0.78 (95% CI 0.65-0.89) at discharge or 7 days after admission, to 1.05 (95% CI 0.83-1.26) 3 months after admission and to 1.54 (95% CI 1.31-1.76) 12 months after admission. The improvements from admission to discharge, 3 months and 12 months were all significant (linear mixed modelling; p=0.020, p<0.001 and p<0.001, respectively), and the improvement from discharge to 3-month follow-up was borderline significant (p<0.1). Conclusion: Diaphragm function was impaired during hospitalisation for COVID-19. During recovery in hospital and up to 1-year follow-up, diaphragm TF improved, suggesting a long recovery time of the diaphragm. Diaphragm ultrasound may be a valuable modality in the screening and follow-up of (post-)COVID-19 patients for diaphragm dysfunction.

Consensus goals and standards for specialist cough clinics: the NEUROCOUGH international Delphi study.

Background: Current guidelines on the management of chronic cough do not provide recommendations for the operation of specialist cough clinics. The objective of the present study was to develop expert consensus on goals and standard procedures for specialist cough clinics. Methods: We undertook a modified Delphi process, whereby initial statements proposed by experts were categorised and presented back to panellists over two ranking rounds using an 11-point Likert scale to identify consensus. Results: An international panel of 57 experts from 19 countries participated, with consensus reached on 15 out of 16 statements, covering the aims, roles and standard procedures of specialist cough clinics. Panellists agreed that specialist cough clinics offer optimal care for patients with chronic cough. They also agreed that history taking should enquire as to cough triggers, cough severity rating scales should be routinely used, and a minimum of chest radiography, spirometry and measurements of type 2 inflammatory markers should be undertaken in newly referred patients. The importance of specialist cough clinics in promoting clinical research and cough specialty training was acknowledged. Variability in healthcare resources and clinical needs between geographical regions was noted. Conclusions: The Delphi exercise provides a platform and guidance for both established cough clinics and those in planning stages.

The beta-human chorionic gonadotropin-related peptide LQGV exerts anti-inflammatory effects through activation of the adrenal gland and glucocorticoid receptor in C57BL/6 mice.

The systemic inflammatory response syndrome is a complex host response to a variety of clinical insults, generally leading to severe pathology. The human chorionic gonadotropin ß-chain-related tetrapeptide leucine-glutamine-glycine-valine (LQGV) reduces hemorrhagic and LPS-induced systemic inflammatory response syndrome, but its mechanisms of action are not yet fully understood. Through the combination of in vivo, in vitro, and ex vivo approaches, we demonstrate that LQGV actively stimulates corticosterone production in mice and thereby suppresses in vivo TLR4-directed inflammation upon LPS administration. Blocking in vivo glucocorticosteroid receptor signaling reduced the prosurvival effect of LQGV. Also, upon multiple TLR activation by heat-killed Listeria monocytogenes, splenocytes from LQGV-treated mice produced significantly less TNF-α and IL-6, which was absent after in vitro blockage of the glucocorticosteroid receptor. Using adrenal gland and adrenal cell line cultures, we show that LQGV stimulates corticosterone production. Moreover, by using specific pharmacological inhibitors of the adrenocorticotropic hormone (ACTH) and luteinizing hormone receptors as well as of cAMP signaling, we demonstrate that LQGV stimulates the ACTH receptor. These data show that the ß-human chorionic gonadotropin-related tetrapeptide LQGV stimulates adrenal glucocorticosteroid production through activation of the ACTH receptor with consequent glucocorticoid receptor activation and immunosuppression in C57BL/6 mice.

Percutaneous ultrasound-guided biopsies in the evaluation of thoracic tumours after PET-CT: a prospective diagnostic study.

BACKGROUND: Lesions detected by positron emission tomography-computed tomography (PET-CT) during the analysis of thoracic tumours are often impalpable at physical examination, and subsequent ultrasound (US) may aid in finding these lesions for pathologic evaluation. OBJECTIVES: The success rate of percutaneous US-guided biopsies of palpable and non-palpable lesions and the impact on tumour stage were studied prospectively. METHODS: Lesions, significant for diagnosis and disease stage, with metabolic activity on PET-CT and presumed appropriate for percutaneous approach under US guidance were selected for cytologic aspiration or tissue core biopsies. RESULTS: In 127 patients, 134 lesions (subdivided into 24 local thoracic, 74 supraclavicular and 36 distant metastatic lesions) were biopsied percutaneously under US guidance. Malignancy, benign disease and inadequate biopsies were found in 80% (106/134), 14% (19/134) and 7% (9/134), respectively. In 55% (56/102) of patients, biopsies confirmed the disease stage. Fifty-one percent (18/35) of distant lesions and 54% (43/68) of supraclavicular lesions were impalpable on physical examination. CONCLUSIONS: US-guided biopsies in patients with suspected thoracic malignancy on PET-CT provide an excellent tool for obtaining a pathological diagnosis, leading to a definitive disease stage in over half of the patients.

The demographics, clinical characteristics and quality of life of patients with chronic cough from the Isala Cough Clinic in the Netherlands.

Introduction: Chronic cough affects ∼10% of the population and adversely impacts quality of life. This retrospective observational cohort study aimed to identify the demographics, clinical characteristics and quality of life of the chronic cough population in a Dutch chronic cough clinic, at baseline and following treatment at 6 months. Patients were categorised based on the underlying phenotype and response to treatment. Methods: Retrospective data on 2397 patients who were diagnosed according to standard guidelines of the American College of Chest Physicians were analysed. Quality of life was captured via the Leicester Cough Questionnaire, the Cough Numeric Rating Scale and the Hospital Anxiety and Depression Scale. Results: Mean patient age was 59 years; 62.5% of the patients were female; and 69.1% had at least one underlying phenotype associated with chronic cough. Of the latter, 52.1% had bronchial hyperresponsiveness/airflow limitation, 33.3% had airway reflux and 20.1% had upper airway cough syndrome. 46% of patients with a phenotype, and 51% without, experienced no improvement in their quality of life or still had significant cough remaining after 6 months. Of patients with available quality-of-life data, 37.5% were categorised as having refractory chronic cough, and 9.5% were categorised as unexplained chronic cough. Discussion: This study highlights the poor quality-of-life outcomes in patients with chronic cough, despite interventions to treat underlying conditions, and indicates a need to manage chronic cough irrespective of phenotype.

The ß-human chorionic gonadotropin-related peptide LQGV reduces mortality and inflammation in a murine polymicrobial sepsis model.

OBJECTIVE: Mortality in sepsis remains high and efforts to modulate the inflammatory response so far mostly failed to improve survival. The human chorionic gonadotropin-related tetrapeptide LQGV was recently shown to exert anti-inflammatory activity. The aim of this study was to assess the effect of LQGV on cecal ligation and puncture-induced mortality and inflammation. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: To examine the effect of LQGV by itself on cecal ligation and puncture-induced mortality and inflammation, C57BL/6 mice were exposed to a moderate cecal ligation and puncture procedure (40% ligation and double puncture) with a mortality rate of approximately 80% within 5 days in control mice. In addition, to examine whether LQGV was of additive value to standard sepsis care (antibiotics and fluid resuscitation), a more severe cecal ligation and puncture procedure was used (80% ligation and double puncture), yielding approximately 100% mortality within 12 days in control mice. LQGV (5 mg/kg body weight), phosphate-buffered saline (as control), or dexamethasone (2.5 mg/kg body weight) was administered perioperatively. Survival was monitored for 21 days and inflammatory markers were determined in plasma, peritoneal cavity, and lungs. MEASUREMENTS AND MAIN RESULTS: LQGV significantly improved survival from 20% to 50% during the first 5 days after moderate cecal ligation and puncture. This was associated with reduced cytokine and E-selectin levels in peritoneal lavage fluid, lungs, and, to a lesser extent, in plasma. LQGV treatment also reduced pulmonary nuclear factor-κB activation and pulmonary damage. In the severe cecal ligation and puncture model, LQGV combined with fluid resuscitation and antibiotics resulted in significantly better survival (70%) than that observed with fluid resuscitation and antibiotics alone (30%). CONCLUSIONS: LQGV improves survival after cecal ligation and puncture. This is likely established by a modest reduction of the acute inflammatory response through a nuclear factor-κB-dependent mechanism. Furthermore, LQGV may be a valuable additive next to the standard care in polymicrobial sepsis.

Mild versus strong anti-inflammatory therapy during early sepsis in mice: a matter of life and death.

OBJECTIVE: A recent literature-based study suggested that low-dose corticosteroid treatment has a beneficial effect on mortality in septic patients, whereas high-dose corticosteroid treatment has not. This suggests that mild down-regulation of the inflammatory response during early sepsis may be beneficial while extensive reduction of the inflammatory response is not. To investigate this hypothesis, we examined the effect of dexamethasone in varying doses on cecal ligation and puncture-induced inflammation and mortality. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: Mice were subjected to cecal ligation and puncture, and dexamethasone was administered intravenously at a dosage of 0.05 (L/DEX), 0.25 (M/DEX), or 2.5 (H/DEX) mg/kg body weight 20 mins postoperatively. Mice receiving phosphate-buffered saline served as controls. Survival was recorded up to 21 days and inflammatory markers were determined in plasma, lungs, liver, and kidney at 6 hrs following cecal ligation and puncture as well as bacterial load in blood and peritoneal fluid. MEASUREMENTS AND MAIN RESULTS: L/DEX treatment significantly improved survival compared with control mice, whereas treatment with higher concentrations of dexamethasone (M/DEX and H/DEX) did not. Treatment with either M/DEX or H/DEX was associated with significantly (p < .05) reduced cytokine plasma levels as compared with controls at 6 hrs after cecal ligation and puncture. In addition, M/DEX or H/DEX powerfully reduced cytokine messenger RNA expression in the lung, liver, and kidney. In contrast, treatment with L/DEX was associated with a mild, but nonsignificant, reduction of cytokine plasma levels. In addition, L/DEX moderately reduced cytokine messenger RNA expression in lung, liver, and kidney tissue and reduced the occurrence of bacteremia. CONCLUSIONS: A modest down-regulation of the early sepsis-associated inflammatory response improves survival in a murine cecal ligation and puncture model. We propose that the success of anti-inflammatory therapies in a septic setting fundamentally depends on finding a treatment balance that reduces the hyper-inflammation-induced pathology but still allows adequate defense against pathogens.

[Chronic cough in adults]. / Chronische hoest bij volwassenen.

Cough is a physiological defense mechanism. However, excessive cough is known to have a great impact on quality of life. Cough is considered to be chronic when it lasts longer than 8 weeks. In the Netherlands, the prevalence is 10.9%. The concept as a whole is called 'cough hypersensitivity' in which there is a hypersensitivity of the cough reflex to aspecific stimuli. Specific treatment of the phenotype is important. If no specific phenotype is found it is called 'unexplained chronic cough' (UCC) and if symptoms persist despite treatment it is called 'chronic refractory cough' (CRC). Neuromodulating drugs are the main treatment in CRC. However, a suitable condition often cannot be achieved because of severe side effect and great interindividual variability in pharmacokinetics. New drugs, P2X3-antagonists, are being developed. These drugs mediate in a late phase of the cough reflex and are thereby considered to have fewer side effects.