Search

Learn when it's necessary to perform a root cause analysis on a sentinel event, and why. [ABSTRACT FROM AUTHOR]

Follow the proper procedure for identifying and reporting sentinel events to the Joint Commission to decrease their incidence. [ABSTRACT FROM AUTHOR]

Learn what Joint Commission analysts do and why they want to hear from you. [ABSTRACT FROM AUTHOR]

Bio-based carbon dioxide removal encompasses a range of (1) natural sink enhancement concepts in agriculture and on organic soils including peatlands, and in forestry, (2) bio-based building materials, and (3) bioenergy production with CO 2 capture and storage (BECCS). A common database on these concepts is crucial for their consideration in strategies and implementation. In this study, we analyse standardised factsheets on these concepts. We find different dynamics of deployment until 2045: for CO 2 removal rates from the atmosphere, natural sink enhancement concepts are characterised by gradually increasing rates, followed by a saturation and potentially a decrease after few decades; forest-related measures ramp up slowly and for construction projects and bioenergy plants, annually constant removal rates are assumed during operation which drop to zero afterwards. The expenses for removing 1 t CO 2 from the atmosphere were found to be between 8 and 520 € t CO 2 -1 , which arises from high divergence both in capital and operational expenditures among the concepts. This high variability of expenses seems to suggest the more cost-effective concepts should be implemented first. However, aspects from economics, resource base and environmental impacts to social and political implications for Germany need to be considered for developing implementation strategies. All concepts investigated could be deployed on scales to significantly contribute to the German climate neutrality target., (© 2024. The Author(s).)

General transcription factor IIIC subunit 5 (GTF3C5) encodes transcription factor IIIC63 (TFIIIC63). It binds to DNA to recruit another transcription factor, TFIIIB, and RNA polymerase III (Pol III) to mediate the transcription of small noncoding RNAs, such as tRNAs. Here, we report four individuals from three families presenting with a multisystem developmental disorder phenotype with biallelic variants in GTF3C5. The overlapping features include growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Using lymphoblastoid cell lines (LCLs) from two affected individuals, we observed a reduction in TFIIIC63 protein levels compared to control LCLs. Genome binding of TFIIIC63 protein is also reduced in LCL from one of the affected individuals. Additionally, approximately 40% of Pol III binding regions exhibited reduction in the level of Pol III occupancy in the mutant genome relative to the control, while approximately 54% of target regions showed comparable levels of Pol III occupancy between the two, indicating partial impairment of Pol III occupancy in the mutant genome. Yeasts with subject-specific variants showed temperature sensitivity and impaired growth, supporting the notion that the identified variants have deleterious effects. gtf3c5 mutant zebrafish showed developmental defects, including a smaller body, head, and eyes. Taken together, our data show that GTF3C5 plays an important role in embryonic development, and that biallelic variants in this gene cause a multisystem developmental disorder. Our study adds GTF3C5-related disorder to the growing list of genetic disorders associated with Pol III transcription machinery., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The extent of resection and neurological outcome are important prognostic markers for overall survival in glioma patients. Confocal laser endomicroscopy is a tool to examine tissue without the need for fixation or staining. This study aims to analyze gliomas in confocal laser endomicroscopy and identify reliable diagnostic criteria for glial matter and glial tumors., Material and Methods: One-hundred-and-five glioma specimens were analyzed using a 670-nm confocal laser endomicroscope and then processed into hematoxylin-eosin-stained frozen sections. All confocal images and frozen sections were evaluated for the following criteria: presence of tumor, cellularity, nuclear pleomorphism, changes of the extracellular glial matrix, microvascular proliferation, necrosis, and mitotic activity. Recurring characteristics were identified. Accuracy, sensitivity, specificity, and positive and negative predictive values were assessed for each feature., Results: All 125 specimens could be processed and successfully analyzed via confocal laser endomicroscopy. We found diagnostic criteria to identify white and grey matter and analyze cellularity, nuclear pleomorphism, changes in the glial matrix, vascularization, and necrosis in glial tumors. An accuracy of > 90.0 % was reached for grey matter, cellularity, and necrosis, > 80.0 % for white matter and nuclear pleomorphism, and > 70.0 % for microvascular proliferation and changes of the glial matrix. Mitotic activity could not be identified. Astroglial tumors showed significantly less nuclear pleomorphism in confocal laser endomicroscopy than oligodendroglial tumors (p < 0.001). Visualization of necrosis aids in the differentiation of low grade gliomas and high grade gliomas  (p < 0.002)., Conclusion: Autofluorescence-based confocal laser endomicroscopy proved not only useful in differentiation between tumor and brain tissue but also revealed useful clues to further characterize tissue without processing in a lab. Possible applications include the improvement of extent of resection and the safe harvest of representative tissue for histopathological and molecular genetic diagnostics., (© 2024. The Author(s).)

Objective: Tumors of the skull base can be accessed through different routes. Recent advantages in minimally invasive techniques have shown that very different routes can be applied for optimal tumor resection depending on the technical equipment, the surgeon's preference, and the individual anatomy of the pathology. Here, the authors present their technique for pure endoscopic transcranial tumor resection in meningiomas., Methods: Out of the cases of the Department of Neurosurgery, Homburg Saar Germany of the last 10 years, all endoscopic procedures for meningiomas were analyzed. Particular attention was given to evaluating the peculiarities of those meningiomas that were treated purely endoscopically., Results: While the endoscope was used in a large number of skull base meningiomas in endonasal approaches or for endoscopic inspection in transcranial skull base surgery, only a small number of meningiomas was selected for a purely endoscopically performed resection. The characteristics of these cases were rather a small lesion, straight access, and a keyhole position of the craniotomy. A complete resection of the tumor was achieved in all cases. Conversion to the microscope was not necessary in any case. There were no technical issues or complications associated with a fully endoscopic resection., Discussion: The endoscope is a valuable tool for visualization in meningioma surgery. In most cases, it is applied for an endonasal route or for endoscopic inspection in transcranial microsurgical cases. However, small to medium-sized meningiomas that can be accessed through the keyhole approach are good candidates for pure endoscopic resection. Because of the very high magnification and the minimally invasive nature of this approach, it should be considered more frequently in suitable lesions., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Arachnoid cysts are benign, mostly congenital lesions that are asymptomatic in most patients. In some cases, due to their location or sheer size, they produce a mass effect or hydrocephalic obstruction of the cerebrospinal fluid (CSF) flow and thus might warrant surgical treatment. The goal of the surgery is usually to reduce pressure inside the cysts, to reduce the mass effect, or to restore the CSF pathway. Surgical treatment options are resection, fenestration, or shunting of the cyst. Over the past decades, treatment under sheer endoscopic control either through a tube or via craniotomy of arachnoid cysts has been studied thoroughly and replaced open microsurgical cyst surgery in the opinion of many neurosurgeons. Endoscopic treatment has proven to be a safe and feasible technique for both patients and surgeons. In the following chapter, the authors describe their indications for surgery and pre- and postoperative workup, where precautions should be taken, and discuss the different possibilities and techniques of endoscopic cyst fenestration. The aim is to give detailed instructions and present cases for ventriculocystostomy, cystocisternostomy, ventriculocystocisternostomy, and cystoventriculostomy and point out specifics deemed to be important to avoid complications and to ensure the best possible outcome for each patient., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Introduction: The treatment concept for slipped capital femoral epiphysis is still controversial. According to studies, there is currently no recommendation for a universal approach. Therefore, the aim of this study is to analyze the care reality of children with ECF in Germany., Methods: The evaluation of the study is performed based on a questionnaire sent to physicians tending to ECF in 2021. Data is compared to the literature., Results: 36 of 47 questionnaires sent out were included. Overall, no significant difference in ECF care was proven in terms of annual caseload or the size of hospital., Conclusion: A high variance in operative SCFE treatment is reported. According to current literature, the modified Dunn procedure is considered the best therapeutic option to date, especially for patients with severe or chronic ECF. However, compared with alternative care options, this is not feasible in every hospital due to its complicating and challenging nature. Central registration, minimum volume regulation, and expansion of continuing education measures can contribute to optimization., (© 2023. The Author(s).)

Purpose: Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact., Methods: Rates of inconclusive results due to VUS were collected from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 to 2021., Results: We found a lower rate of inconclusive test results due to VUSs from ES/GS (22.5%) compared with MGPs (32.6%; P < .0001). For MGPs, the rate of inconclusive results correlated with panel size. The use of trios reduced inconclusive rates (18.9% vs 27.6%; P < .0001), whereas the use of GS compared with ES had no impact (22.2% vs 22.6%; P = ns)., Conclusion: The high rate of VUS observed in diagnostic MGP testing warrants examining current variant reporting practices. We propose several approaches to reduce reported VUS rates, while directing clinician resources toward important VUS follow-up., Competing Interests: Conflict of Interest All authors are or were employed by clinical laboratories offering genetic testing services, as indicated by their affiliations. Additional existing conflicts or those that were relevant at the time of data collection and publication include the following: Swaroop Aradhya, Elaine Chen, Kathryn E. Hatchell, and Dianalee McKnight - stockholders of Invitae Corp.; Christina DiVincenzo, Izabela D. Karbassi - stockholders of Quest Diagnostics; Kyle Retterer - past stockholder of Sema4 and Opko Health; Kyle W. Davis, Nir Neerman, and Christine Stanley - stockholders of Variantyx; Denise Perry, Ryan Taft, Erin Thorpe, and Brittany Thomas - stockholders of Illumina, Inc., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

A variety of ribo-, 2'-deoxyribo-, and 5'-norcarbocyclic derivatives of the 8-aza-7-deazahypoxanthine fleximer scaffolds were designed, synthesized, and screened for antibacterial activity. Both chemical and chemoenzymatic methods of synthesis for the 8-aza-7-deazainosine fleximers were compared. In the case of the 8-aza-7-deazahypoxanthine fleximer, the transglycosylation reaction proceeded with the formation of side products. In the case of the protected fleximer base, 1-(4-benzyloxypyrimidin-5-yl)pyrazole, the reaction proceeded selectively with formation of only one product. However, both synthetic routes to realize the fleximer ribonucleoside ( 3 ) worked with equal efficiency. The new compounds, as well as some 8-aza-7-deazapurine nucleosides synthesized previously, were studied against Gram-positive and Gram-negative bacteria and M. tuberculosis . It was shown that 1-(β-D-ribofuranosyl)-4-(2-aminopyridin-3-yl)pyrazole ( 19 ) and 1-(2',3',4'-trihydroxycyclopent-1'-yl)-4-(pyrimidin-4(3H)-on-5-yl)pyrazole ( 9 ) were able to inhibit the growth of M. smegmatis mc2 155 by 99% at concentrations (MIC 99 ) of 50 and 13 µg/mL, respectively. Antimycobacterial activities were revealed for 4-(4-aminopyridin-3-yl)-1H-pyrazol ( 10 ) and 1-(4'-hydroxy-2'-cyclopenten-1'-yl)-4-(4-benzyloxypyrimidin-5-yl)pyrazole ( 6 ). At concentrations (MIC 99 ) of 40 and 20 µg/mL, respectively, the compounds resulted in 99% inhibition of M. tuberculosis growth.

The Eastern Baltic cod (Gadus morhua) stock is currently in a very poor state, with low biomass and adverse trends in several life history and demographic parameters. This raises concern over whether and to what level recovery is possible. Here, we look for new insights from a historical perspective, extending the time series of various stock health indicators back to the 1940s, i.e. to the beginning of intensive exploitation of the Eastern Baltic cod. The historical data confirm that the stock deterioration in recent years is unprecedented, as all indicators are presently in their worst states on record. Cod body condition and energy reserves were equally low in the 1940s-1950s, accompanied by high parasitic liver worm infection, comparable to that measured in recent years. However, other stock parameters (size structure, size at maturity, stock distribution) are currently in their worst states over the past 80 years. In contrast, the state of cod in the 1970s to early 1990s that is often perceived as a desirable target, was exceptional, with the most favorable indicator levels in the time series. Long-term observation data reveal concurrent or asynchronous trends in different indicators of stock health and to what extent these have coincided with changes in possible external drivers. In this way, the extended time series contribute to ongoing research on understanding the collapse of the cod and its recovery potential., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Eero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether children treated using World Health Organization-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic (PK) exposures., Methods: Titles, abstracts, and full-text articles were screened. We searched PubMed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children aged <18 years being treated for drug-susceptible tuberculosis with rifampicin (RIF), pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO (no. CRD42021274222)., Results: Of 304 studies identified, 46 were eligible for full-text review, and 12 and 18 articles were included for the efficacy and PK analyses, respectively. Of 1830 children included in the efficacy analysis, 82% had favorable outcomes (range, 25%-95%). At World Health Organization-recommended doses, exposures to RIF, pyrazinamide, and ethambutol were lower in children than in adults. Children ≤6 years old have 35% lower areas under the concentration-time curve (AUCs) than older children (mean of 14.4 [95% CI 9.9-18.8] vs 22.0 [13.8-30.1] μg·h/mL) and children with human immunodeficiency virus (HIV) had 35% lower RIF AUCs than HIV-negative children (17.3 [11.4-23.2] vs 26.5 [21.3-31.7] μg·h/mL). Heterogeneity and small sample sizes were major limitations., Conclusions: There is large variability in outcomes, with an average of 82% favorable outcomes. Drug exposures are lower in children than in adults. Younger children and/or those with HIV are underexposed to RIF. Standardization of PK pediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing., Competing Interests: Potential conflicts of interest. K. R. reports a role as chair of the Global Health Community, American Society of Clinical Pharmacology and Therapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Tick-borne encephalitis (TBE) is a potentially fatal disease common in much of Europe and Asia. There is no specific therapy for the treatment of TBE patients. However, several efforts are being made to develop small molecules that specifically interfere with the life cycle of TBE virus. In particular, recently various nucleoside analogues that can inhibit the viral replicase, such as the RNA-dependent RNA polymerase or viral methyltransferases, have been explored. In addition, human or chimeric (i.e., structural chimeras that combine mouse variable domains with human constant domains) monoclonal antibodies with promising potential for post-exposure prophylaxis or early therapy have been developed. This review summarizes the latest directions and experimental approaches that may be used to combat TBE in humans., 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 © 2022 Elsevier B.V. All rights reserved.)

The great interest in studying the structure of human purine nucleoside phosphorylase ( h PNP) and the continued search for effective inhibitors is due to the importance of the enzyme as a target in the therapy of T-cell proliferative diseases. In addition, h PNP inhibitors are used in organ transplant surgeries to provide immunodeficiency during and after the procedure. Previously, we showed that members of the well-known fleximer class of nucleosides are substrates of E. coli PNP. Fleximers have great promise as they have exhibited significant biological activity against a number of viruses of pandemic concern. Herein, we describe the synthesis and inhibition studies of a series of new fleximer compounds against h PNP and discuss their possible binding mode with the enzyme. At a concentration of 2 mM for the flex-7-deazapurines 1-4 , a decrease in enzymatic activity by more than 50% was observed. 4-Amino-5-(1H-pyrrol-3-yl)pyridine 2 was the best inhibitor, with a Ki = 0.70 mM. Docking experiments have shown that ligand 2 is localized in the selected binding pocket Glu201, Asn243 and Phe200. The ability of the pyridine and pyrrole fragments to undergo rotation around the C-C bond allows for multiple binding modes in the active site of h PNP, which could provide several plausible bioactive conformations.

This study examined the effects of different types of masks (no mask, surgical mask (SM), and N95-mask) on physiological and perceptual responses during 30-min of self-paced cycle ergometer exercise. This study was a prospective randomly assigned experimental design. Outcomes included workload (Watts), oxygen saturation (SpO 2 ), end-tidal carbon dioxide (PetCO 2 ), heart rate (HR), respiratory rate (RR), rating of perceived exertion (RPE), and rating of perceived dyspnea (RPD). Volunteers (54-83 years ( n = 19)) completed two familiarization sessions and three testing sessions on an air braked cycle ergometer. No significant difference was found for condition x time for any of the dependent variables. RPE, RPD, and PetCO 2 were significantly higher with an N95-mask vs. no mask (NM) (( p = 0.012), ( p = 0.002), ( p < 0.001)). HR was significantly higher with the SM compared to the NM condition ( p = 0.027) (NM 107.18 ± 9.96) (SM 112.34 ± 10.28), but no significant difference was found when comparing the SM to the N95 condition or when comparing the N95condition to the NM condition. Watts increased across time in each condition ( p = 0.003). Initially RR increased during the first 3 min of exercise ( p < 0.001) with an overall gradual increase noted across time regardless of mask condition ( p < 0.001). SpO 2 significantly decreased across time but remained within normal limits (>95%). No significant difference was found in Watts, RR, or SpO 2 regardless of mask condition. Overall, the N95mask was associated with increased RPE, RPD, and PetCO 2 levels. This suggests trapping of CO 2 inside the mask leading to increased RPE and RPD.

Purpose: Several groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed., Methods: The GenCC drafted harmonized definitions for differing levels of gene-disease validity on the basis of existing resources, and performed a modified Delphi survey with 3 rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members., Results: On the basis of 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contained 15,241 gene-disease assertions on 4569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%., Conclusion: Terminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation., Competing Interests: Conflict of Interest R.E.F. is an employee of SciBite Ltd, an Elsevier company. Her work toward this paper was performed when she was employed by Genomics England. The following authors are employees for a commercial laboratory that offers clinical genetic testing: M.B., A.J.C., K.R., J.T. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)

Although the rates of disease gene discovery have steadily increased with the expanding use of genome and exome sequencing by clinical and research laboratories, only ~16% of genes in the genome have confirmed disease associations. Here we describe our clinical laboratory's experience utilizing GeneMatcher, an online portal designed to promote disease gene discovery and data sharing. Since 2016, we submitted 246 candidates from 243 unique genes to GeneMatcher, of which 111 (45%) are now clinically characterized. Submissions meeting our candidate gene-reporting criteria based on a scoring system using patient and molecular-weighted evidence were significantly more likely to be characterized as of October 2021 versus genes that did not meet our clinical-reporting criteria (p = 0.025). We reported relevant findings related to these newly characterized gene-disease associations in 477 probands. In 218 (46%) instances, we issued reclassifications after an initial negative or candidate gene (uncertain) report. We coauthored 104 publications delineating gene-disease relationships, including descriptions of new associations (60%), additional supportive evidence (13%), subsequent descriptive cohorts (23%), and phenotypic expansions (4%). Clinical laboratories are pivotal for disease gene discovery efforts and can screen phenotypes based on genotype matches, contact clinicians of relevant cases, and issue proactive reclassification reports., (© 2022 Ambry Genetics Corporation. Human Mutation published by Wiley Periodicals LLC.)

A new series of flexible 5'-norcarbocyclic aza/deaza-purine nucleoside analogs were synthesized from 6-oxybicyclo[3.1.0.]hex-2-ene and pyrazole-containing fleximer analogs of heterocyclic bases using the Trost procedure. The compounds were evaluated as potential inhibitors of E. coli purine nucleoside phosphorylase. Analog 1-3 were found to be noncompetitive inhibitors with inhibition constants of 14-24 mM. From the data obtained, it can be assumed that the new 5'-norcarbocyclic nucleoside analogs interact with the active site of the PNP like natural heterocyclic bases. But at the same time the presence of a cyclopentyl moiety with 2' and 3' hydroxyls is necessary for the inhibitory properties, since compounds 8-10 , without those groups did not exhibit an inhibitory effect under the experimental conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Khandazhinskaya, Fateev, Konstantinova, Esipov, Polyakov, Seley-Radtke, Kochetkov and Matyugina.)

Background and Aims: Augmented aortic systolic blood pressure (SBP) and wave reflection via sympathetic-mediated vasoconstriction elevates the risk for adverse cardiovascular events in older adults. L-citrulline (L-CIT) supplementation has shown to reduce aortic SBP and pulse pressure (PP) responses to cold pressor test (CPT) induced sympathoactivation in young men. The aim of this study was to elucidate the efficacy of L-CIT supplementation to attenuate aortic hemodynamic responses to CPT in older adults., Methods and Results: Sixteen older adults were randomly assigned to placebo or L-CIT (6 g/day) for 14-days in a crossover, double-blind, placebo-controlled design. Brachial SBP and aortic SBP, PP, augmented pressure (AP), augmentation index standardized at 75 bpm (AIx@75), and pressure of the forward (Pf) and reflected (Pb) waves were evaluated at rest and during CPT pre- and post-intervention. Although no hemodynamic changes at rest, brachial SBP (Δ-12 ± 18 vs. Δ4 ± 14 mmHg; P = 0.008) and aortic SBP (Δ-10 ± 14 vs. Δ4 ± 12 mmHg; P = 0.005), PP (Δ-10 ± 12 vs. Δ4 ± 11 mmHg; P = 0.002), AP (Δ-4 ± 4 vs. Δ2 ± 7 mmHg; P = 0.004), AIx@75 (Δ-3.2 ± 7.2 vs. Δ2.2 ± 6.9%; P = 0.038), Pf (Δ-6 ± 10 vs. Δ3 ± 9 mmHg; P = 0.019), and Pb (Δ-4 ± 6 vs. Δ2 ± 6 mmHg; P = 0.008) responses to the CPT were significantly attenuated following L-CIT supplementation vs. placebo., Conclusions: L-CIT supplementation attenuated aortic pulsatile pressure and pressure wave reflection responses to CPT in older adults, providing possible cardioprotection during cold-induced sympathoactivation in older adults., (Published by Elsevier Inc.)

Nucleoside analogues have long served as key chemotherapeutic drugs for the treatment of viral infections and cancers. Problems associated with the development of drug resistance have led to a search for the design of nucleosides capable of bypassing point mutations in the target enzyme's binding site. As a possible answer to this, the Seley-Radtke group developed a flexible nucleoside scaffold (fleximers), where the heterocyclic purine base is split into its two components, i.e. pyrimidine and imidazole. Herein, we present a series of new pyrazole-containing flex-bases and the corresponding fleximer analogues of 8-aza-7-deaza nucleosides. Subsequent studies found that pyrazole-containing flex-bases are substrates of purine nucleoside phosphorylase (PNP). We have compared the chemical synthesis of fleximers and enzymatic approaches with both isolated enzymes and the use of E. coli cells overproducing PNP. The latter provided stereochemically pure pyrazole-containing β-d-ribo- and β-d-2'-deoxyribo-fleximers and are beneficial in terms of environmental issues, are more economical, and streamline the steps required from a chemical approach. The reaction is carried out in water, avoiding hazardous chemicals, and the products are isolated by ion-exchange chromatography using water/ethanol mixtures for elution. Moreover, the target nucleosides were obtained on a multi-milligram scale with >97-99% purity, and the reactions can be easily scaled up.

Radiographic measurement of the lower limb alignment in the frontal plane is used to assess limb deformity, to plan corrective surgery and for follow-up. It is essential that age-related normal lower limb alignment and joint orientation angles are known before planning surgical treatment. EOS (EOS™ Imaging, Paris, France) can lead to supplemental information, especially in cases of severe multidimensional joint malalignment. It allows 3D reconstruction of a bone model of the limb to assess multi-dimensional deformity.

Walking tests, such as the 6-min walk test (6MWT), are popular methods of estimating peak oxygen uptake (VO 2 peak) in clinical populations. However, the strength of the distance vs. VO 2 peak relationship is not strong, and there are no equations for estimating ventilatory threshold (VT), which is important for training prescription and prognosis. Since the 6MWT is often limited by walking mechanics, prediction equations that include simple additional predictors, such as the terminal rating of perceived exertion (RPE), hold the potential for improving the prediction of VO 2 max and VT. Therefore, this study was designed to develop equations for predicting VO 2 peak and VT from performance during the 6MWT, on the basis of walking performance and terminal RPE. Clinically stable patients in a cardiac rehabilitation program ( N = 63) performed the 6MWT according to the American Thoracic Society guidelines. At the end of each walk, the subject provided their terminal RPE on a 6-20 Borg scale. Each patient also performed a maximal incremental treadmill test with respiratory gas exchange to measure VO 2 peak and VT. There was a good correlation between VO 2 peak and 6MWT distance ( r = 0.80) which was improved by adding the terminal RPE in a multiple regression formula (6MWT + RPE, R 2 = 0.71, standard error of estimate, SEE = 1.3 Metabolic Equivalents (METs). The VT was also well correlated with walking performance, 6MWT distance ( r = 0.80), and was improved by the addition of terminal RPE (6MWT + RPE, R 2 = 0.69, SEE = 0.95 METs). The addition of terminal RPE to 6MWT distance improved the prediction of maximal METs and METs at VT, which may have practical applications for exercise prescription.

Exercise training is an important component of clinical exercise programs. Although there are recognized guidelines for the amount of exercise to be accomplished (≥70,000 steps per week or ≥150 min per week at moderate intensity), there is virtually no documentation of how much exercise is actually accomplished in contemporary exercise programs. Having guidelines without evidence of whether they are being met is of limited value. We analyzed both the weekly step count and the session rating of perceived exertion (sRPE) of patients ( n = 26) enrolled in a community clinical exercise (e.g., Phase III) program over a 3-week reference period. Step counts averaged 39,818 ± 18,612 per week, with 18% of the steps accomplished in the program and 82% of steps accomplished outside the program. Using the sRPE method, inside the program, the patients averaged 162.4 ± 93.1 min per week, at a sRPE of 12.5 ± 1.9 and a frequency of 1.8 ± 0.7 times per week, for a calculated exercise load of 2042.5 ± 1244.9 AU. Outside the program, the patients averaged 144.9 ± 126.4 min, at a sRPE of 11.8 ± 5.8 and a frequency of 2.4 ± 1.5 times per week, for a calculated exercise load of 1723.9 ± 1526.2 AU. The total exercise load using sRPE was 266.4 ± 170.8 min per week, at a sRPE of 12.6 ± 3.8, and frequency of 4.2 ± 1.1 times per week, for a calculated exercise load of 3359.8 ± 2145.9 AU. There was a non-linear relationship between steps per week and the sRPE derived training load, apparently attributable to the amount of non-walking exercise accomplished in the program. The results suggest that patients in a community clinical exercise program are achieving American College of Sports Medicine guidelines, based on the sRPE method, but are accomplishing less steps than recommended by guidelines.