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Objectives: This study aimed to provide the first evidence of the socioeconomic burden of cystic fibrosis (CF) in Czechia., Methods: In a cross-sectional questionnaire-based primary data collection conducted from 2020 to 2021 among Czech patients with CF, we collected demographic, clinical, and healthcare resource use data, out-of-pocket and social transfer costs, and questionnaires: Cystic Fibrosis Questionnaire-Revised, Work Productivity and Activity Impairment, EQ-5D, and Zarit Burden Interview. Productivity loss/costs were assessed using the human capital approach with patient patient-assumed life expectancy of 45 years and caregiver retirement age of 64 years and discounted by 3%., Results: A total of 257 patients completed the questionnaires (37% of the Czech CF population). The average age was 17 years; most were females (59%), and the average forced expiratory volume in 1 second was 81.4% (SD 25.4%). A total of 107 patients had caregivers with an average age of 39 years and a significant caregiver time burden (extra 4.6 hours/day). The average Zarit Burden Interview score (25.4) was comparable with advanced cancer, dementia, or Duchenne muscular dystrophy. The proportion of unemployed caregivers was 10× higher than the general population (31% vs 3.2%). Total out-of-pocket family costs related to CF were €278/month, mainly for medicines (€105), foods (€73), and transport (€59); 25% received a disability pension and 18% other social security benefits. The work impairment of employed patients and caregivers was 25% and 15%, respectively, mostly due to presenteeism. Total lifetime productivity costs extrapolated to all Czech patients with CF (n = 687) and their caregivers were €155 181 286 (€225 883/person)., Conclusions: The societal burden imposed on Czech patients with CF and their caregivers is significant. Caregivers seem to be affected by higher disease activity more than patients., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2025 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Tacrolimus capsules contain the drug as the amorphous form. It is well known that drug crystallinity is a risk factor for the performance of amorphous formulations. This study investigated the impact of varying levels of crystalline drug on the pharmacokinetics of tacrolimus following oral dosing of a 5 mg capsule under fasting conditions. Two treatments with percent crystallinity of 20% and 50% were achieved by exposing a marketed generic tacrolimus product to open dish storage conditions of 35 °C and 75% relative humidity (RH) for up to 20 days. Crystallinity was monitored with X-ray powder diffraction. Prograf®, the reference listed drug (RLD), an amorphous generic drug product, and generic drug products containing 20% and 50% crystalline tacrolimus were evaluated. All four treatments were administered to healthy participants in a randomized, single-dose, four-treatment, four-period, four-way crossover study. Blood sampling occurred over 24 h. The amorphous generic tacrolimus product was determined not to be bioequivalent to the RLD. The capsules containing both 20% and 50% crystalline tacrolimus also failed the bioequivalence recommendations when compared to the amorphous generic or to the RLD. Both levels of crystalline tacrolimus resulted in BE failure for both C max and AUC parameters. The impact of tacrolimus crystallization was greater for maximum blood concentration (C max ) values relative to the area-under-the-curve (AUC) values. This study demonstrates that crystalline tacrolimus formed in a marketed generic product and these changes resulted in variable pharmacokinetics which could be of significant clinical concern., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: L.S.T is an Editorial Board Member of the Journal of Pharmaceutical Sciences and Editor-in-Chief of Molecular Pharmaceutics and was not involved in the editorial review or the decision to publish this article. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the FDA., (Copyright © 2024 American Pharmacists Association. All rights reserved.)

Background: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs., Patients and Methods: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures., Results: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature., Conclusions: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival., Competing Interests: Disclosure BR served in a consulting/advisory role and received research funding from Neophore LTD. AM owns stock from Centessa Pharmaceuticals, Deka Biosciences, HotSpot Therapeutics, Marengo Therapeutics, Shattuck Labs; served as consultant or in an advisory role from Adagene, AstraZeneca, BiolineRx, Centessa Pharmaceuticals, Clover Biopharmaceuticals, Deka Biosciences, Depth Charge Therapeutics, EISAI, Grey Wolf Therapeutics, Gritstone Bio, Guidepoint Global, HiFiBiO Therapeutics, Hotspot Therapeutics, ImCheck therapeutics, Innate Pharma, Johnson & Johnson/Janssen, Lytix Biopharma, Medicxi, MSD, Neogene Therapeutics, OSE Immunotherapeutics, Pegaone, Pierre-Fabre, Redx Pharma, Roche, Sanofi, SERVIER, Shattuck Labs, Sotio, Third Rock Ventures; received research funding from Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), MSD (Inst), Transgene (Inst); is an inventor on a patent related to monoclonal antibodies against CD81 (Stanford University); received travel, accommodations, expenses from Sotio; and has other relationship with Elsevier. AC declared research funding from Seagen and GSK and has served in advisory boards of Seagen, Merck, Pfizer, Roche, GSK, Abbvie, Illumina, and Amgen. NHS served in consulting/advisory board: Agenus, Regeneron, Puretech, Novartis, Numab, AstraZeneca, GSK, ABL Bio, Revitope; and received research funding from Roche/Genentech, Pfizer, Merck, BMS, AstraZeneca, Puretech, Immunocore, Regeneron, Agenus. LS served in the scientific Advisory Board for Genor Biopharma, Ltd. AMV reports consulting or advisory role for Roche, Lilly, AstraZeneca, PAIGE; has received research funding from Illumina, Lilly, Verastem, BioMed Valley Discoveries, Bristol-Myers Squibb, Silenseed; and received travel support from Roche. RY has served as an advisor for Pfizer, Mirati Therapeutics, Revolution Medicine, Loxo@Lilly, and Amgen; received a speaker’s honorarium from Zai Lab’ and has received research support to her institution from Pfizer, Boehringer Ingelheim, Mirati Therapeutics, Daiichi-Sankyo, and Boundless Bio. GYK received research funding to institution from AstraZeneca, BMS, CARsgen, Daiichi-Sankyo, I-MAB, Jazz, Merck, Oncolys, Pieris, Triumvira, Zymeworks; served as a consultant for Astellas, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, I-MAB, Jazz, Merck, Pieris, Zymeworks; and travel support from Dava Oncology and I-MAB. CBW has received honoraria/speakers’ fees from Amgen, Bayer, BMS, Chugai, Celgene, Falk, GSK, MSD, Merck, Janssen, Ipsen, Roche, Servier, SIRTeX, Taiho; served on advisory boards for Amgen, Bayer, BMS, Celgene, Incyte, Janssen, MSD, Servier, Shire/Baxalta, Rafael Pharmaceuticals, RedHill, Roche; has received travel support by Bayer, Celgene, Janssen, RedHill, Roche, Servier, Taiho; has received research grants (institutional) by Roche; serves as an officer for the European Society of Medical Oncology (ESMO) and Arbeitsgemeinschaft internistische Onkologie (AIO) and on expert committees for the German Cancer Aid (Deutsche Krebshilfe) and German Cancer Society (Deutsche Krebsgesellschaft); is a member of the EU Commission expert group: Mission Board for Cancer. BD and ABS are full time employees of Foundation Medicine and own stock and or stock options in Roche Holdings, Inc. CC served as expert testimony for Amgen; received honoraria as invited speaker for Bayer, Merck Serono, Servier; participated in advisory board for MSD, Nordic Pharma, Pierre-Fabre, Roche, Takeda; reports institutional financial interest for Bayer as Coordinating PI, Hutchinson as Local PI, Merck as Coordinating PI, Roche as Coordinating PI, Seagen as Local PI, Servier as Coordinating PI. SL reports research funding (to institution) from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, Servier; personal honoraria as invited speaker from Amgen, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre-Fabre, Roche, Servier; participation in advisory board for Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, Takeda. FP reports institutional research grants from BMS, Incyte, Agenus, Amgen, Lilly and AstraZeneca; and personal fees from BMS, MSD, Amgen, Merck Serono, Pierre-Fabre, Servier, Bayer, Takeda, Astellas, Johnson&Johnson, Rottapharm, Ipsen, AstraZeneca, GSK, Daiichi-Sankyo, and Seagen. All other authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Advanced bladder squamous cell carcinoma (aBSCC) is an uncommon form of urinary bladder malignancy when compared with the much higher urothelial carcinoma incidence. We studied the genomic alteration (GA) landscape in a series of aBSCC based on the association with human papilloma virus (HPV) to determine if differences in GA would be observed between the positive and negative groups., Methods: Using a hybrid capture-based FDA-approved CGP assay, a series of 171 aBSCC were sequenced to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. Programmed cell death ligand -1 (PD-L1) expression was determined by IHC (Dako 22C3) with negative expression when PD-L1 was 0, lower expression of positivity set at 1 to 49%, and higher expression set at ≥50% expression., Results: Overall, 11 (6.4%) of the aBSCC were found to harbor HPV sequences (10 HPV16 and 1 HPV 11). HPV+ status was identified slightly more often in women (NS) and in younger patients (P = 0.04); 2 female patients with aBSCC had a prior history of SCC including 1 anal SCC and 1 vaginal SCC. HPV+ aBSCC had fewer GA/tumor (P < 0.0001), more inactivating mutations in RB1 (P = 0.032), and fewer inactivating GA in CDKN2A (P < 0.0001), CDKN2B (P = 0.05), TERT promoter (P = 0.0004) and TP53 (P < 0.0001). GA in genes associated with urothelial carcinoma including FGFR2 and FGFR3 were similar in both HPV+ and HPV- aBSCC groups. MTAP loss (homozygous deletion) which has emerged as a biomarker for PRMT5 inhibitor-based clinical trials was not identified in any of the 11 HPV+ aBSCC cases, which was significantly lower than the 28% positive frequency of MTAP loss in the HPV- aBSCC group (P < 0.0001). MTOR and PIK3CA pathway GA were not significantly different in the 2 groups. Putative biomarkers associated with immunotherapy (IO) response, including MSI and TMB status, were also similar in the 2 groups. PD-L1 expression data was available for a subset of both HPV+ and HPV- cases and showed high frequencies of positive staining which was not different in the 2 groups., Conclusions: HPV+ aBSCC tends to occur more often in younger patients. As reported in other HPV-associated squamous cell carcinomas, HPV+ aBSCC demonstrates significantly reduced frequencies of inactivating mutations in cell cycle regulatory genes with similar GA in MTOR and PIK3CA pathways. The implication of HPV in the pathogenesis of bladder cancer remains unknown but warrants further exploration and clinical validation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Premenstrual dysphoric disorder (PMDD) disrupts the lives of millions of people each month. The timing of symptoms suggests that hormonal fluctuations play a role in the pathogenesis. Here, we tested whether a heightened sensitivity of the serotonin system to menstrual cycle phase underlies PMDD, assessing the relationship of serotonin transporter (5-HTT) changes with symptom severity across the menstrual cycle., Methods: In this longitudinal case-control study, we acquired 118 [ 11 C]DASB positron emission tomography scans measuring 5-HTT nondisplaceable binding potential (BP ND ) in 30 patients with PMDD and 29 controls during 2 menstrual cycle phases (periovulatory, premenstrual). The primary outcome was midbrain and prefrontal cortex 5-HTT BP ND . We tested whether BP ND changes correlated with depressed mood., Results: Linear mixed effects modeling (significant group × time × region interaction) showed a mean increase of 18% in midbrain 5-HTT BP ND (mean [SD] periovulatory = 1.64 [0.40], premenstrual = 1.93 [0.40], delta = 0.29 [0.47]: t 29  = -3.43, p = .0002) in patients with PMDD, whereas controls displayed a mean 10% decrease in midbrain 5-HTT BP ND (periovulatory = 1.65 [0.24] > premenstrual = 1.49 [0.41], delta = -0.17 [0.33]: t 28  = -2.73, p = .01). In patients, increased midbrain 5-HTT BP ND correlated with depressive symptom severity (R 2  = 0.41, p < .0015) across the menstrual cycle., Conclusions: These data suggest cycle-specific dynamics with increased central serotonergic uptake followed by extracellular serotonin loss underlying the premenstrual onset of depressed mood in patients with PMDD. These neurochemical findings argue for systematic testing of pre-symptom-onset dosing of selective serotonin reuptake inhibitors or nonpharmacological strategies to augment extracellular serotonin in people with PMDD., (Copyright © 2023. Published by Elsevier Inc.)

Rearrangements involving KMT2A are common in de novo and therapy-related acute myeloid and lymphoblastic leukemias. There is a diverse recombinome associated with KMT2A involving at least 135 partner genes, with more being discovered due to advances in molecular genetic diagnostics. KMT2A-ARHGEF12 fusion has only rarely been reported, in five cases of acute leukemia and a single case of high-grade B-cell lymphoma. We present a 12-year-old boy with high-grade B-cell lymphoma and KMT2A-ARHGEF12 fusion, whose clinical, morphologic, phenotypic and genotypic profile is strikingly similar to the other case of high grade B cell lymphoma, both otherwise perfectly mimicking Burkitt lymphoma., Competing Interests: Declaration of Competing Interest BD and CM are employees of Foundation Medicine, Inc. and are stockholders of Roche Holdings. KTS, JAW, BIC and RMT declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: This study aims to assess the association between patient contact and intestinal carriage of multidrug-resistant organisms (MDRO) by sampling healthcare personnel (HCP) and staff without patient contact., Methods: For this observational study, we recruited 400 HCP who worked in our 200-bed research hospital and 400 individuals without patient contact between November 2013 and February 2015. Participants submitted two self-collected perirectal swabs and a questionnaire. Swabs were processed for multidrug-resistant Gram-negative bacteria and vancomycin-resistant enterococci (VRE). Questionnaires explored occupational and personal risk factors for MDRO carriage., Results: Among 800 participants, 94.4% (755/800) submitted at least one swab, and 91.4% (731/800) also submitted questionnaires. Extended spectrum β-lactamase-producing organisms were recovered from 3.4% (26/755) of participants, and only one carbapenemase-producing organism was recovered. No VRE were detected. The potential exposure of 68.9% (250/363) of HCP who reported caring for MDRO-colonized patients did not result in a rate of MDRO carriage among HCP (4.0%; 15/379) significantly higher than that of staff without patient contact (3.2%; 12/376; p 0.55)., Conclusions: This is the largest US study of HCP intestinal MDRO carriage. The low colonization rate is probably reflective of local community background rates, suggesting that HCP intestinal colonization plays a minor role in nosocomial spread of MDROs in a non-outbreak setting., Trial Registration: clinicaltrials.gov Identifier: NCT01952158., (Published by Elsevier Ltd.)

Objectives: Implementing new programs to support precision medicine in clinical settings is a complex endeavor. We describe challenges and potential solutions based on the Indiana GENomics Implementation: an Opportunity for the Underserved (INGenious) program at Eskenazi Health-one of six sites supported by the Implementing GeNomics In pracTicE network grant of the National Institutes of Health/National Human Genome Research Institute. INGenious is an implementation of a panel of genomic tests., Methods: We conducted a descriptive case study of the implementation of this pharmacogenomics program, which has a wide scope (14 genes, 27 medications) and a diverse population (patients who often have multiple chronic illnesses, in a large urban safety-net hospital and its outpatient clinics)., Challenges: We placed the clinical pharmacogenomics implementation challenges into six categories: patient education and engagement in care decision making; clinician education and changes in standards of care; integration of technology into electronic health record systems; translational and implementation sciences in real-world clinical environments; regulatory and reimbursement considerations, and challenges in measuring outcomes. A cross-cutting theme was the need for careful attention to workflow. Our clinical setting, a safety-net health care system, presented some distinctive challenges. Patients often had multiple chronic illnesses and sometimes were taking more than one pharmacogenomics-relevant medication. Reaching patients for recruitment or follow-up was another challenge., Conclusions: New, large-scale endeavors in health care are challenging. A description of the challenges that we encountered and the approaches that we adopted to address them may provide insights for those who implement and study innovations in other health care systems., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: Real-time cardiovascular magnetic resonance (rtCMR) is considered attractive for guiding TAVI. Owing to an unlimited scan plane orientation and an unsurpassed soft-tissue contrast with simultaneous device visualization, rtCMR is presumed to allow safe device navigation and to offer optimal orientation for precise axial positioning. We sought to evaluate the preclinical feasibility of rtCMR-guided transarterial aortic valve implatation (TAVI) using the nitinol-based Medtronic CoreValve bioprosthesis., Methods: rtCMR-guided transfemoral (n = 2) and transsubclavian (n = 6) TAVI was performed in 8 swine using the original CoreValve prosthesis and a modified, CMR-compatible delivery catheter without ferromagnetic components., Results: rtCMR using TrueFISP sequences provided reliable imaging guidance during TAVI, which was successful in 6 swine. One transfemoral attempt failed due to unsuccessful aortic arch passage and one pericardial tamponade with subsequent death occurred as a result of ventricular perforation by the device tip due to an operating error, this complication being detected without delay by rtCMR. rtCMR allowed for a detailed, simultaneous visualization of the delivery system with the mounted stent-valve and the surrounding anatomy, resulting in improved visualization during navigation through the vasculature, passage of the aortic valve, and during placement and deployment of the stent-valve. Post-interventional success could be confirmed using ECG-triggered time-resolved cine-TrueFISP and flow-sensitive phase-contrast sequences. Intended valve position was confirmed by ex-vivo histology., Conclusions: Our study shows that rtCMR-guided TAVI using the commercial CoreValve prosthesis in conjunction with a modified delivery system is feasible in swine, allowing improved procedural guidance including immediate detection of complications and direct functional assessment with reduction of radiation and omission of contrast media.

Purpose: We report a male child who presented at 15 months with perianal abscesses and proctitis, progressing to transmural pancolitis with colocutaneous fistulae, consistent with a Crohn disease-like illness. The age and severity of the presentation suggested an underlying immune defect; however, despite comprehensive clinical evaluation, we were unable to arrive at a definitive diagnosis, thereby restricting clinical management., Methods: We sought to identify the causative mutation(s) through exome sequencing to provide the necessary additional information required for clinical management., Results: After sequencing, we identified 16,124 variants. Subsequent analysis identified a novel, hemizygous missense mutation in the X-linked inhibitor of apoptosis gene, substituting a tyrosine for a highly conserved and functionally important cysteine. X-linked inhibitor of apoptosis was not previously associated with Crohn disease but has a central role in the proinflammatory response and bacterial sensing through the NOD signaling pathway. The mutation was confirmed by Sanger sequencing in a licensed clinical laboratory. Functional assays demonstrated an increased susceptibility to activation-induced cell death and defective responsiveness to NOD2 ligands, consistent with loss of normal X-linked inhibitor of apoptosis protein function in apoptosis and NOD2 signaling., Conclusions: Based on this medical history, genetic and functional data, the child was diagnosed as having an X-linked inhibitor of apoptosis deficiency. Based on this finding, an allogeneic hematopoietic progenitor cell transplant was performed to prevent the development of life-threatening hemophagocytic lymphohistiocytosis, in concordance with the recommended treatment for X-linked inhibitor of apoptosis deficiency. At >42 days posttransplant, the child was able to eat and drink, and there has been no recurrence of gastrointestinal disease, suggesting this mutation also drove the gastrointestinal disease. This report describes the identification of a novel cause of inflammatory bowel disease. Equally importantly, it demonstrates the power of exome sequencing to render a molecular diagnosis in an individual patient in the setting of a novel disease, after all standard diagnoses were exhausted, and illustrates how this technology can be used in a clinical setting.

Background: Cardiovascular magnetic resonance (CMR) is considered an attractive alternative for guiding transarterial aortic valve implantation (TAVI) featuring unlimited scan plane orientation and unsurpassed soft-tissue contrast with simultaneous device visualization. We sought to evaluate the CMR characteristics of both currently commercially available transcatheter heart valves (Edwards SAPIEN™, Medtronic CoreValve®) including their dedicated delivery devices and of a custom-built, CMR-compatible delivery device for the Medtronic CoreValve® prosthesis as an initial step towards real-time CMR-guided TAVI., Methods: The devices were systematically examined in phantom models on a 1.5-Tesla scanner using high-resolution T1-weighted 3D FLASH, real-time TrueFISP and flow-sensitive phase-contrast sequences. Images were analyzed for device visualization quality, device-related susceptibility artifacts, and radiofrequency signal shielding., Results: CMR revealed major susceptibility artifacts for the two commercial delivery devices caused by considerable metal braiding and precluding in vivo application. The stainless steel-based Edwards SAPIEN™ prosthesis was also regarded not suitable for CMR-guided TAVI due to susceptibility artifacts exceeding the valve's dimensions and hindering an exact placement. In contrast, the nitinol-based Medtronic CoreValve® prosthesis was excellently visualized with delineation even of small details and, thus, regarded suitable for CMR-guided TAVI, particularly since reengineering of its delivery device toward CMR-compatibility resulted in artifact elimination and excellent visualization during catheter movement and valve deployment on real-time TrueFISP imaging. Reliable flow measurements could be performed for both stent-valves after deployment using phase-contrast sequences., Conclusions: The present study shows that the Medtronic CoreValve® prosthesis is potentially suited for real-time CMR-guided placement in vivo after suggested design modifications of the delivery system.

Numerous types of biological motion are driven by myosin thick filaments. Although the exact structure of the filament backbone is not known, it has long been hypothesized that periodically arranged charged regions along the myosin tail are the main contributors to filament stability. Here we provide a direct experimental test of this model by mechanically pulling apart synthetic myosin thick filaments. We find that unzipping is accompanied by broad force peaks periodically spaced at 4-, 14- and 43-nm intervals. This spacing correlates with the repeat distance of highly charged regions along the myosin tail. Lowering ionic strength does not change force-peak periodicity but increases the forces necessary for unzipping. The force peaks are partially reversible, indicating that the interactions are rapidly re-established upon mechanical relaxation. Thus, the zipping together of myosin tails via consecutive formation of periodically spaced bonds may be the underlying mechanism of spontaneous thick filament formation.

Co-elution of cationic methylated arsenic, e.g. arsenobetaine may interfere with the determination of arsenite on the Hamilton PRP-X100 anion-exchange column using a phosphate buffer isocratically. Therefore, a sample pre-treatment method with self-packed AG MP-50 cation-exchange cartridges was proposed, which enables the arsenite determination in samples containing arsenobetaine on a PRP-X100 column using a phosphate buffer (pH 5.6) isocratically. Methylated arsenic, including dimethylarsinic acid, trimethylarsine oxide, tetramethylarsonium ion, arsenobetaine and arsenocholine, with concentrations below 1000microgAsL(-1), may be completely retained in the AG MP-50 cartridge without any changes of arsenite, arsenate and monomethylarsonic acid speciation. Such retention was independent of the pH and matrix. It is proposed to be based on hydrophobic interaction. With the help of AG MP-50 cartridges, 11 arsenic species were detected in fish (DORM-2), mussels (BCR-477) and red algae (Porphyra tenera) in 10min on the PRP-X100 column using a phosphate buffer isocratically. Arsenite was the only minor species (up to 0.9%) among all water extractable arsenic species in fish, mussel and red algae.

It remains unclear when to perform a discoid or segmental bowel resection for large endometriotic nodules with intestinal invasion. Moreover, endometriosis series are rather small to fully evaluate functional consequences of bowel resection. We therefore reviewed the incidence of leakage and functional problems after anterior and sigmoid resection as reported in the surgical literature albeit for other indications. Endoscopic resection clearly is feasible but requires an experienced surgeon. The incidence of leakage is not different after hand-sewn or stapled anastomosis, but is higher after a low rectum resection than after a sigmoid resection. Similarly, functional bowel problems are higher after a low rectum resection than after sigmoid resection. Low rectum resection in addition can be associated with functional bladder problems and sexual disturbances as anorgasmia. In conclusion, short- and long-term complications are much higher after a low rectum than after a sigmoid resection. This seems to be important in making the decision to perform a discoid or a segmental bowel resection for severe endometriosis.

The health care industry is a massive system that is changing so rapidly that it is reinventing itself. With these changes, added demands have been placed on the knowledge base and practice of nurse-midwifery with emphasis on primary care, administration, and research as well as traditionally accepted nurse-midwifery practice. The American College of Nurse-Midwives (ACNM) has a history of being alert to consumer demands, sociopolitical forces, and the health care industry itself as stimuli for change after full dialogue with the membership and appropriate study. Because the ACNM Division of Accreditation will be requiring a baccalaureate degree upon entrance or completion of each midwifery education program by June 1999, dialogue should begin now about the benefits of requiring a masters degree as the entry-level credential.

In the female German black-faced sheep the posterior cruciate ligament was replaced by a free patellar tendon autograft and after 2, 6, 16, 26 and 52 weeks tissue samples of the graft's center (axial region far from bones) were removed for histochemistry and electron microscopy. To localize the proteoglycans Alcian Blue and 0.3 M MgCl2 were added to the fixative solution. The distribution of the proteoglycans in the graft was compared to that of a normal patellar tendon and of a normal posterior cruciate ligament. In the patellar tendon spindle-shaped cells predominated and proteoglycans appeared as short filaments at regular intervals between the collagen fibrils. In the posterior cruciate ligament chondroid cells and long filaments in a net-work-like arrangement were seen. In the patellar tendon autografts short interfibrillar filaments prevailed after 2, 6 and 16 weeks. After 26 weeks and particularly after 52 weeks long filaments also appeared. Digestion with Chondroitinase ABC, AC and Hyaluronidase suggested that the short filaments were PGs containing dermatan sulfate. In grafts, in the early phases the fibroblasts predominated, while in the late phases mainly chondroid cells were observed. The grafts showed aspects of the normal posterior cruciate ligament. However, differences remained, for example the thin collagen fibrils, which could represent one of the reasons for a secondary graft failure.

The left knee joints of female German sheep were operated, replacing the posterior cruciate ligament by the central third of the patellar tendon. After 2, 6, 16, 26 and 52 weeks the graft of the operated leg as well as the contralateral central third of the patellar tendon and the posterior cruciate ligament were dissected and used for biochemical analysis. The total glycosaminoglycan content in grafts increases within the first year up to 5 fold and is higher than that of the patellar tendon, but is lower than that of the cruciate ligament. The distribution pattern of glycosaminoglycans differ in the posterior cruciate ligament and the patellar tendon. In cruciate ligament the main components are chondroitin sulfate (76%) and hyaluronan (15%). In the patellar tendon a higher portion of dermatan sulfate (approx. 16%) was found, next to 52% chondroitin sulfate and 22% hyaluronan. During the examination time the grafts show changes in the concentration and the distribution pattern of glycosaminoglycans. The chondroitin sulfate content increases during the experimental period from 1.4 +/- 1.2 mumol/g dry weight (d.w.) to 8.7 +/- 2.9 mumol/g d.w. After 1 year the chondroitin sulfate content in the graft does not differ significantly from that of the cruciate ligament. In the grafts the concentration of chondroitin (non sulfated) increases after 6 weeks up to 1.3 +/- 0.6 mumol/g d.w. in comparison to the value after 2 weeks (0.2 +/- 0.1 mumol/g d.w.) and also in the other groups (16, 26 and 52 weeks) it remains significantly increased. After 1 year the dermatan sulfate content in the graft has increased up to the fifth-fold compared to the value after 2 weeks and is higher than in the patellar tendon and in the cruciate ligament. In graft the hyaluronan content (1.0 +/- 0.4 mumol/g d.w. does not differ significantly in the groups 2, 6, 16, 26 and 52 weeks after operation, but in all five groups it is lower than in the cruciate ligament (2.4 +/- 1.0 mumol/g d.w.). Dermatan and heparan sulfate are not or only little detected in all three tissues. The distribution pattern of glycosaminoglycans in graft shows chondroitin sulfate and dermatan sulfate being the major parts of glycosaminoglycans with a slight increase of these components in the different groups during the experimental period. Hyaluronan makes up to 24 +/- 5% of the whole content of glycosaminoglycans after 2 weeks and decrease to 8 +/- 1% after 52 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)

A survey of all nurse-midwifery programs in operation during 1987 was designed to answer the questions: (1) to what extent were elements of mastery learning being implemented in nurse-midwifery programs, and (2) were there patterns of implementation associated with particular organizational characteristics of the programs. Mastery learning was introduced in nurse-midwifery education in 1972; in this study elements of mastery learning were found to be widely implemented in both mastery and non-mastery learning programs. Data about organizational characteristics of the programs revealed them to be homogeneous in several respects. There were no important differences in implementation of elements of mastery learning associated with the organizational characteristics studied.