Long-term Follow-up of a Randomized Clinical Trial Comparing Endovascular Revascularization Plus Supervised Exercise With Supervised Exercise Only for Intermittent Claudication.

OBJECTIVE: The goal of this study was to assess the long-term effectiveness of combination therapy for intermittent claudication, compared with supervised exercise only. BACKGROUND: Supervised exercise therapy is recommended as first-line treatment for intermittent claudication by recent guidelines. Combining endovascular revascularization plus supervised exercise shows promising results; however, there is a lack of long-term follow-up. METHODS: The ERASE study is a multicenter randomized clinical trial, including patients between May 2010 and February 2013 with intermittent claudication. Interventions were combination of endovascular revascularization plus supervised exercise (n = 106) or supervised exercise only (n = 106). Primary endpoint was the difference in maximum walking distance at long-term follow-up. Secondary endpoints included differences in pain-free walking distance, ankle-brachial index, quality of life, progression to critical limb ischemia, and revascularization procedures during follow-up. This randomized trial report is based on a post hoc analysis of extended follow-up beyond that of the initial trial. Patients were followed up until 31 July 2017. Data were analyzed according to the intention-to-treat principle. RESULTS: Median long-term follow-up was 5.4 years (IQR 4.9-5.7). Treadmill test was completed for 128/212 (60%) patients. Whereas the difference in maximum walking distance significantly favored combination therapy at 1-year follow-up, the difference at 5-year follow-up was no longer significant (53 m; 99% CI-225 to 331; P = 0.62). No difference in pain-free walking distance, ankle-brachial index, and quality of life was found during long-term follow-up. We found that supervised exercise was associated with an increased hazard of a revascularization procedure during follow-up (HR 2.50; 99% CI 1.27-4.90; P < 0.001). The total number of revascularization procedures (including randomized treatment) was lower in the exercise only group compared to that in the combination therapy group (65 vs 149). CONCLUSIONS: Long-term follow up after combination therapy versus supervised exercise only, demonstrated no significant difference in walking distance or quality of life between the treatment groups. Combination therapy resulted in a lower number of revascularization procedures during follow-up but a higher total number of revascularizations including the randomized treatment. TRIAL REGISTRATION: Netherlands Trial Registry Identifier: NTR2249.

Endovascular Revascularization Plus Supervised Exercise Versus Supervised Exercise Only for Intermittent Claudication: A Cost-Effectiveness Analysis.

[Figure: see text].

Regional Coronavirus Hotspots During the COVID-19 Outbreak in the Netherlands.

We explore the impact of COVID-19 hotspots and regional lockdowns on the Dutch labour market during the outbreak of COVID-19. Using weekly administrative panel microdata for 50 per cent of Dutch employees until the end of March 2020, we study whether individual labour market outcomes, as measured by employment, working hours and hourly wages, were more strongly affected in provinces where COVID-19 confirmed cases, hospitalizations and mortality were relatively high. The evidence suggests that labour market outcomes were negatively affected in all regions and local higher virus case numbers did not reinforce this decline. This suggests that preventive health measures should be at the regional level, isolating hotspots from low-risk areas.

Endovascular Revascularization and Supervised Exercise for Peripheral Artery Disease and Intermittent Claudication: A Randomized Clinical Trial.

IMPORTANCE: Supervised exercise is recommended as a first-line treatment for intermittent claudication. Combination therapy of endovascular revascularization plus supervised exercise may be more promising but few data comparing the 2 therapies are available. OBJECTIVE: To assess the effectiveness of endovascular revascularization plus supervised exercise for intermittent claudication compared with supervised exercise only. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 212 patients allocated to either endovascular revascularization plus supervised exercise or supervised exercise only. Data were collected between May 17, 2010, and February 16, 2013, in the Netherlands at 10 sites. Patients were followed up for 12 months and the data were analyzed according to the intention-to-treat principle. INTERVENTIONS: A combination of endovascular revascularization (selective stenting) plus supervised exercise (n = 106) or supervised exercise only (n = 106). MAIN OUTCOMES AND MEASURES: The primary end point was the difference in maximum treadmill walking distance at 12 months between the groups. Secondary end points included treadmill pain-free walking distance, vascular quality of life (VascuQol) score (1 [worst outcome] to 7 [best outcome]), and 36-item Short-Form Health Survey (SF-36) domain scores for physical functioning, physical role functioning, bodily pain, and general health perceptions (0 [severe limitation] to 100 [no limitation]). RESULTS: Endovascular revascularization plus supervised exercise (combination therapy) was associated with significantly greater improvement in maximum walking distance (from 264 m to 1501 m for an improvement of 1237 m) compared with the supervised exercise only group (from 285 m to 1240 m for improvement of 955 m) (mean difference between groups, 282 m; 99% CI, 60-505 m) and in pain-free walking distance (from 117 m to 1237 m for an improvement of 1120 m vs from 135 m to 847 m for improvement of 712 m, respectively) (mean difference, 408 m; 99% CI, 195-622 m). Similarly, the combination therapy group demonstrated significantly greater improvement in the disease-specific VascuQol score (1.34 [99% CI, 1.04-1.64] in the combination therapy group vs 0.73 [99% CI, 0.43-1.03] in the exercise group; mean difference, 0.62 [99% CI, 0.20-1.03]) and in the score for the SF-36 physical functioning (22.4 [99% CI, 16.3-28.5] vs 12.6 [99% CI, 6.3-18.9], respectively; mean difference, 9.8 [99% CI, 1.4-18.2]). No significant differences were found for the SF-36 domains of physical role functioning, bodily pain, and general health perceptions. CONCLUSIONS AND RELEVANCE: Among patients with intermittent claudication after 1 year of follow-up, a combination therapy of endovascular revascularization followed by supervised exercise resulted in significantly greater improvement in walking distances and health-related quality-of-life scores compared with supervised exercise only. TRIAL REGISTRATION: Netherlands Trial Registry Identifier: NTR2249.

Osteolysis after rotator cuff repair with bioabsorbable anchors.

PURPOSE: The current study was designed to evaluate the rate of osteolysis and the clinical and functional outcomes in patients who underwent mini-open rotator cuff repairs using first generation bioabsorbable suture anchors. Our hypothesis was that patients with osteolysis noted on post-repair MRI would have an accompanying decrease in functional and clinical patient outcomes when compared with patients who did not have osteolysis evident on post-repair MRI. TYPE OF STUDY: Clinical retrospective study. METHODS: Between September 2000 and May 2004, 76 patients were repaired using first generation Bio-Corkscrew suture anchors (Arthrex, Naples, FL). 30 patients were available for complete follow-up evaluation. The mean follow-up time was 36 months (range 24-58). Patients were assessed with the Constant-Murley Score, radiographs and magnetic resonance imaging (MRI). Post-operative strength was measured using an Isokinetic Cybex-Dynamometer. 14 patients had osteolysis evident on MRI (Group A) while 16 patients did not have osteolysis on MRI (Group B). RESULTS: In both groups, a total of 70 bio-anchors were used. 22 anchors showed osteolytic changes on MRI (Group A). Concerning ROM, there was no statistical difference in both groups. The Constant-Score was statistically not different in both groups A (92.4) and B (83.7). On MRI-scans, there were repair failures in both groups (A, 2 reruptures; B, 3 reruptures). CONCLUSIONS: Although, we found a high rate of osteolysis after rotator cuff repair with bioabsorbable anchors, these results did not change the clinical outcomes after rotator cuff repair. Recurrent tears were not significantly different in both groups and are comparable to rerupture rates in prior studies. More studies are needed to verify the effect of osteolysis over the long term.

Time-bound opportunity costs of informal care: consequences for access to professional care, caregiver support, and labour supply estimates.

The opportunity costs associated with the provision of informal care are usually estimated based on the reduced potential of the caregiver to partake in paid work (both in terms of whether they are able to undertake paid work, and if so the hours of work undertaken). In addition to the hours of informal care provided, these opportunity costs are also likely determined by the necessity to perform particular informal care tasks at specific moments of the day. The literature, to date, has largely overlooked this dimension of informal care. We used Dutch data from time use diaries which report patterns of informal care throughout the day which enables investigation of when particular activities are undertaken. We found that whereas some tasks must be performed at a relatively fixed time of day, others are shiftable and can be performed at other times or even on different days. Household and organisation activities are more likely to be undertaken by employed caregivers, and seem largely to be shiftable; whereas personal care contains unshiftable activities. This implies additional opportunity costs of providing personal care tasks - we term these "time-bound" opportunity costs. Since the care recipient's need for care may in part relate to unshiftable tasks, we conclude that one should be careful with using care need as an instrument of informal care in labour supply equations.

Symmetry energy of dilute warm nuclear matter.

The symmetry energy of nuclear matter is a fundamental ingredient in the investigation of exotic nuclei, heavy-ion collisions, and astrophysical phenomena. New data from heavy-ion collisions can be used to extract the free symmetry energy and the internal symmetry energy at subsaturation densities and temperatures below 10 MeV. Conventional theoretical calculations of the symmetry energy based on mean-field approaches fail to give the correct low-temperature, low-density limit that is governed by correlations, in particular, by the appearance of bound states. A recently developed quantum-statistical approach that takes the formation of clusters into account predicts symmetry energies that are in very good agreement with the experimental data. A consistent description of the symmetry energy is given that joins the correct low-density limit with quasiparticle approaches valid near the saturation density.

[Complementary system of health care in cooperation with migrant communities--requirements for successful integration in health care]. / Gesundheitshilfen für und mit Migranten--Voraussetzungen für erfolgreiche Integration im Gesundheitswesen.

National and ethnic diversities among and within groups of migrants present great challenges to health care, not only in Germany. Access to regular health care, in particular for relatively small migrant groups and new immigrants is sometimes difficult. In addition, specific cultural aspects and legal implications--such as the residence status--must be taken into account when setting up a complementary system of health care. Methods and arrangements should make use of already existing resources of the health care system as well as proceed to direct cooperation with migrant communities. The public health service with its wide range of technical and organisational efficiency can play a key role here, especially in the municipal sector, both for an effective medical care for those who have difficulties in gaining access to the system, as well as for developing municipal networks, cooperating with a maximum number of medical service providers, organisations, and regarding specific migrant lifestyles. Social and ethic aspects of medical care for people living in precarious conditions ought to be supplemented by practice models which render a flexible and economic organisation of a complementary system of health care, the only way to a sustainable medical care for small migrant groups or not optimally integrated immigrant populations.

Cash benefits in long-term home care.

This paper tests empirically for differences in prices paid between parts of the cash benefit that clients may and not may keep when it is unspent. In The Netherlands, demand-side subsidies were introduced in 1996. Clients receive a cash benefit to purchase the type of home care (housework, personal care, support with mobility, organisational tasks or social support) they need from the care supplier of their choice (private care provider, regular care agency, commercial care agency or paid informal care provider). Furthermore, they negotiate with the care supplier about price and quantity. Our main findings are the following: (1) the component of the cash benefit that a client may not keep when it is unspent has a positive impact on the price of care. (2) In contrast, the components of the cash benefit a client may keep when it is unspent, have no or a negative impact on the price of care. Both results have important implications for designing health policy. If cash benefits are introduced in long-term home care in an attempt to make consumers more conscious about prices, it is only successful when consumers may keep the unspent part of the cash benefit.

Isospin effects on subthreshold kaon production at intermediate energies.

We show that in collisions with neutron-rich heavy ions at energies around the production threshold K0 and K+ yields probe the isospin-dependent part of the nuclear equation of state at high baryon densities. In particular, we suggest the K0/K+ ratio as a promising observable. Results obtained in a covariant relativistic transport approach are presented for Au+Au collisions at 0.8-1.8A GeV. The focus is put on the equation of state influence which goes beyond the collision-cascade picture. The isovector part of the in-medium interaction affects the kaon multiplicities via two mechanisms: (i) a symmetry potential effect, i.e., a larger neutron repulsion in n-rich systems, and (ii) a threshold effect, due to the change in the self-energies of the particles involved in inelastic processes. Genuine relativistic contributions are revealed that could allow one to directly "measure" the Lorentz structure of the effective isovector interaction.

Managed competition and consumer price sensitivity in social health insurance.

This paper examines whether the introduction of managed competition in Dutch social health insurance has resulted in effective price competition among insurance funds. We find evidence of limited price competition, which may be caused by low consumer price sensitivity. Using aggregate panel data from all insurance funds over the period 1996-1998, estimated premium elasticities of market share are -0.3 for compulsory coverage and -0.8 for supplementary coverage. These elasticities are much smaller than in managed competition settings in US group insurance. This may be explained by differences in switching experience and higher search costs associated with individual insurance.

Genetic changes in stage pT2N0 prostate cancer studied by comparative genomic hybridization.

OBJECTIVE: To identify chromosomal regions important for progression in clinically organ-confined prostate cancer, as the genetic changes underlying the development and progression of prostate cancer are poorly understood. MATERIALS AND METHODS: Comparative genomic hybridization (CGH) was used to search for DNA sequence copy-number changes in a series of 50 primary organ-confined prostate adenocarcinomas (pT2N0) removed by radical prostatectomy. RESULTS: CGH analysis indicated that 23 (46%) of the primary prostate adenocarcinomas showed chromosome alterations. The percentage of tumours with losses (38%) was higher than with gains (28%). Losses of 13q (24%), 8p (18%), 6q (10%), 16q (8%), 18q (6%) and 5q (6%) and gains of 17q (12%), 20q (12%), 9q (10%), 17p (8%) and 8q (6%) were the most frequent alterations. Amplifications were found at 8q24-qter. Minimal overlapping regions of loss, indicative of the presence of tumour-suppressor genes, were mapped to 13q21.1-q21.3 and 8p21.2, and minimal overlapping regions of gain, indicative of the presence of oncogenes, were found at 9q34.4-qter, 17q25-qter and 20q13.3-qter. There was a significant association between Gleason score and losses and gains (P = 0.003), and an association between chromosomal imbalance and high histological grade (P = 0.008). CONCLUSION: These results suggest that losses or gains of DNA in these regions are important for prostate cancer progression, and document the spectrum of chromosomal alterations in stage pT2N0 of clinically organ-confined prostate cancer.

Cluster analysis of comparative genomic hybridization (CGH) data using self-organizing maps: application to prostate carcinomas.

Comparative genomic hybridization (CGH) is a modern genetic method which enables a genome-wide survey of chromosomal imbalances. For each chromosome region, one obtains the information whether there is a loss or gain of genetic material, or whether there is no change at that region. Usually it is not possible to evaluate all 46 chromosomes of a metaphase, therefore several (up to 20 or more) metaphases are analyzed per individual, and expressed as average. Mostly one does not study one individual alone but groups of 20-30 individuals. Therefore, large amounts of data quickly accumulate which must be put into a logical order. In this paper we present the application of a self-organizing map (Genecluster) as a tool for cluster analysis of data from pT2N0 prostate cancer cases studied by CGH. Self-organizing maps are artificial neural networks with the capability to form clusters on the basis of an unsupervised learning rule, i.e., in our examples it gets the CGH data as only information (no clinical data). We studied a group of 40 recent cases without follow-up, an older group of 20 cases with follow-up, and the data set obtained by pooling both groups. In all groups good clusterings were found in the sense that clinically similar cases were placed into the same clusters on the basis of the genetic information only. The data indicate that losses on chromosome arms 6q, 8p and 13q are all frequent in pT2N0 prostatic cancer, but the loss on 8p has probably the largest prognostic importance.

Detailed marker chromosome analysis in cell line U-BLC1, established from transitional-cell carcinoma of the bladder.

A permanent cell line, U-BLC1, was established from a primary transitional-cell carcinoma, TCC, of the urinary bladder. Karyotype analysis showed the line to be highly aberrant, with a near-triploid chromosome number of 68 to 73. Comparative genomic hybridization revealed some distinct differences between the primary tumor and the established cell line. Karyotype analysis showed 3 marker chromosomes with homogeneously staining regions, HSRs, in the cell line. The HSRs were isolated by microdissection and the microdissection probes were hybridized to normal metaphase chromosomes. The HSRs contain sequences known to be frequently involved in amplification in transitional-cell carcinoma of the bladder, 6p22, 7p11-p12, 9p23-pter, and one region not yet reported to be amplified in primary TCC of the bladder, 1p31-p32. A candidate-gene approach showed that in the region 7p11-p12 the EGFR locus is amplified and highly expressed.

Fluorodeoxyglucose whole-body positron emission tomography in colorectal cancer patients studied in routine daily practice.

PURPOSE: To evaluate the routine clinical value of attenuation-corrected whole-body fluorodeoxyglucose positron emission tomography in colorectal cancer, a total of 59 patients who were referred for evaluation of suspected or proven colorectal cancers were studied. METHODS: Positron emission tomography scans were recorded using a Siemens ECAT Exact 921/47. RESULTS: Median follow-up after the positron emission tomography study was 11 (mean, 12.3; range, 1-21) months. According to computed tomography, coloscopy, and ultrasound, we recorded eight apparently false-positive results. During later follow-up, however, three of those cases, which were negative with computed tomography, magnetic resonance imaging, sonography, or laparoscopy, turned out to be true-positive instead. In 3 patients, a primary colorectal cancer was suspected; in 26 patients, a recurrence of colorectal cancer was suspected. Eight patients were studied for follow-up after the history of colorectal cancer with no suspicion of recurrence. In 12 patients, the rise of serum tumor marker concentrations was the reason for the positron emission tomography study; 12 patients with known metastatic disease were also included ("restaging"). With regard to the entire patient population, we found an overall sensitivity of 100 percent, a specificity of 67 percent, and positive and negative predictive values of 92 and 100 percent, respectively. Being merely confirmative with respect to tumor recurrence or distant metastases in the majority of patients, positron emission tomography revealed a primary tumor in one patient and confirmed metastatic foci in several patients that had not been delineated by other imaging modalities. CONCLUSION: A whole-body positron emission tomography scan provides optimum conditions to locate metastatic lesions that might not be seen otherwise. There is a trend showing that positron emission tomography diagnostics as a consequence of early increased tumor markers is a highly sensitive combination, because computed tomography and magnetic resonance imaging were not as sensitive in early recurrences. Positron emission tomography, as performed in daily clinical practice, proved to be a powerful diagnostic tool in our subset of colorectal cancer patients.

Co-existence of the enkephalinergic system and the melanotropinergic system in the rat duodenum shown by immunohistochemistry.

The immunohistochemical distribution of alpha-melanotropin (alpha-MSH) and Met-enkephalin (Met-ENK) immunoreactivities in the rat duodenum was examined by using immunofluorescence microscopy. Alternately staining of adjacent frozen serial sections with specific antisera directed to alpha-MSH or Met-ENK revealed that within a subpopulation of myenteric plexus perikarya alpha-MSH immunostaining co-exists with that of Met-ENK. Some myenteric plexus nerve fibres also contain both Met-ENK and alpha-MSH immunoreactivity. These findings might indicate that the genes encoding for the precursors of melanotropins (the pro-opiomelanocortin precursor) and enkephalin (the pro-enkephalin precursor) are generated from a common, large and single ancestor gene which remained conserved during evolution in the rat enteric nervous system.

beta-Endorphin is contained within presumptive receptosomes and lysosomes of the myenteric plexus of the rat.

Using the microdissection technique combined with the pre-embedding immunostaining method, beta-endorphin immunoreactivity (beta-END-IR) was noted within ring-shaped elements lying singly or in groups in nerve processes of the duodenal myenteric plexus of the rat. The beta-END-IR was noted as a strongly electron-dense precipitate rim on the inner surface of these elements. The membrane of the ring-shaped element as well as the beta-END precipitate rim were strikingly often unilaterally interrupted at the same site. Some of the ring-shaped beta-END-positive elements were noted within large osmiophilic bodies. The beta-END immunoreactive ring structure was 60-300 nm in diameter and possessed an empty electron-lucent space as well as a thin electron-dense membrane. The osmiophilic bodies were pleormorph, had a mean diameter of 250 nm and revealed thick electron-opaque membranes. Their inner spaces were homogenously filled with electron-dense materials. These findings might indicate that the beta-END-IR-containing ring-shaped elements represent receptosomes and that the pleomorph osmiophilic bodies are identical to lysosomes.

Identification of the tridecapeptide dynorphin B (rimorphin) within perikarya of rat duodenum.

Using an immunofluorescence microscopic staining technique, the opioid peptide dynorphin B (rimorphin) was revealed within neuronal cell bodies of the rat duodenum. Dynorphin B immunoreactive perikarya were revealed in the myenteric and submucousal plexus as well as in the longitudinal muscle layer. They were large in diameter and round in shape and they contained a large round nucleus. Because no dynorphin B immunofluorescent nerve fibre and terminal could be noted it might be that dynorphin B is further cleaved by proteases into the bioactive opioid pentapeptide Leu-enkephalin and dynorphin B(6-13). These findings might also indicate that dynorphin B is processed within duodenal perikarya and that it has important physiological roles in the rat duodenum.

Alpha-neo-endorphin coexists with dynorphin-A(1-8) within intramurally lying perikarya of rat duodenum.

By the use of the immunofluorescent microscopic staining technique, adjacent serial sections through the rat duodenum were alternately stained with specific antisera directed to the opioid peptides alpha-neo-endorphin and dynorphin-A(1-8). alpha-Neo-endorphin immunoreactivity has been revealed exclusively within perikarya lying intramurally in the longitudinal muscle layer. These alpha-neo-endorphin and dynorphin-A(1-8) immunoreactive perikarya were large in diameter, round in shape, contained a large and round nucleus, and were recognized only occasionally there. alpha-Neo-endorphin immunoreactivity was coexistent with dynorphin-A(1-8)-positive material within these perikarya. Since no alpha-neo-endorphin material was detected within duodenal nerve fibres and terminals, it might be concluded that this peptide is further enzymatically cleaved to the opioid pentapeptide Leu-enkephalin during its axonal transport from intramural perikarya to nerve terminals and during its storage there.

Localization of Met-enkephalin-Arg6-Gly7-Leu8 immunoreactivity in rat duodenum.

The distribution of Met-enkephalin-Arg6-Gly7-Leu8 (Met-ENK-Arg6-Gly7-Leu8) in the rat duodenum was determined using specific antibodies against Met-ENK-Arg6-Gly7-Leu8 and the immunofluorescence microscope technique. Met-ENK-Arg6-Gly7-Leu8 immunoreactive perikarya have been detected in the myenteric plexus. These neuronal cell bodies were large in diameter and round in shape. Met-ENK-Arg6-Gly7-Leu8 immunostained nerve fibres were noted in both the circular muscle layer and, more abundantly, in interconnecting myenteric plexus nerve fibre bundles. These findings might indicate that Met-ENK-Arg6-Gly7-Leu8 has important physiological roles as neurotransmitter and/or neuromodulator in the human and mammalian gastrointestinal tract.