Investigating the Associations among Overtime Work,Health Behaviors,and Health: A Longitudinal Study among Full-time Employees

Background  

It has often been suggested that high levels of overtime lead to adverse health outcomes. One mechanism that may account for this association is that working overtime leads to elevated levels of stress, which could affect worker’s behavioral decisions or habits (such as smoking and lack of physical activity). In turn, this could lead to adverse health.     

Pharmacologic profiling of corifollitropin alfa, the first developed sustained follicle stimulant

Corifollitropin alfa (Elonva?, MSD, previously N.V. Organon or Schering-Plough Oss, The Netherlands) is a newly developed sustained follicle stimulant composed of the α subunit of human follicle-stimulating hormone (FSH) and a hybrid β subunit formed by fusion of the human chorionic gonadotropin β subunit carboxy terminal peptide with the β subunit of human FSH. Binding characteristics of corifollitropin alfa at the rat FSH receptor and transactivation properties at the rat FSH receptor, human luteinizing hormone (LH) receptor, and human thyroid-stimulating hormone receptor (TSH receptor) were assessed in vitro. Bioactivity of corifollitropin alfa in rats was also assessed. Serum corifollitropin alfa levels in rats and dogs were used to derive the main pharmacokinetic parameters of corifollitropin alfa. Binding and transactivation profile of corifollitropin alfa to rat FSH receptor was specific and comparable to that of recombinant human FSH, with no intrinsic TSH receptor or LH receptor activation. From pharmacokinetic studies, circulating half-life of corifollitropin alfa was calculated to be 17.3h in rats and 46.9h in dogs, 1.5- to 2-fold longer than recombinant FSH. Corifollitropin alfa demonstrated a 2- to 4-fold increase in bioactivity (ovarian weight, serum estradiol and progesterone, ovulated ova) over recombinant FSH across all in vivo parameters assessed. These data demonstrate that corifollitropin alfa is a specific ligand with high affinity for FSH receptor, lacking intrinsic activity for LH receptor and TSH receptor. By virtue of its increased in vivo half-life, corifollitropin alfa can be a valuable alternative to FSH by acting as a sustained follicle stimulant.     

Phagocytosis and killing of Actinobacillus pleuropneumoniae by alveolar macrophages and polymorphonuclear leukocytes isolated from pigs.

To study the cellular response of phagocytic cells to Actinobacillus pleuropneumoniae, we investigated whether porcine alveolar macrophages (AM) and polymorphonuclear leukocytes (PMN) are able to phagocytize and intracellularly kill A. pleuropneumoniae in vitro. Bacterial cultivation methods of A. pleuropneumoniae were used to assess in vitro phagocytosis and the ability to kill. A specific-pathogen-free pig was killed, blood was collected, and PMN were isolated and counted. The AM were isolated by lung lavage of the same animal and counted. In addition, convalescent-stage serum was collected from a specific-pathogen-free pig that was infected with A. pleuropneumoniae. Both porcine AM and porcine PMN effectively phagocytized A. pleuropneumoniae in the presence of convalescent-stage pig serum. PMN killed 90 to 99% of the bacteria intracellularly, whereas AM did not. Because A. pleuropneumoniae produces exotoxins that kill porcine AM and porcine PMN, we incubated equal amounts of bacteria and phagocytic cells and tested the viability of the cells 120 min later. In the presence of convalescent-stage pig serum, A. pleuropneumoniae was toxic to AM but not to PMN. Probably in porcine AM, intracellular released toxins of A. pleuropneumoniae lessen the ability of the cell to kill the bacterium. Consecutive lysis of AM and release of viable A. pleuropneumoniae may initiate the characteristic porcine pleuropneumonia.     

Convalescent pigs are protected completely against infection with a homologous Actinobacillus pleuropneumoniae strain but incompletely against a heterologous-serotype strain.

To study whether Actinobacillus pleuropneumoniae induces a species-specific immunity, we infected pigs in the left lung with serotype 3 or 9 and after 3 weeks we infected their right lungs with serotype 9. Convalescent pigs were protected against homologous strain reinfection, but after heterologous strain reinfection the degree of protection varied. Neutralizing antibodies were not essential for protection.     

Peroral absorption of octreotide in pigs formulated in delivery systems on the basis of superporous hydrogel polymers

Purpose. The aim of this study was to investigate the enhancement of peroral octreotide absorption using delivery systems based on superporous hydrogel (SPH) and SPH composite (SPHC) polymers. Methods. Six female pigs (BW of 23.5 kg) were used in this study. SPH-based delivery systems were made of two components: 1) a conveyor system made of SPH and SPHC; 2) a core that contained octreotide. The core was inserted into the conveyor system (core inside, c.i.) or attached to the surface of the conveyor system (core outside, c.o.). Four different peroral formulations were investigated: c.i., c.o., core outside including trimethyl chitosan chloride (c.o.t.), and octreotide only in the absence of any polymer (o.o.). All formulations were placed in enteric-coated gelatin capsules (size 000) and administered perorally. Intravenous administration was used to determine bioavailability (F) values. Blood samples taken from the cannulated jugular vein were analyzed by radioimmunoassay. Results. Peroral administration of 15 mg o.o. resulted in low F values of 1.0 ± 0.6% (mean ± SEM) whereas c.i. and c.o. administrations resulted in remarkably higher F values of 12.7 ± 3.6% and 8.7 ± 2.4%, respectively. By the addition of trimethyl chitosan chloride as an extra absorption enhancer to c.o.t., the highest bioavailability (16.1 ± 3.3%) was achieved. Conclusions. These novel delivery systems based on SPH and SPHC polymers are able to increase the peroral bioavailability of octreotide by mechanical fixation and increasing the retention of the dosage form at the absorption site.     

Time interval from primary melanoma to first distant recurrence in relation to patient outcomes in advanced melanoma

Since the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune-surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first-line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression-free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti-PD-1-based treatment (n = 1844) or BRAF(/MEK) inhibition (n = 1618). For ICI-treated patients with a TFDR <2 years, median OS was 25.0 months, compared to 37.3 months for a TFDR >5 years (P = .014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6 months for TFDR <2 years compared to 11.1 months for >5 years, P = .004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first-line ICI or targeted therapy.     

A prediction model for response to immune checkpoint inhibition in advanced melanoma

Predicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal–external cross-validation. Included patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence—all at start of ICI—, and location and type of primary melanoma, the presence of satellites and/or in-transit metastases at primary diagnosis and sex. The over-optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64–0.66). The range of predicted response probabilities was 7%–81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression-free survival (20.0 vs 2.8 months; P < .001) and median overall survival (62.0 vs 8.0 months; P < .001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis.