Predicting pharmacy naloxone stocking and dispensing following a statewide standing order, Indiana 2016.

BACKGROUND: While naloxone, the overdose reversal medication, has been available for decades, factors associated with its availability through pharmacies remain unclear. Studies suggest that policy and pharmacist beliefs may impact availability. Indiana passed a standing order law for naloxone in 2015 to increase access to naloxone. OBJECTIVE: To identify factors associated with community pharmacy naloxone stocking and dispensing following the enactment of a statewide naloxone standing order. METHODS: A 2016 cross-sectional census of Indiana community pharmacists was conducted following a naloxone standing order. Community, pharmacy, and pharmacist characteristics, and pharmacist attitudes about naloxone dispensing, access, and perceptions of the standing order were measured. Modified Poisson and binary logistic regression models attempted to predict naloxone stocking and dispensing, respectively. RESULTS: Over half (58.1%) of pharmacies stocked naloxone, yet 23.6% of pharmacists dispensed it. Most (72.5%) pharmacists believed the standing order would increase naloxone stocking, and 66.5% believed it would increase dispensing. Chain pharmacies were 3.2 times as likely to stock naloxone. Naloxone stocking was 1.6 times as likely in pharmacies with more than one full-time pharmacist. Pharmacies where pharmacists received naloxone continuing education in the past two years were 1.3 times as likely to stock naloxone. The attempted dispensing model yielded no improvement over the constant-only model. CONCLUSIONS: Pharmacies with larger capacity took advantage of the naloxone standing order. Predictors of pharmacist naloxone dispensing should continue to be explored to maximize naloxone access.

High-throughput generation and engineering of recombinant human antibodies.

The first version of the Human Combinatorial Antibody Library (HuCAL) is a single-chain Fv-based phage display library (HuCAL-scFv) with 2x10(9) members optimised for high-throughput generation and targeted engineering of human antibodies. 61% of the library genes code for functional scFv as judged by sequencing. We show here that since HuCAL-scFv antibodies are expressed in high levels in Escherichia coli, automated panning and screening in miniaturised settings (96- and 384-well format) have now become feasible. Additionally, the unique modular design of HuCAL-genes and -vectors allows the distinctly facilitated conversion of scFv into Fab, miniantibody and immunoglobulin formats, and the fusion with a variety of effector functions and tags not only convenient for therapeutic applications but also for high-throughput purification and detection. Thus, the HuCAL principle enables the rapid and high-throughput development of human antibodies by optimisation strategies proven useful in classical low molecular weight drug development. We demonstrate in this report that HuCAL is a very convenient source of human antibodies for various applications.

Messenger RNAs encoding the beta subunits of guinea pig (Cavia porcellus) luteinizing hormone (gpLH) and putative chorionic gonadotropin (gpCG) are transcribed from a single-copy gpLH/CGbeta gene.

Neither gene locus nor gene sequence characterizations have been reported for the beta subunits of guinea pig (gp) LH and putative gp chorionic gonadotropin (CG). Descriptions of this locus would allow comparison with functionally relevant molecular genetic features of other species' homologous loci including the single-copy equid LH/CGbeta gene and the primate LHbeta-CGbeta gene cluster locus. Contiguous cDNA and genomic DNA fragments spanning the entire mature coding sequence of gpLHbeta mRNA, gpCGbeta mRNA and a homologous gpLH/CGbeta gene were amplified using PCR methodologies. With the exception of one silent mutation, the two cDNA and the genomic sequences were identical where they overlapped. Comparison of guinea pig coding sequence with LHbeta, CGbeta and LH/CGbeta sequences of other vertebrate species revealed the following order of similarity expressed as per cent coding sequence identity: rhinoceros LHbeta (83.6%)>pig LHbeta (81.8%)>donkey LH/CGbeta=bovine LHbeta (81.5%)> horse LH/CGbeta (80.6%)>dog LHbeta (79.7%)>human LHbeta (78.2%)>rat LHbeta (77.9%)>human CGbeta (75.8%)>turkey LHbeta (52.7%); values that are generally consistent with recently postulated phylogenetic relationships. Like the consensus mammalian LHbeta gene, the 5'-flanking region of the gpLH/CGbeta gene contains a single TATA sequence 37 bp upstream of the translation start codon. The first in-frame stop codon occurred at codon position +122 which is consistent with the 121 amino acid residue length of the consensus mammalian mature LHbeta peptide. To estimate gene copy number, full-length gpLHbeta cDNA was radiolabeled and hybridized to Southern blots of guinea pig genomic DNA digested with a panel of six restriction endonucleases. The resulting simple hybridization pattern strongly suggested that there is a single-copy gpLH/CGbeta gene. Northern analysis of total pituitary RNA using the same probe indicated that gpLHbeta transcript size is indistinguishable from that of consensus mammalian pituitary LHbeta mRNAs ( approximately 750 nucleotides). Despite amplifying gpCGbeta from placental RNA, positive signal was not detected in Northern blot lanes containing guinea pig total RNA prepared from placentae collected at three gestational ages (17.3 days, 24.3 days and 68 days (term)). Other data suggest that inability to detect Northern blot signal could have been due to low relative tissue concentrations of gpCGbeta transcript and/or sampling at gestational time-points that missed peak periods of mRNA expression. We conclude that, with respect to gene copy number, coding sequence and pituitary mRNA size, the gpLH/CGbeta gene locus reflects the CTP-less consensus mammalian LHbeta condition. However, based on the capacity of this single-copy gene to express in both pituitary and placental tissues, gpLH/CGbeta also exhibits functional similarities with the single-copy equine LH/CGbeta locus.

Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial.

PURPOSE: To investigate the feasibility and the clinical response of a stereotactic single-dose radiation treatment for liver tumors. PATIENTS AND METHODS: Between April 1997 and September 1999, a stereotactic single-dose radiation treatment of 60 liver tumors (four primary tumors, 56 metastases) in 37 patients was performed. Patients were positioned in an individually shaped vacuum pillow. The applied dose was escalated from 14 to 26 Gy (reference point), with the 80% isodose surrounding the planning target volume. Median tumor size was 10 cm(3) (range, 1 to 132 cm(3)). The morbidity, clinical outcome, laboratory findings, and response as seen on computed tomography (CT) scan were evaluated. RESULTS: Follow-up data could be obtained from 55 treated tumors (35 patients). The median follow-up period was 5.7 months (range, 1.0 to 26.1 months; mean, 9.5 months). The treatment was well tolerated by all patients. There were no major side effects. Fifty-four (98%) of 55 tumors were locally controlled after 6 weeks at the initial follow-up based on the CT findings (22 cases of stable disease, 28 partial responses, and four complete responses). After a dose-escalating and learning phase, the actuarial local tumor control rate was 81% at 18 months after therapy. A total of 12 local failures were observed during follow-up. So far, the longest local tumor control is 26.1 months. CONCLUSION: Stereotactic single-dose radiation therapy is a feasible method for the treatment of singular inoperable liver metastases with the potential of a high local tumor control rate and low morbidity.

Comparison of intensity-modulated radiotherapy with conventional conformal radiotherapy for complex-shaped tumors.

PURPOSE: Conformal and intensity-modulated radiotherapy (IMRT) plans for 9 patients were compared based on characterization of plan quality and effects on the oncology department. METHODS AND MATERIALS: These clinical cases, treated originally with conformal radiotherapy (CRT), required extraordinary effort to produce conformal treatment plans using nonmodulated, shaped noncoplanar fields with multileaf collimators (MLCs). IMRT plans created for comparison included rotational treatments with slit collimator, and fixed-field MLC treatments using equispaced coplanar, and noncoplanar fields. Plans were compared based upon target coverage, target conformality, dose homogeneity, monitor units (MU), user-interactive planning time, and treatment delivery time. The results were subjected to a statistical analysis. RESULTS: IMRT increased target coverage an average of 36% and conformality by 10%. Where dose escalation was a goal, IMRT increased mean dose by 4-6 Gy and target coverage by 19% with the same degree of conformality. Rotational IMRT was slightly superior to fixed-field IMRT. All IMRT techniques increased integral dose and target dose heterogeneity. IMRT planning times were significantly less, whereas MU increased significantly; estimated delivery times were similar. CONCLUSION: IMRT techniques increase dose and target coverage while continuing to spare organs-at-risk, and can be delivered in a time frame comparable to other sophisticated techniques.

Conformal radiotherapy of challenging paraspinal tumors using a multiple arc segment technique.

PURPOSE: Target volumes that wrap around the spinal cord are difficult to treat. We present and evaluate a refined multiple arc segment (MAS) technique that is applicable with standard three-dimensional (3D) radiotherapy equipment and may be a solution for facilities that do not yet have full access to intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: The presented technique consisted of 13 isocentric coplanar beam's eye view shaped fields, delivered as 20 degrees or 10 degrees arc segments with an integrated multileaf collimator (MLC) using automatic sequential field delivery. Dose-volume histograms (DVH) for this technique were compared to a modified bar-arc technique (MBA) modeled as 30 static fields and to an inverse planned IMRT technique using 7 coplanar, equispaced beams delivered with the same MLC. RESULTS: Compared to the MBA technique, maximum dose and target coverage were similar when using 80% of the maximum dose as the reference dose. However, the MAS technique reduced the maximum doses (to > or = 1% of the organs at risk [OAR]) by 9% for the spinal cord, 17% for the esophagus, and 25% for the trachea, as well as the mean doses. Although inverse planned IMRT could further reduce exposure of OAR except for the spinal cord and improve target coverage, our forward planned MAS technique seems to achieve clinically comparable results. CONCLUSION: Substituting a series of small split-field arc segments for large static fields and using additional narrow paraspinal segments significantly improves the sparing of organs at risk for paraspinal targets. Although these results are not quite as good as those achieved with IMRT, for facilities not yet equipped with inverse treatment planning capability, the presented technique enables dose escalation for primary paraspinal tumors and retreatment of recurrent lesions.

Fractionated stereotactic conformal radiation therapy of brain stem gliomas: outcome and prognostic factors.

BACKGROUND AND PURPOSE: Evaluation of outcome and prognostic factors in patients with brain stem glioma (BSG) following fractionated stereotactic radiotherapy (FSRT). MATERIALS AND METHODS: Between 1990 and 1997, we treated 41 patients with FSRT in a phase I/II trial. Median age was 24 years. Out of 36 patients with histologically proven glioma, ten had a partial tumour resection. Histology revealed low grade gliomas in 30 patients and anaplastic gliomas in six patients. A mean total dose of 54 Gy was given in daily fractions of 1.8 Gy. Median follow-up was 12 months. RESULTS: Three patients died during FSRT. Neurological improvement was achieved in 19/38 patients. Reduction of tumour size was reported in 12/38, in 16 patients the lesion was unchanged, ten showed progression. Median time to progression was 23 months, median overall survival 40 months with an actuarial survival of 83% at 1 year, 55% at 3 years and 33% at 5 years. In 20 of 22 patients with recurrence progression was inside the target volume. Significant prognostic factors for survival were clinical and radiological response 6 weeks after FSRT. Treatment toxicity was mild. Ototoxicity occurred in one patient. CONCLUSIONS: FSRT is a feasible treatment modality for BSG with tolerable toxicity. The risk of marginal failure is low.

Conformal three-dimensional photon radiotherapy for paranasal sinus tumors.

BACKGROUND: Tumors in the nasal cavity and paranasal sinus are difficult to treat with radiotherapy. Usually, in addition to a two- or three-field photon technique, an interorbital electron field is required. This may result, however, in severe over- or underdosage, the latter being especially detrimental when occurring in the main tumor bulk. METHODS AND RESULTS: We present a conformal three-dimensional treatment technique that provides sufficient interorbital dose with photons only while sparing the eyes, optic nerves and chiasm, and may be considered for selected tumors in this region.

Extracranial stereotactic radiation therapy: set-up accuracy of patients treated for liver metastases.

PURPOSE: Patients with liver metastases might benefit from high-dose conformal radiation therapy. A high accuracy of repositioning and a reduction of target movement are necessary for such an approach. The set-up accuracy of patients with liver metastases treated with stereotactic single dose radiation was evaluated. METHODS AND MATERIALS: Twenty-four patients with liver metastases were treated with single dose radiation therapy on 26 occasions using a self-developed stereotactic frame. Liver movement was reduced by abdominal pressure. The effectiveness was evaluated under fluoroscopy. CT scans were performed on the planning day and directly before treatment. Representative reference marks were chosen and the coordinates were calculated. In addition, the target displacement was quantitatively evaluated after treatment. RESULTS: Diaphragmal movement was reduced to median 7 mm (range: 3-13 mm). The final set-up accuracy of the body was limited to all of median 1.8 mm in latero-lateral direction (range: 0.3-5.0 mm) and 2.0 mm in anterior-posterior direction (0.8-3.8 mm). Deviations of the body in cranio-caudal direction were always less than the thickness of one CT slice (<5 mm). However, a repositioning was necessary in 16 occasions. The final target shift was median 1.6 mm (0.2-7.0 mm) in latero-lateral and 2.3 mm in anterior-posterior direction (0.0-6.3 mm). The median shift in cranio-caudal direction was 4.4 mm (0.0-10.0 mm). CONCLUSIONS: In patients with liver metastases, a high set-up accuracy of the body and the target can be achieved. This allows a high-dose focal radiotherapy of these lesions. However, a control CT scan should be performed directly before therapy to confirm set-up accuracy and possibly prompt necessary corrections.

Time requirements in conformal radiotherapy treatment planning.

To investigate the influence of implementing three-dimensional treatment planning on staffing needs, valid questionnaire responses from 22 radiotherapy institutions have been evaluated. Average time requirements per plan rise from 213 to 439 min upon implementation, but with experience decrease to 317 min. No institution reports additional staff positions according to estimated requirements.

The NAC proton treatment planning system.

A three-dimensional proton treatment planning system called PROXELPLAN has been used at the National Accelerator Centre (NAC) since October 1994. This system is entirely based on the VOXELPLAN planning system, developed at the Deutches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. The VOXELPLAN system provides the treatment planning infrastructure while the proton dose distributions are calculated using a software module that was initially developed at the Royal Marsden Hospital, UK. The proton module has been extensively modified and refined. It uses a rayline-tracing algorithm which is suitable for planning current treatments but is not sufficiently dynamic to accommodate the use of compensators. A sophisticated pencil beam algorithm is currently under development.

Fractionated stereotactic radiotherapy (FSRT) for optic glioma.

PURPOSE: To determine efficacy and toxicity of fractionated stereotactic radiotherapy (FSRT) in patients with optic glioma. METHODS AND MATERIALS: Ten patients suffering from optic glioma were treated by FSRT between December 1990 and December 1995 at the German Cancer Research Center (DKFZ) in Heidelberg. Eight patients were treated for progressive recurrent tumor following partial tumor resection and 2 patients were treated postoperatively. Dose distributions were calculated by a 3D treatment planning system (Voxelplan, Heidelberg). Patients were treated with a noninvasive repeatable stereotactic fixation system using a manually driven midsize multileaf collimator attached to a linear accelerator. We applied a median prescribed total dose to the isocenter of 52.4 Gy with a median daily fraction size of 1.8 Gy. RESULTS: All patients treated by definitive radiotherapy remained free from local tumor progression during the follow-up period (range 12-72 months) except the 1 patient treated for recurrence after previous radiotherapy. A complete remission was achieved in 3 patients with subsequent improvement of visual acuity. None of the patients with locally controlled tumor experienced any further impairment of vision. One patient developed new ACTH deficiency. No other clinically significant late effects attributable to radiotherapy were observed. CONCLUSION: FSRT permits treatment of optic glioma with excellent tumor control and without clinically relevant morbidity. Compared to conventional techniques there is the potential of sparing the pituitary gland in chiasmatic lesions.

On the quality of treatment planning systems in radiation therapy.

PURPOSE: To assist in the design of quality assurance activities of 3D treatment planning systems (TPSs), a postal survey has been carried out, addressing TPS users on quality characteristics and their relative importance in clinical routine planning. MATERIAL AND METHODS: The approach as described in ISO/IEC 9126 has been used to analyze TPS quality. Both TPS quality characteristics and how these may be used to establish a quality model are included. A questionnaire on ranking of these TPS quality characteristics has been sent out to the German DEGRO members in February 1997. RESULTS: By the end of July 1997, 90 individual assessments (of 45 physicists, 35 physicians, and 10 radiographers) had been collected. On an importance scale from 1 (very important) to 6 (unimportant), weight factors of 1.71 (portability), 2.84 (maintainability), 3.18 (efficiency), 3.85 (usability), 4.52 (functionality) and 4.90 (reliability) have been determined from the data. From user satisfaction data also obtained from the questionnaire responses, baseline quality indices could be established from the quality model for the RTPs Cadplan, TMS Helax, and Voxelplan. CONCLUSION: The responses highlight the need for TPS quality assurance at the same time along the lines of safety-related, research-oriented, and interactive end-user software systems in radiotherapy treatment planning. Quality assurance activities must take this into account. Their effect can be monitored by using quality indices as derivable from the established quality model.

[Computerized procedures in 3-dimensional radiotherapy planning]. / Computerverfahren in der dreidimensionalen Strahlentherapieplanung.

UNLABELLED: The aim of 3D radiotherapy treatment planning is to match the dose as closely as possible to the target volume, thus avoiding side effects in healthy tissue and radiosensitive organs at risk. A virtual radiotherapy simulator designed for the definition of treatment parameters and the analysis of precalculated dose distributions enables iterative optimization of treatment plans. METHODS: VOXELPLAN is a software package for 3D radiotherapy treatment planning developed at the German Cancer Research Center; it consists of user interfaces for image segmentation, virtual therapy simulation, dose calculation, plan evaluation and patient documentation. It is written in C and FORTRAN and runs on VAXstation 4000, IBM RS/6000 and DEC ALPHA hardware. RESULTS: Since 1990 a pilot installation of VOXELPLAN has been applied in clinical routine at the Center and at the University Clinic for Radiology, Heidelberg. Treatment for more than 1500 patients has been planned and carried out using the system, proving its technical and organizational applicability. CONCLUSIONS: We expect better acceptance and further dissemination of the techniques described, conformation therapy as well as (after its technical realization) inverse planning, from continuous optimization of the planning process.

[Echocardiographic variables related to mitral insufficiency in dilated cardiomyopathy]. / Variáveis ecocardiográficas relacionadas à insuficiência mitral na miocardiopatia dilatada.

PURPOSE: To evaluate the prevalence of mitral regurgitation (MR) in dilated cardiomyopathy (DC) and its relationship with left ventricular (LV) size and function. METHODS: Forty-five patients, age ranged 2 to 84 (mean = 50 +/- 16) years, 32 male, with DC submitted to dopplerechocardiogram between October 1991 and December 1992 were studied. RESULTS: Among 45 patients with DC, MR was found in 26 (58%). The systolic diameter (LVSD) and diastolic diameter (LVDD) of LV were significantly higher in patients with MR (60.7 x 51.5, p < 0.001 e 70.2 x 65.4, p < 0.02), respectively, and the left ventricular ejection fraction (LVEF) was significantly smaller in patients with MR (29.6 x 42.0, p < 0.001), when compared to the patients without MR. CONCLUSION: The majority of the patients with DC were found to have MR. The LV size and contractile function showed a direct correlation with the MR prevalence. The echocardiographic findings LVEF > or = or < 40%, LVSD > or = or < 50mm and LVDD > or = or < 65mm can identify group of patients with high (+/- 75%) or low (< 25%) MR prevalence.

[Rupture of sinus of Valsalva aneurysm]. / Rotura de aneurisma do seio de Valsalva.

A 35 year-old man with aneurysm of the noncoronary sinus of Valsalva ruptured into the right atrium, detected by echodopplercardiogram and submitted to surgical correction is reported. The authors discuss peculiar aspects of this disease, with emphasis to the echodopplercardiographic diagnosis.

Qualitative mechanoperception of natural teeth and endosseous implants.

The responses of 100 patients to load on Tübingen ceramic implants and natural teeth were analyzed to learn about the facets of qualitative mechanoperception. This approach revealed four factors of mechanoperception: dullness, intensity, localization, and persistence. Dullness, localization, and persistence were discriminated between teeth and implants. Intensity perception, however, depended on load only.

The finger domain of simian virus 40 large T antigen controls DNA-binding specificity.

The specificity and regulation of protein-DNA interactions play a crucial role in all aspects of communication between genotype and phenotype in a cell. The large T antigen of simian virus 40 binds to identical, yet quite differently arranged, pentanucleotide motifs in the simian virus 40 control region, sites I and II. Wild-type T antigen preferentially binds site I. We demonstrate that a bacterial peptide encoding residues 1 to 259 (T260) includes the essential amino acids required for binding to both DNA sites but predominantly binds site II. However, a longer peptide (residues 1 to 369; T370) binds almost exclusively to site I. Thus, the addition of amino acids 260 to 369 to the T260 peptide results in the loss of site II binding. This region includes a single putative metal-binding region, and mutation of T370 at either conserved cysteine of the finger results in equal but inefficient binding to both sites. While no metal binding has been shown to be directly associated with this sequence, these results suggest a novel, perhaps structural, function for such a finger motif, since this domain of T antigen appears to play a crucial role in modulating the DNA-binding behavior of T-antigen peptides.