Prevalence of healthcare-associated infections in Dutch long-term care facilities from 2009 to 2019.

OBJECTIVE: We assessed trends in the prevalence of healthcare-associated infections (HCAIs) and associated resident and facility characteristics in a national network of long-term care facilities (LTCFs) in the Netherlands from 2009 to 2019. METHODS: Participating LTCFs registered the prevalence of urinary tract infection (UTI), lower respiratory tract infection (LRTI), gastrointestinal infection (GI), bacterial conjunctivitis, sepsis and skin infection, using standardized definitions, in biannual point-prevalence surveys (PPSs). In addition, resident and LTCF characteristics were collected. Multi-level analyses were performed to study changes in the HCAI prevalence over time and to identify resident and LTCF-related risk factors. Analyses were performed for HCAIs overall and for UTI, LRTI and GI combined as these were recorded throughout the period. RESULTS: Overall, 1353 HCAIs were registered in 44,551 residents with a prevalence of 3.0% (95% confidence interval: 2.8-3.1; range between years 2.3-5.1%). When including only UTI, LRTI and GI the prevalence decreased from 5.0% in 2009 to 2.1% in 2019. Multi-variable regression analyses for UTI, LRTI and GI combined indicated that both prolonged participation and calendar time were independently associated with HCAI prevalence; in LTCFs that participated ≥4 years, the HCAI risk was decreased (OR 0.72 (0.57-0.92)) compared with the first year, and the OR per calendar year was 0.93 (0.88-0.97). CONCLUSIONS: Over 11 years of PPS in LTCFs the HCAI prevalence decreased over time. Prolonged participation further reduced the HCAI prevalence, in particular UTIs, despite the increasing age and associated frailty of the LTCF population, illustrating the potential value of surveillance.

Gait alteration strategies for knee osteoarthritis: a comparison of joint loading via generic and patient-specific musculoskeletal model scaling techniques.

Gait modifications and laterally wedged insoles are non-invasive approaches used to treat medial compartment knee osteoarthritis. However, the outcome of these alterations is still a controversial topic. This study investigates how gait alteration techniques may have a unique effect on individual patients; and furthermore, the way we scale our musculoskeletal models to estimate the medial joint contact force may influence knee loading conditions. Five patients with clinical evidence of medial knee osteoarthritis were asked to walk at a normal walking speed over force plates and simultaneously 3D motion was captured during seven conditions (0°-, 5°-, 10°-insoles, shod, toe-in, toe-out, and wide stance). We developed patient-specific musculoskeletal models, using segmentations from magnetic resonance imaging to morph a generic model to patient-specific bone geometries and applied this morphing to estimate muscle insertion sites. Additionally, models were created of these patients using a simple linear scaling method. When examining the patients' medial compartment contact force (peak and impulse) during stance phase, a 'one-size-fits-all' gait alteration aimed to reduce medial knee loading did not exist. Moreover, the different scaling methods lead to differences in medial contact forces; highlighting the importance of further investigation of musculoskeletal modeling methods prior to use in the clinical setting.

Workflow assessing the effect of gait alterations on stresses in the medial tibial cartilage - combined musculoskeletal modelling and finite element analysis.

Knee osteoarthritis (KOA) is most common in the medial tibial compartment. We present a novel method to study the effect of gait modifications and lateral wedge insoles (LWIs) on the stresses in the medial tibial cartilage by combining musculoskeletal (MS) modelling with finite element (FE) analysis. Subject's gait was recorded in a gait laboratory, walking normally, with 5° and 10° LWIs, toes inward ('Toe in'), and toes outward ('Toe out wide'). A full lower extremity MRI and a detailed knee MRI were taken. Bones and most soft tissues were segmented from images, and the generic bone architecture of the MS model was morphed into the segmented bones. The output forces from the MS model were then used as an input in the FE model of the subject's knee. During stance, LWIs failed to reduce medial peak pressures apart from Insole 10° during the second peak. Toe in reduced peak pressures by -11% during the first peak but increased them by 12% during the second. Toe out wide reduced peak pressures by -15% during the first and increased them by 7% during the second. The results show that the work flow can assess the effect of interventions on an individual level. In the future, this method can be applied to patients with KOA.

Optimal graft stiffness and pre-strain restore normal joint motion and cartilage responses in ACL reconstructed knee.

Anterior cruciate ligament (ACL) rupture leads to abnormal loading of the knee joint and increases the risk of osteoarthritis. It is unclear how different ACL reconstruction techniques affect knee joint motion and mechanics. As the in vivo measurement of knee joint loading is not possible, we used finite element analysis to assess the outcome of ACL reconstruction techniques. Effects of different ACL reconstruction techniques on knee joint mechanics were studied using six models during gait; with 1) healthy ACL, 2) ACL rupture, 3) single bundle ACL reconstruction, 4) double bundle ACL reconstruction, 5) weakened (softer) single bundle reconstruction and 6) single bundle reconstruction with less pre-strain. Early in the gait, the ACL rupture caused substantially increased tibial translation in the anterior direction as well as a smaller but increased lateral translation and internal tibial rotation. ACL rupture substantially reduced average stresses and strains, while local peak stresses and strains could be either increased or decreased. Single bundle and double bundle reconstructions restored joint motion close to normal levels. However, cartilage strains and stresses were elevated during the entire gait cycle. Models with modulated graft stiffness and pre-strain restored the joint motion and cartilage stresses and strains close to the normal, healthy levels. Results suggest that rather than the choice of reconstruction technique, stiffness and pre-strain of the ACL reconstruction affect the motion and mechanics of the operated knee. We suggest that an optimal choice of graft properties might help restore normal knee joint function and cartilage responses, thus, minimizing the risk of osteoarthritis.

Importance of Patella, Quadriceps Forces, and Depthwise Cartilage Structure on Knee Joint Motion and Cartilage Response During Gait.

In finite-element (FE) models of the knee joint, patella is often omitted. We investigated the importance of patella and quadriceps forces on the knee joint motion by creating an FE model of the subject's knee. In addition, depthwise strains and stresses in patellar cartilage with different tissue properties were determined. An FE model was created from subject's magnetic resonance images. Knee rotations, moments, and translational forces during gait were recorded in a motion laboratory and used as an input for the model. Three material models were implemented into the patellar cartilage: (1) homogeneous model, (2) inhomogeneous (arcadelike fibrils), and (3) random fibrils at the superficial zone, mimicking early stages of osteoarthritis (OA). Implementation of patella and quadriceps forces into the model substantially reduced the internal-external femoral rotations (versus without patella). The simulated rotations in the model with the patella matched the measured rotations at its best. In the inhomogeneous model, maximum principal stresses increased substantially in the middle zone of the cartilage. The early OA model showed increased compressive strains in the superficial and middle zones of the cartilage and decreased stresses and fibril strains especially in the middle zone. The results suggest that patella and quadriceps forces should be included in moment- and force-driven FE knee joint models. The results indicate that the middle zone has a major role in resisting shear forces in the patellar cartilage. Also, early degenerative changes in the collagen network substantially affect the cartilage depthwise response in the patella during walking.

Deformation of articular cartilage during static loading of a knee joint--experimental and finite element analysis.

Novel conical beam CT-scanners offer high resolution imaging of knee structures with i.a. contrast media, even under weight bearing. With this new technology, we aimed to determine cartilage strains and meniscal movement in a human knee at 0, 1, 5, and 30 min of standing and compare them to the subject-specific 3D finite element (FE) model. The FE model of the volunteer׳s knee, based on the geometry obtained from magnetic resonance images, was created to simulate the creep. The effects of collagen fibril network stiffness, nonfibrillar matrix modulus, permeability and fluid flow boundary conditions on the creep response in cartilage were investigated. In the experiment, 80% of the maximum strain in cartilage developed immediately, after which the cartilage continued to deform slowly until the 30 min time point. Cartilage strains and meniscus movement obtained from the FE model matched adequately with the experimentally measured values. Reducing the fibril network stiffness increased the mean strains substantially, while the creep rate was primarily influenced by an increase in the nonfibrillar matrix modulus. Changing the initial permeability and preventing fluid flow through noncontacting surfaces had a negligible effect on cartilage strains. The present results improve understanding of the mechanisms controlling articular cartilage strains and meniscal movements in a knee joint under physiological static loading. Ultimately a validated model could be used as a noninvasive diagnostic tool to locate cartilage areas at risk for degeneration.

Importance of depth-wise distribution of collagen and proteoglycans in articular cartilage--a 3D finite element study of stresses and strains in human knee joint.

Proteoglycans and collagen fibrils are distributed inhomogeneously throughout the depth of articular cartilage, providing the tissue with its unique depth-dependent properties and directly influencing local tissue deformations and stresses in in vitro/in situ. The aim of this study was to investigate the importance of the proteoglycan and collagen distributions for cartilage stresses and strains resulting from dynamic joint loading (i.e., a simulated gait cycle) and mechanical equilibrium in a knee joint. A 3D finite element model of a human knee joint including femoral and tibial cartilages and menisci was created. In order to characterize the effects of collagen orientation, collagen distribution and proteoglycan distribution on knee joint stresses and strains, five fibril-reinforced poroviscoelastic models with different depth-wise tissue structure were created. For each model strains and stresses were evaluated at four different depths in the medial tibial compartment during a gait cycle (simulating walking) and at mechanical equilibrium (simulating standing). The model with arcade-like collagen fibril architecture predicted substantially lower stresses than the homogeneous model, especially during dynamic joint loading. The depth-wise proteoglycan gradient caused a substantial increase in stresses and axial strains in the superficial layer, and reduced stresses and strains in the deep layer under static loading. The effect of fibril volume density distribution was minor during both dynamic joint loading and at mechanical equilibrium. The present study emphasizes the importance of the arcade-like collagen fibril orientation for cartilage function in a human knee joint. However, we suggest that, for practical reasons, a constant fibril volume density may be used in 3D models of knee joints, whereas a realistic depth-wise proteoglycan distribution should be applied when simulating the cartilage response during mechanical equilibrium.

Effects of ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women.

Ospemifene is a novel selective estrogen receptor modulator (SERM). Here we studied the effects of ospemifene on bone turnover in postmenopausal women. This was a randomized, double-blind study in which 159 healthy postmenopausal women received 30 (n = 40), 60 (n = 40) or 90 mg (n = 40) of ospemifene or placebo (n = 39) for 3 months. Bone resorption was assessed by measuring the urinary outputs of N- and C-terminal crosslinking telopeptides of type I collagen (NTX and CTX, respectively). Bone formation was assessed by measuring the levels of procollagen type I N propeptide (PINP), procollagen type I C propeptide (PICP), and bone-specific alkaline phosphatase (bone ALP) in serum. All markers were studied at baseline, 3 months, and 2-4 weeks after cessation of the medication. Ospemifene decreased bone resorption dose-dependently, as seen from falls in NTX by 6.1, 9.4 and 12.9% in the 30, 60 and 90 mg ospemifene groups, respectively (p < 0.05 for all dose levels when compared to placebo). CTX values decreased in the 90 mg ospemifene group by 4.8% (p < 0.05). A dose-dependent decrease was also observed in the bone formation markers: PINP values decreased by 9.8 (p < 0.05) and 15.3% (p < 0.01), and PICP values by 12.0 and 11.9% in the 60 and 90 mg ospemifene groups, respectively. Bone ALP decreased in 60 and 90 mg ospemifene groups by 1.9 and 2.6%, respectively (p < 0.05 for both dose levels when compared to placebo). These results show that ospemifene is effective in reducing bone turnover in postmenopausal women.

Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women.

OBJECTIVE: Selective estrogen receptor modulators (SERMs) are drugs that exhibit both estrogen agonistic and antagonistic effects that are tissue-specific. Ospemifene (FC-1271a) is a novel SERM compound, which has been shown in animal models to have estrogen-like effects on bone and the cardiovascular system, while having antiestrogen-like effects in uterus and breast. In this study, we investigated the effects of ospemifene on the uterine endometrium, vaginal maturation index and hormonal status in healthy postmenopausal women. METHODS: The study was conducted as a double-blind, placebo-controlled phase I study, where 40 healthy postmenopausal women volunteers were randomized to receive daily oral doses of ospemifene either 25, 50, 100 or 200 mg or placebo for 12 weeks. Vaginal ultrasonography and endometrial biopsy were performed and vaginal maturation index determined at baseline and at 12 weeks' visit. Serum concentrations of estradiol, luteinizing hormone, follicle stimulating hormone (FSH), sex-hormone binding globulin (SHBG), parathyroid hormone and prolactin were determined from samples taken at baseline, at 4 days and at 4, 12, and 16 weeks' visits. Climacteric symptoms were assessed using 12 visual analogue scales (VAS) at baseline and at the end of the study. RESULTS: No clinically significant changes were seen in endometrial thickness at any dose level. Ospemifene exerted a very weak estrogenic effect on endometrial histology. On the other hand, it induced a clear estrogenic effect on vaginal epithelium. Among the endocrine parameters only FSH and SHBG showed significant dose dependent changes; FSH decreased and SHBG increased during the treatment. In general, ospemifene was well tolerated. The 25 and 50 mg doses tended to reduce climacteric symptoms, but no statistically significant differences were observed between different doses of ospemifene and placebo. The highest dose level (200 mg) induced more subjective adverse reactions, especially hot flushes, than lower doses. CONCLUSION: Our study suggests that a safe and well tolerated dose of ospemifene for potential clinical use may be between 25 and 100 mg. Further studies are needed to substantiate the results of this Phase I pilot study.

Pharmacokinetics of finrozole (MPV-2213ad), a novel selective aromatase inhibitor, in healthy men.

AIMS: To investigate the pharmacokinetics of finrozole (MPV-2213ad), a novel competitive aromatase enzyme inhibitor, in healthy male volunteers. METHODS: The study was an open, partly randomized cross-over study including 23 volunteers receiving single doses of 3, 9 mg or 30 mg of finrozole as tablets or solution with 14 days between the administrations. The highest dose was given as tablets only. Serum concentrations of finrozole were determined using high performance liquid chromatography combined with mass spectrometry. RESULTS: The mean time to peak serum concentration ranged from 2.5 to 3.1, and 0.6-0.7 h after tablets and solution, respectively. The Cmax values increased as the dose increased. The calculated apparent mean elimination half-life (t(1/2,z)) was approximately 3 h after the solution, and approximately 8 h after the tablet. The AUC(0,infinity) after finrozole tablets increased proportionally from 3 mg to 9 mg and from 3 to 30 mg. The calculated relative mean bioavailabilities (AUC(0,infinity)-ratio) for the 3 mg and 9 mg doses of finrozole as tablets were 89% and 78%, respectively. CONCLUSIONS: The absorption of finrozole from the tablet formulation was relatively rapid, and the apparent elimination half-life was longer after the tablet than after the solution, probably reflecting overlap of the absorption with the elimination phase.

Pharmacokinetics of (deaminohydroxy)toremifene in humans: a new, selective estrogen-receptor modulator.

PURPOSE: New selective estrogen-receptor modulators for the treatment and prevention of osteoporosis, cardiovascular disease and breast cancer are currently the focus of intense research. (Deaminohydroxy)toremifene (Z-2-[4-(4-chloro- 1,2-diphenyl-but-1-enyl)phenoxy]ethanol; FC-1271a) has been shown to prevent bone resorption in rats while having no or weak estrogen-like effects on the uterus, which makes it a good candidate drug for osteoporosis prevention. Our purpose here was to examine the pharmacokinetics of (deaminohydroxy)toremifene in humans included in two phase-I studies. METHODS: The first was a single-dose, dose-escalation study with 28 healthy male volunteers. Doses ranged from 10 mg to 800 mg. The second study was conducted during a 12-week period with 40 healthy, post-menopausal women, who received repeated oral doses of 25-200 mg. Standard pharmacokinetic parameters were assessed. RESULTS: In the single-dose study, time to reach peak concentration (tmax) ranged from 1.3 h to 4.0 h; peak concentration (Cmax) ranged from 15 ng/ml to 445 ng/ ml; and the estimated terminal elimination half-life (mean +/- SD; t1/2) was 24.8 +/- 7.0 h. In the repeated-dose study, tmax ranged from 1.9 h to 2.6 h at 6 weeks and from 2.5 h to 2.9 h at 12 weeks. Cmax ranged from 295 ng/ml to 1,043 ng/ml at 6 weeks and from 25 ng/ml to 1211 ng/ml at 12 weeks. The average t1/2 at all dose levels was 29.7 +/- 1.5 h (overall mean +/- SD). Strong linear correlations between the dose and Cmax and between the dose and the area under the curve were observed in both studies. CONCLUSION: Our results indicate that (deaminohydroxy)toremifene has pharmacokinetics suitable for single daily dosing. The prophylactic use of this agent in women susceptible to development of osteoporosis, cardiovascular disease and breast cancer could, therefore, be tested using a once-daily dosing schedule similar to those of other hormone-replacement therapy regimens.

Severe acute pancreatitis: prognostic factors in 270 consecutive patients.

Acute pancreatitis (AP) is a common abdominal disorder with severity varying from mild to fatal disease. Predicting a patient's outcome remains problematic. The aim of this study was to analyze a large consecutive series of patients with severe AP and to identify prognostic factors for hospital mortality. Between 1989 and 1997, a consecutive series of 270 patients with severe AP were included in the study. All patients fulfilled the criteria of Atlanta classification for severe AP. Retrospectively and prospectively collected data included age, gender, etiology, number of previous episodes of pancreatitis, medication history, type of admission, body-mass index (BMI), respiratory failure, renal failure, need for pressor support, and abdominal surgery performed during hospitalization. The overall mortality rate was 24.4%. In univariate survival analysis advanced age, history of continuous medication, patient transferred from other hospital, high BMI, respiratory or renal failure, need for pressor support, and need for abdominal surgery were significant prognostic factors for hospital mortality. In a multivariate stepwise logistic regression analysis, the need of pressor support, renal failure requiring dialysis, advanced age, history of continuous medication and need for abdominal surgery were identified as independent prognostic factors for mortality. A logistic regression analysis of variables available on admission (the first seven above mentioned variables) showed that transferral admission, advanced age, and history of continuous medication were independent prognostic factors for mortality. In patients with severe AP, advanced age, history of continuous medication, and need for dialysis, mechanical ventilator support, and pressor support predict fatal outcome and thus should be taken into account in clinical evaluation.

Correlates of cognitive status of old patients with isolated systolic hypertension: the Syst-Eur Vascular Dementia Project.

OBJECTIVE: To assess cognitive functions and their correlates for a dementia-free cohort of old patients with isolated systolic hypertension. DESIGN: Cross-sectional data from the randomization period of the European Trial in Elderly with Systolic Hypertension (Syst-Eur Vascular Dementia Project). SETTING: Sixteen European countries and Israel. PARTICIPANTS: We studied 2252 patients aged 60-100 years (mean 70). MAIN OUTCOME MEASURES: Mini Mental State Examination (MMSE) and Spearman correlation of MMSE scores to demographic data or blood pressure. RESULTS: The MMSE was successfully completed for 1474 women and 751 men. The baseline blood pressure averaged 173 +/- 10/86 +/- 6 mmHg (means +/- SD). Median age at which education of patients at school had stopped was 15 years. Men and women who consumed alcohol (28%) had median intakes of 8 and 3 g/day, respectively. The median MMSE score was 29 (range 15-30). The maximum score of 30 was attained by 609 (30%) subjects. Fifty-nine (3%) patients had a MMSE score of 23 or less. The MMSE score decreased with advancing age (r = -0.21, P < 0.001). Both for men and for women, it was positively correlated to the level of education (r = 0.30 and r = 0.32, P < 0.001). For women after adjustment for age and the level of education, the score was correlated negatively to systolic blood pressure (r = -0.07, P < 0.05) but positively to intake of alcohol (r = 0.06, P < 0.05). CONCLUSION: In a cohort of elderly patients with isolated systolic hypertension, baseline cognitive function measured in terms of the MMSE score was high, probably due to selective recruitment of patients who were not clinically demented. Blood pressure was a weak contributor to cognitive status compared with age and level of education. Baseline cognitive function of women was negatively and independently correlated to systolic blood pressure.

Hormonal effects of MPV-2213ad, a new selective aromatase inhibitor, in healthy male subjects. A phase I study.

AIMS: A novel non-steroidal competitive inhibitor of the aromatase enzyme, MPV-2213ad, was entered into an open dose-escalation study. The objective of this study was to investigate the tolerability and efficiency of this new compound with assessment of the hormonal effects after study drug administration. METHODS: MPV-2213ad was given to 39 healthy male volunteers. Single increasing oral doses of 0.003, 0.03, 0.3, 3, 9, 30 and 100 mg were given to three subjects at each dose level, after which ten subjects received the 300 mg dose and eight subjects the highest 600 mg dose of MPV-2213ad. RESULTS: Serum oestradiol levels were suppressed by 58-65% when MPV-2213ad was given at doses between 0.3 and 30 mg. A reduction in serum oestradiol levels by 83% from baseline was achieved with the 300 mg dose. No additional decrease was seen with the highest dose. The suppression lasted longer with higher doses of MPV-2213ad. After the 300 and 600 mg doses serum oestradiol returned to baseline within 4 days. Marked increases in serum concentrations of testosterone, androstenedione, 17-OH-progesterone, LH and FSH were also observed at doses between 100 and 600 mg of MPV-2213ad. The drug was well-tolerated and the adverse events were mild or moderate including hot flushes, mild vertigo, nausea, acne and gastrointestinal discomfort. CONCLUSIONS: MPV-2213ad has a potent, dose-dependent inhibitory effect on serum oestradiol. It was selective for the aromatase enzyme with no signs of adreno-cortical suppression or haematological or biochemical toxicity.

Frozen-section biopsy in perendoscopic diagnosis of Helicobacter pylori.

BACKGROUND: Our goal was to investigate how reliably Helicobacter pylori infection can be diagnosed from gastric biopsy specimens by frozen-section technique. PATIENTS AND METHODS: The series consisted of 105 consecutive outpatients who underwent diagnostic upper gastrointestinal endoscopy for abdominal complaints at Jorvi Hospital (Espoo, Finland) during the beginning of 1996. Endoscopic biopsies from antrum and corpus were taken for both frozen-section and traditional histology, the latter serving as reference (control) material. In the frozen-section technique, the biopsy specimens were transferred immediately to the pathology laboratory, were prefixed for 30 sec in 10% neutral formalin, were frozen in liquid nitrogen, and were cut into sections with a cryostat. The sections were stained for 10 minutes with 1% toluidine blue. The control biopsy specimens were fixed overnight in 10% neutral formalin and embedded in paraffin, and the sections were stained with the modified Giemsa method. RESULTS: In the diagnosis of H. pylori infection, both the sensitivity and the specificity of the frozen-section technique were 98% compared to the findings in the reference series. One false-negative result occurred among 41 positive cases, and one case erroneously was classified positive among 64 cases that were negative for H. pylori in the ordinary histology. The frozen-section technique slightly underestimated the degree of colonization of the gastric mucosa by H. pylori, compared to the findings in the reference material. In the diagnosis of gastritis (chronic inflammation of any degree), the sensitivity and specificity of frozen sections were 92% and 95%, respectively. In the frozen-section technique, the report of the pathologist of the presence or absence of H. pylori gastritis in biopsy specimens could be given to the gastroenterologist by telephone in approximately 20 minutes. CONCLUSIONS: The frozen-section technique is a reliable and rapid method for the diagnosis of H. pylori and provides possibilities for perendoscopic diagnosis of the infection in the hospitals where the frozen-section service is available.