New reimbursement model in Icelandic primary care in 2017: first-year comparison of public and private primary care.

OBJECTIVE: To analyze and compare the effect of a new reimbursement model (based on a modified version of the Swedish free choice reform) on private and public primary care in Iceland during its first year of use. DESIGN: Descriptive comparison based on official data from the Ministry of Welfare, Directorate of Health, and the Icelandic Health Insurance on payments in the Icelandic primary care system. SETTING: Primary care system operating in the Reykjavik capital area. Public primary care has dominated the Icelandic health sector. Both public and private primary care is financed by public taxation. SUBJECTS: Fifteen public and four private primary care centers in the capital region. MAIN OUTCOME MEASURES: Different indexes used in the reimbursement model and public vs. private primary care costs. RESULTS: No statistically significant cost differences were found between public and private primary care centers regarding total reimbursements, reimbursements per GP, number of registered patients, or per visit. Two indexes covered over 80% of reimbursements in the model. CONCLUSION: The cost for Icelandic taxpayers was equal in numerous indexes between public and private primary care centers. Only public centers got reimbursements for the care need index, which considers a patient's social needs, strengths, and weaknesses.KEY POINTSThe Icelandic primary care system underwent a reform in 2017 to improve availability and quality. A new reimbursement model was introduced, and two new private centers opened following a tender.Two out of 14 indexes cover over 80% of total reimbursements from the new model.Only 5 primary care centers, all publicly driven, got reimbursement for the care need index, which is a social deprivation index.Reimbursement systems should mirror the policies of health authorities and empower the workforce.

[Complex regional pain syndrome, CRPS].

Complex regional pain syndrome, CRPS, occurs with severe disabling pain, usually in the leg or hand, coupled with changes in pain perception, hyperesthesia and allodynia. There is as well, edema, changes in the color of the skin, trophic changes, and dystonia. The pain syndrome is often triggered by minor trauma. The pain perception is severe and out of context with the initial trauma. The syndrome is rare, occurring in a population-based study in the United States, with an incidence of only 5.5 per hundred thousand people per year. The incidence in Iceland, from the National Register of Diseases from the Directorate of Health, was 1.3 per annum, per hundred thousand people. The exact etiology of the disease is unknown. It is presumed that inflammation is the cause, often resulting from an autoimmune reaction. The term pain sensitization is also used to describe the pain mechanism, both in peripheral nerves and in the central nervous system. There are changes and displacement of the area of the neocortex that is coupled with pain perception. The criteria of the International Association for the Study of Pain (IASP) were the basis for the diagnosis. Interdisciplinary team management according to the biopsychosocial model is thought to be the preferred treatment approach. The members of the team are occupational therapists, physiotherapists, social workers, psychologists, nurses, and medical doctors, augmented by other disciplines as needed. One treatment option is mirror therapy, where the diseased extremity is held behind a mirror during the training and the patient observes movements of the healthy extremity. Initially treatment is aimed at treating the inflammation, often with NSAID drugs, or with steroids. Medical treatments are the same as apply for the treatment of neural pain, with drugs such as Gabapentin, or anti depressive agents as duloxetine or imipramine. There is an indication to use bisphosphonates such as alendronate, especially if there is osteoporosis. It is assumed that the function of the NMDA receptor has changed in the central nervous system and treatment with intravenous ketamine, is an option. Spinal cord stimulation of the dorsal horns of the spine has been effective as well. In majority of cases the syndrome resolves in the first two years, but for the rest the prognosis is dire, symptoms getting worse and persisting for years and even decades.

[Ablation of ganglionated plexi to treat symptomatic parasympathetic induced atrioventricular block].

According to clinical guidelines a symptomatic atrioventricular block (AV block) is treated with a pacemaker. For young individuals such a therapy can be difficult due to possible long term complications such as infections, lead disruptions and pacemaker induced cardiomyopathy. We describe a twenty year old man with recurrent syncopes due to intermittent parasympathetic caused AV block of grade 2. The patient underwent cardioneuroablation where parasympathetic ganglia in the right atrium were ablated. After the procedure the PR interval normalized. This procedure has never been performed in Iceland before and there is a limited amount of case reports in the literature.

Safety of fluoroscopy-guided transseptal approach for ablation of left-sided arrhythmias.

AIMS: The transseptal approach is used for left atrial access during the ablation of atrial fibrillation (AF) and other left-sided arrhythmia substrates. Transseptal puncture (TP) is commonly performed with fluoroscopic guidance, contrast injection, and pressure monitoring. In many centres, additional techniques [intracardiac echocardiography (ICE), transoesophageal echocardiography (TEE), radiofrequency needle] are used to facilitate TP but its use adds costs. In this retrospective study, we studied the safety and complication rate when TP was routinely done with fluoroscopic guidance, contrast injection, and pressure monitoring using ICE or TEE only in selected cases. METHODS AND RESULTS: This study analysed 4690 consecutive TP performed between 2000 and 2015: 3408 (72.6%) were ablation of AF, left-sided atrial flutter, or left-sided atrial tachycardia (non-AP group); 1153 (24.6%) were ablation of left-sided accessory pathway, AP group; and 129 (2.8%) were ablation of ventricular tachycardia. Transseptal puncture was done under fluoroscopy, pressure monitoring, and commonly using contrast media injection. In 27 procedures, ICE or TEE was used to guide the TP. We found 34 tamponades (Tx) that required pericardial drainage of which 28 (0.59%) could possibly be TP related and six could not. The total complication rate for all Tx was 0.72%. A higher rate of tamponades was observed in the AF (non-AP) group than in the AP group (0.88 vs. 0.17%, P < 0.02). The highest rate of tamponades was registered during the operators 51-100 cases, 1.3%, and decreased to 0.4% in cases 101-200, P = 0.04. CONCLUSION: TP can safely be done under fluoroscopy and pressure monitoring without routine use of additional techniques. With experience, operators should be able to further decrease complication rate.

Smoking during pregnancy: A population-based study.

AIMS: Tobacco is a major cause of disease and mortality in modern times. The risk of smoking in pregnancy is a serious threat to the development and future health of an unborn child. The aim of this study was to explore the epidemiological factors associated with smoking during pregnancy in a primary healthcare setting. METHODS: All 856 maternity records at the Glaesibaer Health Care Centre in Reykjavik during 2006-2013 were reviewed and information on smoking habits investigated. RESULTS: The records showed that in 108 (12.2%) pregnancies, women smoked at first visit and 63 stopped smoking in early pregnancy, leaving 45 (5.3%) mothers smoking throughout the whole gestational period. The mean age of the smoking women was 27.8 years and for the non-smokers 29.7 years. Low social status (odds ratio (OR) = 2.66; 95% confidence interval (CI): 1.19-5.96), previous mental health diagnosis (OR = 2.7; 95% CI: 1.3-5.6), and unstable relationship with a partner (OR = 3.78; 95% CI: 2.1-7.0) were associated with smoking. Smoking fewer cigarettes was associated with a 0.04-unit lower risk of smoking during pregnancy (OR = 0.04: 95% CI: 0.02-0.08). CONCLUSIONS: Our results indicated that the women who smoked during pregnancy were often heavy smokers and living without a partner. They were younger, had worse mental health, and a lower social status than those pregnant women who did not smoke. Bearing in mind the consequence of smoking in pregnancy, this subgroup should get increased assistance to quit smoking before and during early pregnancy, as well as appropriate medical and social support.

Cryoablation of substrates adjacent to the atrioventricular node: acute and long-term safety of 1303 ablation procedures.

AIMS: Radiofrequency (RF) ablation is effective for ablation of atrial arrhythmias. However, RF ablation in the vicinity of the atrioventricular (AV) node is associated with a risk of inadvertent, irreversible high-grade AV block, depending on the type of substrate. Cryoablation is an alternative method. The objective was to investigate the acute and long-term risks of AV block during cryoablation. METHODS AND RESULTS: We studied 1303 consecutive cryoablations of substrates in the vicinity of the AV node in 1201 patients (median age 51 years, range 6-89 years) on acute and long-term impairment to the AV nodal conduction system. The arrhythmias treated were AV nodal reentrant tachycardias (n=1116), paraseptal and superoparaseptal accessory pathways (n=100), and focal atrial tachycardias (n=87). In 158 (12%) procedures, cryomapping (38 cases) or cryoablation (120 cases) were stopped due to transient AV block (first-degree AV block 74 cases, second-degree AV block 67 cases, and third-degree AV block 17 cases) after which another site was tested. Transient AV block occurred within seconds of mapping up to 3 min of ablation. The incidence of AV block was similar for different substrates. In most cases, AV nodal conduction was restored within seconds but in two cases transient AV block lasted 21 and 45 min, respectively. There were no cases of acute permanent AV blocks. No late AV blocks occurred during follow-up (mean 24 months, range 6-96 months). CONCLUSION: Cryoablation adjacent to the AV node carries a negligible risk of permanent AV block. Transient AV block during ablation is a benign finding.

Association of Morbus Ledderhose with Dupuytren's contracture.

BACKGROUND: Fibromatous nodules in the sole of the foot are often called Ledderhose disease. It is a benign nodular formation in the plantar aponeurosis, typically at the distal medial border. A lump forms and it can be a few centimeters in diameter. It is frequently seen as an isolated disease, but a relationship to Dupuytren's has been noted in some patients. METHODS: The study was a part of a large cohort study, the Reykjavík study. Men with Dupuytren's disease (n = 122) were invited to follow-up 18 years after the initial observation. An equal number of controls, matched for age and smoking habits, were also invited. A total of 92 Dupuytren's patients and 101 control subjects attended for follow-up and were examined for plantar nodules. Statistical evaluation was carried out using chi-square test and presented as odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: Ledderhose disease was identified in 14 of the 92 (15.2%) men with Dupuytren's disease, while it was only in 4 of the 101 (3.9%) matched controls (OR = 4.35, 95% CI, 1.3-16.7, P < 0.01). Men operated for Dupuytren's disease or with finger contractures were more likely to have plantar nodules than those with only nodules or strings in the palms (OR = 6.1, 95% CI, 1.8-27.1, P < 0.001). The plantar involvement was related to family history of Dupuytren's disease (OR = 3.1, 95% CI, 1.1-8.5, P = 0.02). CONCLUSION: Men with manifestations of finger contractures or who need surgery for Dupuytren's disease are more likely to also develop plantar fibromas. LEVEL OF EVIDENCE: Level III, retrospective comparative series.

Blockade of X4-tropic HIV-1 cellular entry by GSK812397, a potent noncompetitive CXCR4 receptor antagonist.

GSK812397 is a potent entry inhibitor of X4-tropic strains of HIV-1, as demonstrated in multiple in vitro cellular assays (e.g., in peripheral blood mononuclear cells [PBMCs] and a viral human osteosarcoma [HOS] assay, mean 50% inhibitory concentrations [IC50s]+/-standard errors of the means were 4.60+/-1.23 nM and 1.50+/-0.21 nM, respectively). The primary in vitro potency of GSK812397 was not significantly altered by the addition of serum proteins (2.55 [+/-0.12]-fold shift in the presence of human serum albumin and alpha-acid glycoprotein in the PBMC assay). Pharmacological characterization of GSK812397 in cell-based functional assays revealed it to be a noncompetitive antagonist of the CXCR4 receptor, with GSK812397 producing a concentration-dependent decrease in both an SDF-1-mediated chemotaxis and intracellular calcium release (IC50s were 0.34+/-0.01 nM and 2.41+/-0.50 nM, respectively). With respect to the antiviral activity of GSK812397, it was effective against a broad range of X4- and X4R5-utilizing clinical isolates. The potency and efficacy of GSK812397 were dependent on the individual isolate, with complete inhibition of infection observed with 24 of 30 isolates. GSK812397 did not show any detectable in vitro cytotoxicity and was highly selective for CXCR4, as determined using a wide range of receptors, enzymes, and transporters. Moreover, GSK812397 demonstrated acceptable pharmacokinetic properties and bioavailability across species. The data demonstrate that GSK812397 has antiviral activity against a broad range of X4-utilizing strains of HIV-1 via a noncompetitive antagonism of the CXCR4 receptor.

Novel N-substituted benzimidazole CXCR4 antagonists as potential anti-HIV agents.

The lead optimization of a series of N-substituted benzimidazole CXCR4 antagonists is described. Side chain modifications and stereochemical optimization led to substantial improvements in potency and protein shift to afford compounds with low nanomolar anti-HIV activity.

Synthesis and SAR of novel isoquinoline CXCR4 antagonists with potent anti-HIV activity.

Using AMD070 as a starting point for structural modification, a novel series of isoquinoline CXCR4 antagonists was developed. A structure-activity scan of alternate lower heterocycles led to the 3-isoquinolinyl moiety as an attractive replacement for benzimidazole. Side chain optimization in the isoquinoline series led to a number of compounds with low nanomolar anti-HIV activities and promising rat PK properties.

Synthesis of a novel tricyclic 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system and CXCR4 antagonists with potent activity against HIV-1.

Stereorandom and diastereoselective syntheses of a novel 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system are described. Derivatives of all four diastereomers were prepared and isolated in >98% ee. The pure enantiomers were compared in order to determine the preferred absolute and relative configuration required for optimal anti-HIV activity. Anti-HIV potency and pharmacokinetic properties of the newly synthesized tricyclic octahydrophenanthroline inhibitors are presented and comparisons are made to previously reported bicyclic (8S)-N-methyl-5,6,7,8-tetrahydro-8-quinolinamine analogs.

Substituted tetrahydro-beta-carbolines as potential agents for the treatment of human papillomavirus infection.

The identification and optimization of a series of substituted tetrahydro-beta-carbolines with potent activity against human papillomavirus is described. Structure-activity studies focused on the substitution pattern and chirality of the beta-carboline ring system are discussed. Optimization of these parameters led to compounds with antiviral activities in the low nanomolar range.

Pyrazolopyrimidines and pyrazolotriazines with potent activity against herpesviruses.

Synthesis of several pyrazolo[1,5-c]pyrimidines, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines with potent activity against herpes simplex viruses is described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity similar or better than acyclovir are described.

Imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV-1.

Synthesis of several novel imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV are described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity and pharmacokinetics are highlighted. Several compounds with low nanomolar anti-HIV activity and oral bioavailability are described.

Amine substituted N-(1H-benzimidazol-2ylmethyl)-5,6,7,8-tetrahydro-8-quinolinamines as CXCR4 antagonists with potent activity against HIV-1.

Several novel amine substituted N-(1H-benzimidazol-2ylmethyl)-5,6,7,8-tetrahydro-8-quinolinamines were synthesized which had potent activity against HIV-1. The synthetic approaches adopted allowed for variation of the substitution pattern and resulting changes in antiviral activity are highlighted. This led to the identification of compounds with low and sub-nanomolar anti-HIV-1 activity.

Substituted tetrahydrocarbazoles with potent activity against human papillomaviruses.

The synthesis and SAR of a series of substituted 1-aminotetrahydrocarbazoles with potent activity against human papillomaviruses are described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the low nanomolar range were identified and (1R)-6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazole-1-amine was selected for further evaluation.

Tetrahydrocarbazole amides with potent activity against human papillomaviruses.

Synthesis of a series of tetrahydrocarbazole amides with potent activity against human papillomaviruses is described. Synthetic approaches allowing for variation of the substitution pattern of the tetrahydrocarbazole and the amide are outlined and resulting changes in antiviral activity and certain developability parameters are highlighted. Several compounds with in vitro antiviral activity (W12 antiviral assay) in the single digit nanomolar range were identified and N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-pyridinecarboxamide was selected for further evaluation.

Pyrazolopyridines with potent activity against herpesviruses: effects of C5 substituents on antiviral activity.

Synthesis of a series of 5-substituted as well as 5,7-disubstituted 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-phenylpyrazolo[1,5-a]pyridin-7-amines with potent activity against herpes simplex viruses is described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity similar to or better than acyclovir are described.

[General practice in Iceland and Norway: GP's experience of different primary health care systems].

INTRODUCTION: Most GPs in Iceland are public employees on fixed salaries which is very different from their Norwegian colleagues. The aim of this study was to explore the experience of Icelandic GPs who have also worked as GPs in Norway and compare their experience of working in these two neighboring countries. MATERIAL AND METHODS: Data were collected through interviews with 16 GPs that during the study period 2009-2010 were all working in Iceland. Two to ten years had passed since their return from Norway. We used qualitative methodology, the Vancouver-School of doing phenomenology. This methodology seeks to increase understanding of human phenomena for the purpose of improving healthcare services. RESULTS: The doctors discussed the benefits of the different systems of delivering medical services. They saw the advantages of the Norwegian healthcare system mostly in that all Norwegians have their own GP, thus achieving a good overview of the health problems of each individual. The GPs are gatekeepers for medical services which potentially -reduces duplication of medical services. The participants also noted more efficient medical services in Norway than in Iceland. What characterizes Icelandic healthcare outside the hospital from their perspective is direct patient contact with specialists without referrals from GPs and incomplete registration system of patients and much use of emergency services in Iceland. CONCLUSION: Participants agreed upon stronger primary healthcare system in Norway compared to Iceland. Moreover, a good job situation in primary care is needed in Iceland to appeal to junior doctors. When changes are made to the Icelandic healthcare system it is important to acknowledge the experience of neighboring countries in terms of advancing health care system reforms. Key words: general practitioner, primary care, job situation, health service research, qualitative research. Correspondence: Hedinn Sigurdsson, hedinn.sigurdsson@heilsugaeslan.is.

Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives.

We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.