Cost-of-illness of metastatic gastroenteropancreatic neuroendocrine tumours in Sweden-A population-based register-linkage study.

The objective was to estimate the cost-of-illness of grades 1 and 2 metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in Sweden in 2013 in a population-based study including all patients diagnosed between 2005 and 2013. Data were obtained from national registers, and patients who utilised healthcare resources due to metastatic GEP-NETs in 2013 were included. The study included 478 patients (mean age 64 [SD=11] years, 51% men). The majority (80%) had small intestinal NET, 10% had pancreatic NET, and 41% had carcinoid syndrome. The total cost-of-illness was €12,189,000 in 2013, of which direct costs constituted 77% and costs from production loss constituted 22%. The largest contributor to the direct medical costs was prescription drugs (54%; primarily somatostatin analogues [91% of the total drug cost]). Production loss due to sickness absence constituted 52% of the total costs of production loss. The total annual cost per patient was €25,500. By patient group, the cost was €24,800 (95% CI €21,600-€28,100) for patients with small intestinal NET, €37,300 (95% CI €23,300-€51,300) for those with pancreatic NET and €18,600 (95% CI €12,600-€24,500) for patients with other GEP-NETs. To conclude, the total annual cost of grades 1 and 2 metastatic GEP-NETs in Sweden was €25,500 per patient and year.

Inhibition of phospholipase A(2) abrogates intracellular processing of NADPH-oxidase derived reactive oxygen species in human neutrophils.

Upon activation of human neutrophils, superoxide can be produced at two cellular sites; either in the plasma membrane, giving extracellular release of oxidants, or in intracellular organelles, resulting in oxidants being retained in the cell. The involvement of phospholipase A(2) (PLA(2)) in phorbol myristate acetate (PMA)-induced activation of the two pools of NADPH-oxidase was investigated using a variety of PLA(2) inhibitors and the oxidase activity was measured by luminol/isoluminol-amplified chemiluminescence (CL). Two of the seven inhibitors were without effect, two inhibitors inhibited both intra- and extracellular ROS production equally, and three inhibitors inhibited intracellular but not extracellular CL. Using another technique to measure ROS, PHPA oxidation, we found that intracellular ROS production was unaltered with the three last inhibitors, indicating that PLA(2) is not involved in the NADPH-oxidase activity per se, but in the intracellular processing of the radicals necessary for the CL reaction to take place. The PLA(2) inhibitors did not abolish the activity of myeloperoxidase (MPO), an enzyme necessary for intracellular CL to occur. Instead, we suggest that these PLA(2) inhibitors block heterotypic granule fusion and prohibit the colocalization of ROS and MPO needed for intracellular CL activity.

Individualized metal implants for focal cartilage lesions in the knee can be cost-effective: A simulation on 47-year-old in a Swedish setting.

OBJECTIVES: In the aging population, the knee is the joint most commonly causing impaired function and incapacity. While definite treatment by prosthetic replacement is often performed late, symptomatic knee cartilage lesions cause much suffering also in younger ages. Early intervention could, therefore, be instituted at an early stage to the benefit of both patients and society. Small, metal surface, resurfacing implants have been tested with promising results. A system that features patient-specific implants and surgical instruments shows good clinical results and favorable survival rates. This study aims to assess the cost utility of this metal device compared with microfracture (MFX), being the standard procedure in Sweden. METHODS: We constructed a simulation model in Excel. In the model, a cohort of 47-year-old patients (which is the mean age of patients treated with the metal implant) with symptomatic knee cartilage lesions received either MFX or metal implantation. Outcomes for the cohort were simulated over 40 years, such as in a previously published model based on MFX, and sensitivity analyses (deterministic and probabilistic) of the results were undertaken. Data on transition probabilities, costs, and quality of life were taken from clinical data, published literature, and official price lists. Only direct medical costs were included. RESULTS: Results from the analysis showed that the metal device is a cost-effective treatment strategy compared with MFX. The incremental cost-effectiveness ratio (ICER) reached acceptable levels at ∼5 years postoperatively. Over the full-time horizon of 40 years, the metal device was cost saving with concomitant gains in quality-adjusted life years (QALYs), translating to a dominant treatment strategy. Results were robust according to sensitivity analysis with the initial success rate of up to three years for both metal and MFX having the largest impact. CONCLUSIONS: A metal implant may be a cost-effective treatment alternative for patients in their 40's when compared to MFX in a Swedish setting. LEVEL OF EVIDENCE: 5 [1].

Carpal tunnel syndrome in acromegaly: a nationwide study.

OBJECTIVE: Carpal tunnel syndrome (CTS) is common in patients with acromegaly, with a reported prevalence of 19-64%. We studied CTS in a large national cohort of patients with acromegaly and the temporal relationship between the two diagnoses. DESIGN: Retrospective, nationwide, cohort study including patients diagnosed with acromegaly in Sweden, 2005-2017, identified in the Swedish Healthcare Registries. METHODS: CTS (diagnosis and surgery in specialised healthcare) was analysed from 8.5 years before the diagnosis of acromegaly until death or end of the study. Standardised incidence ratios (SIRs) with 95% CIs were calculated for CTS with the Swedish population as reference. RESULTS: The analysis included 556 patients with acromegaly (50% women) diagnosed at mean (s.d.) age 50.1 (15.0) years. During the study period, 48 patients were diagnosed with CTS and 41 patients underwent at least one CTS surgery. In the latter group, 35 (85%) were operated for CTS before the acromegaly diagnosis; mean interval (range) 2.2 (0.3-8.5) years and the SIR for having CTS surgery before the diagnosis of acromegaly was 6.6 (4.8-8.9). Women with acromegaly had a higher risk for CTS than men (hazard ratio: 2.5, 95% CI: 1.3-4.7). CONCLUSIONS: Patients with acromegaly had a 6-fold higher incidence for CTS surgery before the diagnosis of acromegaly compared with the general population. The majority of patients with both diagnoses were diagnosed with CTS prior to acromegaly. Increased awareness of signs of acromegaly in patients with CTS might help to shorten the diagnostic delay in acromegaly, especially in women.

Treatment Patterns and Survival among Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumours in Sweden - a Population-based Register-linkage and Medical Chart Review Study.

Background: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are neoplasms derived from the endocrine system in the gastrointestinal tract and pancreas. Treatment options include surgery; pharmacological treatments like somatostatin analogues (SSA), interferon alpha, molecular targeted therapy and chemotherapy; and peptide receptor radionuclide therapy. The objective of this study was to describe treatment patterns and survival among patients with metastatic GEP-NET grade 1 or 2 in Sweden. Methods: Data was obtained via linkage of nationwide registers. Patients diagnosed with metastatic GEP-NET grade 1 or 2 in Sweden between 2005 and 2013 were included (n=811; National population). In addition, medical chart review was performed for the subpopulation diagnosed at Sahlgrenska University Hospital, Gothenburg (n=127; Regional population). Treatment patterns, including treatment sequences, and overall survival were assessed. Results: Most patients had small intestinal NET (76%). In the regional population, 72% had grade 1 tumours; 50% had functioning tumours. The two most common first-line treatments were surgery (57%) and SSA (25%). After first-line surgery, 46% received SSA, while 40% had no further treatment. After first-line SSA, 52% received surgery, while 27% had no further treatment. Overall median survival time from date of diagnosis was 7.0 years (95% CI 6.2-not reached). Among patients with distant metastases, pancreatic NET (vs. small intestinal NET) was associated with poorer survival (HR 1.9; 95% CI 1.1-3.3), as were liver metastases (HR 3.2; 95% CI 1.5-7.0). Conclusions: First-line surgery was typically followed by SSA or no further treatment. Among patients with distant metastases, pancreatic NET or liver metastases were associated with a poorer survival.

Decreasing mortality and changes in treatment patterns in patients with acromegaly from a nationwide study.

CONTEXT: New therapeutic strategies have developed for the management of acromegaly over recent decades. Whether this has improved mortality has not been fully elucidated. OBJECTIVE: The primary aim was to investigate mortality in a nationwide unselected cohort of patients with acromegaly. Secondary analyses included time trends in mortality and treatment patterns. DESIGN: A total of 1089 patients with acromegaly were identified in Swedish National Health Registries between 1987 and 2013. To analyse time trends, the cohort was divided into three periods (1987-1995, 1996-2004 and 2005-2013) based on the year of diagnosis. MAIN OUTCOME MEASURES: Using the Swedish population as reference, standardized mortality ratios (SMRs) were calculated with 95% confidence intervals (CIs). RESULTS: Overall SMR was 2.79 (95% CI: 2.43-3.15) with 232 observed and 83 expected deaths. Mortality was mainly related to circulatory diseases (SMR: 2.95, 95% CI: 2.35-3.55), including ischemic heart disease (2.00, 1.35-2.66) and cerebrovascular disease (3.99, 2.42-5.55) and malignancy (1.76, 1.27-2.26). Mortality decreased over time, with an SMR of 3.45 (2.87-4.02) and 1.86 (1.04-2.67) during the first and last time period, respectively (P = .015). During the same time periods, the frequency of pituitary surgery increased from 58% to 72% (P < 0.001) and the prevalence of hypopituitarism decreased from 41% to 23% (P < 0.001). CONCLUSIONS: Excess mortality was found in this nationwide cohort of patients with acromegaly, mainly related to circulatory and malignant diseases. Although still high, mortality significantly declined over time. This could be explained by the more frequent use of pituitary surgery, decreased prevalence of hypopituitarism and the availability of new medical treatment options.

Comorbidities, treatment patterns and cost-of-illness of acromegaly in Sweden: a register-linkage population-based study.

OBJECTIVE: Acromegaly is a complex endocrine disease with multiple comorbidities. Treatment to obtain biochemical remission includes surgery, medical therapy and radiation. We aimed to describe comorbidities, treatment patterns and cost-of-illness in patients with acromegaly in Sweden. DESIGN: A nationwide population-based study. METHODS: Patients with acromegaly were identified and followed in national registers in Sweden. Longitudinal treatment patterns were assessed in patients diagnosed between July 2005 and December 2013. The cost-of-illness during 2013 was estimated from a societal perspective among patients diagnosed between 1987 and 2013. RESULTS: Among 358 patients with acromegaly (48% men, mean age at diagnosis 50.0 (s.d. 15.3) years) at least one comorbidity was reported in 81% (n = 290). The most common comorbidities were hypertension (40%, n = 142), neoplasms outside the pituitary (30%, n = 109), hypopituitarism (22%, n = 80) and diabetes mellitus (17%, n = 61). Acromegaly treatment was initiated on average 3.7 (s.d. 6.9) months after diagnosis. Among the 301 treated patients, the most common first-line treatments were surgery (60%, n = 180), somatostatin analogues (21%, n = 64) and dopamine agonists (14%, n = 41). After primary surgery, 24% (n = 44) received somatostatin analogues. The annual per-patient cost was €12 000; this was €8700 and €16 000 if diagnosed before or after July 2005, respectively. The cost-of-illness for acromegaly and its comorbidities was 77% from direct costs and 23% from production loss. CONCLUSIONS: The prevalence of comorbidity is high in patients with acromegaly. The most common first-line treatment in acromegalic patients was surgery followed by somatostatin analogues. The annual per-patient cost of acromegaly and its comorbidities was €12 000.

Capacitative Ca2+ influx and activation of the neutrophil respiratory burst. Different regulation of plasma membrane- and granule-localized NADPH-oxidase.

The neutrophil NADPH-oxidase may be activated in the plasma membrane, resulting in release of oxygen metabolites extracellularly, or in the granule or phagosomal membranes, giving intracellular production of oxidants. An increase in [Ca2+]i mediated through binding of fMLF to its receptor is part of a signaling cascade that activates the plasma membrane-localized oxidase. In contrast, a rise in [Ca2+]i induced by a Ca2+ ionophore results in activation of the intracellular pool of oxidase. We mimicked fMLF-induced emptying of intracellular Ca2+ stores with thapsigargin. This induced a pronounced intracellular oxidase activity but no extracellular release of oxidants. The thapsigargin-induced effect was dependent on capacitative Ca2+ influx, because the effect was inhibited dose-dependently by EGTA and the Ca2+ channel blocker La3+. At La3+ concentrations between 200 and 400 microM, thapsigargin also induced a massive extracellular production of superoxide anion. No other channel blockers tested induced a similar effect. We conclude that elevation in [Ca2+]i by capacitative Ca2+ influx induces NADPH-oxidase activation at an intracellular site. Further, activation of the plasma membrane-localized NADPH-oxidase is regulated by a more complex Ca2+ signaling, involving capacitative Ca2+ influx and possibly the specific action of La3+-sensitive Ca2+ channels.

Neutrophil secretion induced by an intracellular Ca2+ rise and followed by whole-cell patch-clamp recordings occurs without any selective mobilization of different granule populations.

We have investigated calcium-induced secretion in human neutrophils, using a whole-cell patch-clamp technique. Mobilization of subcellular granules to the cell membrane was followed as the change in membrane capacitance (deltaC(m)). Both the magnitude and the kinetics of the response differed between low and high concentrations of Ca(2+). A sustained secretion following a short lag phase was induced by high concentrations of Ca(2+) (100 microM and higher). A stable plateau was reached after 5-7 minutes at deltaC(m) values corresponding to values expected after all specific as well as azurophil granules have been mobilized. Capacitance values of the same magnitude could be obtained also at lower Ca(2+) concentrations, but typically no stable plateau was reached within the measuring time. In contrast to previous studies, we were unable to detect any pattern of secretion corresponding to a distinct submaximal response or selective mobilization of granule subsets specified by their Ca(2+)-sensitivity.

Controlling desensitized states in ligand-receptor interaction studies with cyclic scanning patch-clamp protocols.

Ligand-gated ion channels are important control elements in regulation of cellular activities, and increasing evidence demonstrates their role as therapeutic targets. The receptors display complex desensitization kinetics, occurring on vastly different time scales. This is not only important in biology and pharmacology but might also be of technological significance since populations of receptors under microfluidic control can function analogously to DRAM memory circuits. Using a novel microfluidic method, and computer modeling of the receptor state distributions, we here demonstrate that GABAA receptor populations can be controlled to display high or low EC50 values, depending on input function (i.e., the exact pattern of agonist application). The sensitivity of the receptors can be tuned up to 40-fold (beta-alanine) by the particular agonist exposure pattern. By combining patch-clamp experiments with computer modeling of receptor state distributions, we can control the assembly of receptors in desensitized states. The technique described can be used as an analytical tool to study the effect of desensitization on the activity of ion channel effectors. We describe the differential blocking effect of the competitive antagonist bicuculline on the high- and low-EC50 GABAA receptor preparations and conclude that the inhibition is dramatically dependent on how the different desensitized states are populated. Furthermore, we show that both GABA and beta-alanine, two agonists with different affinity but similar efficacy, induce the same type of desensitization behavior and memory effects in GABAA receptors.

A biohybrid dynamic random access memory.

We report that GABA(A) receptors in a patch-clamped biological cell form a short-term memory circuit when integrated with a scanning-probe microfluidic device. Laminar patterns of receptor activators (agonists) provided by the microfluidic device define and periodically update the data input which is read and stored by the receptors as state distributions (based on intrinsic multistate kinetics). The memory is discharged over time and lasts for seconds to minutes depending on the input function. The function of the memory can be represented by an equivalent electronic circuit with striking similarity in function to a dynamic random access memory (DRAM) used in electronic computers. Multiplexed biohybrid memories may form the basis of large-scale integrated biocomputational/sensor devices with the curious ability to use chemical signals including odorants, neurotransmitters, chemical and biological warfare agents, and many more as input signals.

A chemical waveform synthesizer.

Algorithms and methods were developed to synthesize complex chemical waveforms in open volumes by using a scanning-probe microfluidic platform. Time-dependent variations and oscillations of one or several chemical species around the scanning probe, such as formation of sine waves, damped oscillations, and generation of more complex patterns, are demonstrated. Furthermore, we show that intricate bursting and chaotic calcium oscillations found in biological microdomains can be reproduced and that a biological cell can be used as a probe to study receptor functionalities as a function of exposure to time-dependent variations of receptor activators and inhibitors. Thus, the method allows for studies of biologically important oscillatory reactions. More generally, the system allows for detailed studies of complex time-varying chemical and physical phenomena in solution or at solution/surface interfaces.

Reactivation of formyl peptide receptors triggers the neutrophil NADPH-oxidase but not a transient rise in intracellular calcium.

In neutrophils, coupling of chemoattractants to their cell surface receptor at low temperature (