bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Food or Sucralfate on the Bioavailability of S(+) and R(−) Enantiomers of Ibuprofen
Authors: Levine M. A. H. , Walker S. E. , Paton T. W.
Published: September 2022

This randomized, multiple cross‐over pharmacokinetic study was undertaken to determine if food or sucralfate alter the bioavailability of the active S(+) enantiomer of Ibuprofen. Eleven healthy adult male volunteers were given three single 600‐mg doses of ibuprofen (separated by 1 week) administered either in a fasting state, after a standardized breakfast, or with sucralfate 1 g. The main outcome measures were area under the concentration (AUC), maximum peak plasma concentration (Cmax), and time to reach peak concentration (tmax) for total, S(+), and R(−) enantiomer serum ibuprofen levels, drawn up to 10 hours after dosing. The AUC for R(−) ibuprofen was significantly lower than S(+) ibuprofen in all three treatment groups. The treatments had no different effects on AUC for S(+), R(+), or total ibuprofen. There was no difference in the ratio of S(+):R(−) enantiomers across different treatment groups, but the intersubject variability was significant (P <.05). The S(+) ibuprofen Cmax was greater than the R(−) ibuprofen Cmax for ail treatment groups (P <.05). Sucralfate reduced the peak concentration of both S(+) and R(−) enantiomers when compared with fasting (P <.05). There was a slight but nonsignificant increase in the mean time to achieve peak concentration of both S(+) and R(−) enantiomers. Neither food nor sucralfate has a significant effect on ibuprofen enantiomer pharmacokinetics, but interindividual variability contributes significantly to the variability of enantiomer bioavailability.
Pyrazinoylguanidine: Antihypertensive, Hypocholesterolemic, and Renin Effects
Authors: Chambers Charles E. , Vesell Elliot S. , Helm Cindy , Passananti G. Thomas , Beyer Karl H.
Published: September 2022

In a single‐blind, placebo‐controlled study of 12 subjects diagnosed as having mild to moderate hypertension and hypercholesterolemia, pyrazinoylguanidine (PZG) in a dose of 600 mg twice daily for 4 weeks reduced systolic blood pressure and heart rate. Pyrazinoylguanidine also reduced diastolic pressures, but to a lesser extent. Pyrazinoylguanidine reduced total serum cholesterol and low‐density lipoprotein (LDL). Regression analysis indicated a dose‐dependent reduction of both total cholesterol and LDL by PZG, i.e., the higher the presenting serum concentration, the greater the reduction by PZG. The extent of the reductions produced by PZG in elevated cholesterols and LDLs was highly correlated (r = .949). Normal high‐density lipoprotein levels were unchanged by PZG. Pyrazinoylguanidine increased 24‐hour urine volume and urinary excretion of sodium. Serum Na+, K+, or Cl− concentrations were unaltered. Means for plasma aldosterone and renin activities tended to decrease, but these trends did not attain statistical significance. Pyrazinoylguanidine was well tolerated. An activity profile that includes antihypertensive effects as well as reduction in hypercholesterolemia without major impact on serum renin or electrolyte balance makes PZG an attractive candidate for the management of hypertension.
Asthma Therapy from the Practice Perspective: Changes in the Wind
Authors: Pierce Charles H.
Published: September 2022

The management of asthma presents a challenge to practicing primary care physicians, which is about to escalate considerably First, it is becoming crystal clear that asthma is a heterogeneous condition that continues to be more prevalent in the community. This makes objective data (FEV1, PEFR, etc.) as essential as the care taken to work with patients so that they not only understand their disease but also how to properly use the medications they have been prescribed. Second, the number of new classes of agents will increase in the next decade far faster than an understanding of the asthmatic process, making it imperative for the physician to return to the basic principles of therapeutics.
The Role of the Common Cold in Asthma
Authors: Busse William W.
Published: September 2022

It has long been known that patients with viral respiratory infections develop temporary asthma‐like symptoms or see a worsening of their existing asthmatic symptoms or develop full‐blown asthma during the infection. It should not be surprising, in view of this observation, that these same viruses have been found to initiate the same inflammatory processes as seen and characterized in the asthmatic patient. This has clear implications for therapy of asthmatic patients.
Hormonal Effects on Tirilazad Clearance in Women: Assessment of the Role of CYP3A
Authors: Fleishaker Joseph C. , Pearson Laura K. , Pearson Paul G. , Wienkers Larry C. , Hopkins Nancy K. , Peters Gary R.
Published: September 2022

This study assessed whether the previously reported difference in tirilazad clearance between pre‐ and postmenopausal women is reversed by hormone replacement and whether this observation can be explained by differences in CYP3A4 activity. Ten healthy women from each group were enrolled: premenopausal (ages 18–35), postmenopausal (ages 50–70), postmenopausal receiving estrogen, and postmenopausal women receiving estrogen and progestin. Volunteers received 0.0145 mg/kg midazolam and 3.0 mg/kg tirilazad mesylate intravenously on separate days. Plasma tirilazad and midazolam were measured by HPLC/dual mass spectrophotometry (MS/MS) assays. Tirilazad clearance was significantly higher in premenopausal women (0.51 ± 0.09 L/hr/kg) than in postmenopausal groups (0.34 ± 0.07, 0.32 ± 0.06, and 0.36 ± 0.08 L/hr/kg, respectively) (p = 0.0001). Midazolam clearance (0.64 ± 0.12 L/hr/kg) was significantly higher in premenopausal women compared to postmenopausal groups (0.47 ± 0.11, 0.49 ± 0.11, and 0.53 ± 0.19 L/hr/kg, respectively) (p = 0.037). Tirilazad clearance was weakly correlated with midazolam clearance (r2 = 0.129, p = 0.02). Tirilazad clearance is faster in premenopausal women than in postmenopausal women, but the effect of menopause on clearance is not reversed by hormone replacement. Tirilazad clearance in these women is weakly related to midazolam clearance, a marker of CYP3A activity.
Risk Factors for Long‐Term Outcome of Ifosfamide‐Induced Nephrotoxicity in Children
Authors: Loebstein Ronen , Atanackovic Gordana , Bishai Raafat , Wolpin Jacob , Khattak Sohail , Hashemi Goli , Gobrial Marcus , Baruchel Sylvian , Ito Shinya , Koren Gideon
Published: September 2022

Ifosfamide is widely used in the treatment of pediatric solid tumors. Its main adverse effects are various forms of renal tubular and glomerular damage. The authors sought to determine factors that predict the risk for the development and severity of ifosfamide‐induced nephrotoxicity in children and to examine the long‐term outcome of this complication. A total of 174 children who had received ifosfamide for various cancers were studied. Nephrotoxicity was assessed by laboratory markers of glomerular and tubular function and a grading score (none, mild, moderate, severe). Patients were assessed 4 to 12 weeks after each ifosfamide course, 3 months after completion of chemotherapy, and 5 years later. Of 174 children, 72 (41.4%) developed tubular dysfunction, whereas only 11 (6.3%) demonstrated glomerular dysfunction; 40 (23.0%) demonstrated mild toxicity, 16 (9.2%) demonstrated moderate toxicity, and 16 (9.2%) developed severe nephrotoxicity. The four severity subgroups (none, mild, moderate, severe) received comparable doses/m2/cycle of ifosfamide and mesna. Children exhibiting severe toxicity were significantly younger compared to those with moderate, mild, or no nephrotoxicity (median age: 2.2, 7.0, 8.2, and 10.5 years, respectively; p < 0.001) and received significantly higher cumulative doses of ifosfamide (49.6 ± 12.3, 46.0 ± 13.1, 36.2 ± 9.7, and 33.8 ± 7.6 g/m2, respectively; p < 0.001). Cumulative doses of cisplatin were higher among children with severe nephrotoxicity compared to those with moderate, mild, or no toxicity, although this difference did not reach statistical significance. Of all risk factors analyzed by multiple regression analysis, age was the most significant predictor for the grade of nephrotoxicity (p < 0.001), followed by the cumulative dose of ifosfamide (p = 0.005). Seven out of 16 children (44.0%) with severe nephrotoxicity and 4 out of 16 children (25.0%) with moderate nephrotoxicity demonstrated severe chronic tubular toxicity over a follow‐up period of 5 years. Since severe ifosfamide‐induced renal toxicity tends to be chronic in a substantial number of treated children, it should be balanced carefully against efficacy. Cumulative ifosfamide doses of 45 g/m2 and above should be carefully considered, especially in children younger than age 3.
The Pharmacokinetics and Safety Profile of Oral Ganciclovir Combined with Zalcitabine or Stavudine in Asymptomatic HIV‐ and CMV‐Seropositive Patients
Authors: Jung Donald , AbdelHameed Magdy H. , Teitelbaum Philip , Dorr Albert , Griffy Kay
Published: September 2022

Two open‐label, randomized, multiple‐dose, three‐way crossover studies were performed to assess the pharmacokinetics and safety of oral ganciclovir 1000 mg q8h in asymptomatic patients seropositive for human immunodeficiency virus and cytomegalovirus. Ganciclovir was administered alone and in combination with zalcitabine 0.75 mg q8h (study 1) or stavudine 40 mg q12h (study 2). In the presence of zalcitabine, the only statistically significant change in the pharmacokinetic parameters of ganciclovir was a 22.2% mean increase in AUC0–8. However, there was no significant change in the renal clearance of ganciclovir when coadministered with zalcitabine, suggesting that the increase in serum ganciclovir concentration cannot be attributed to competition for active renal tubular secretion. No change in zalcitabine pharmacokinetics was observed in combination with ganciclovir. There were no significant changes in the pharmacokinetics of ganciclovir or stavudine when coadministered. Ganciclovir was well tolerated when given alone and in combination with either zalcitabine or stavudine.
The Safety Profile of Nonprescription Ibuprofen in Multiple‐Dose Use: A Meta‐Analysis
Authors: Kellstein David E. , Waksman Joel A. , Furey Sandy A. , Binstok Giselle , Cooper Stephen A.
Published: September 2022

A meta‐analysis was performed to compare the incidence of adverse experiences (AEs) during the multiple‐dose use of nonprescription ibuprofen to a placebo. Eight studies, with doses ranging from 800 to 1200 mg/day and durations of 1 to 10 days, met the criteria for inclusion. AEs were classified according to COSTART, except that “abdominal pain” was conservatively reassigned to the digestive system. In each study, the overall AE frequency among ibuprofen‐treated subjects (n = 1094) was numerically less than or equal to the placebo (n = 1093). Pooled across all studies, placebo subjects reported AEs significantly (p = 0.018) more often (31.7%) than ibuprofen subjects (27.4%). The frequency of digestive system AEs was comparable (p = 0.420) for the placebo (11.0%) and ibuprofen (12.1%); there was no significant difference for any specific digestive system AE. AE frequency in the “body‐as‐a‐ whole” category was significantly higher (p < 0.001) in the placebo (20.4%) than in ibuprofen (14.8%). The number of severe AEs in all of these categories was lower for ibuprofen than for the placebo. These data indicate that nonprescription ibuprofen has an excellent side effect profile in multiple‐dose use, with a frequency of gastrointestinal AEs comparable to a placebo.
Are the Elderly Underrepresented in Clinical Drug Trials?
Authors: Schmucker Douglas L. , Vesell Elliot S.
Published: September 2022

In many industrialized nations, the elderly comprise the fastest growing subpopulation and constitute an increasing proportion of the total population compared to other age groups. The elderly use a disproportionately larger amount of health care resources since they experience a higher incidence of disease‐related morbidities, consume more drugs, are subject to more extensive multiple medication regimens, and account for more adverse drug events. In response to the great demand for geriatric pharmacotherapy, the pharmaceutical industry has targeted more drugs to the elderly. However, the elderly are too often excluded from clinical trials on drugs primarily destined for their consumption. Comprehensive analyses to assess participation of elderly subjects in clinical drug trials are needed to design and implement trials that will enhance the safety and efficacy of drugs intended for this pharmacologically sensitive subpopulation
Use of a Mail‐Out Continuing Education Article to Teach Health Professionals about Drug‐Induced Disease
Authors: Goldman Stephen A.
Published: September 2022

A U.S. Food and Drug Administration (FDA)/Georgetown University Medical Center conference was the basis for “Clinical Therapeutics and the Recognition of Drug‐Induced Disease,” the first medWatch continuing education (CE) mail‐out article. Developed as a major component of FDA medWatch post‐marketing surveillance outreach, the article used a clinical therapeutic approach to discuss topics including adverse drug events (ADEs) pharmacology and ADE reporting. Distributed nationwide through the medWatch Partners, health professionals applied for CE credit by completing a self‐assessment examination. With the overall response rate slightly more than 2%, 15,260 health professionals (55% physicians and 37% pharmacists) received CE credit. Evaluation of the initial approximate two‐thirds (N = 10,021) of successfully completed exams found 99% agreement that stated learning objectives were met, and the article relevant to their clinical practice; spontaneous comments/letters were also very positive. The highest percentage responding specialists were internists (28%) and psychiatrists (17%), with notable differences found among specialties for response rate versus relative article distribution (such as relatively low response rates among surgeons and radiology/radiation physics specialists). The number of health professionals receiving CE credit, coupled with examination performance and overall response, indicates that “Clinical Therapeutics and the Recognition of Drug‐Induced Disease” was well received and fulfilled learning objectives. The results provide encouragement for this continuing educational approach.
Pharmacokinetics of Clinafloxacin Enantiomers in Humans
Authors: Humphrey Gaye H. , Shapiro Martin A. , Randinitis Edward J. , Guttendorf Robert J. , Brodfuehrer Joanne I.
Published: September 2022

The pharmacokinetics of R‐clinafloxacin and S‐clinafloxacin enantiomers of the broad‐spectrum fluoroquinolone antibiotic, clinafloxacin, were characterized in selected volunteer subjects and patients after the administration of oral and intravenous doses of racemic drug. The absorption of each enantiomer was rapid and nearly complete after a single, oral 400 mg racemic dose. The mean (± SD) bioavailability of R‐clinafloxacin was 87.5% ± 4.8% compared to 86.2% ± 5.8% for S‐clinafloxacin. The mean Cmax of each enantiomer was 1.19 μg/mL, with plasma concentrations of each enantiomer remaining above 0.1 μg/mL for at least 12 hours. No notable differences in the disposition of R‐clinafloxacin and S‐clinafloxacin were observed. After a single 400 mg intravenous dose of racemic drug, mean (± SD) t1/2 was 5.6 ± 0.3 hours and 5.7 ± 0.4 hours, plasma Cl was 329 ± 49 mL/min and 314 ± 45 mL/min, and Vdss was 138 ± 18 L and 134 ± 16 L for R‐ and S‐clinafloxacin, respectively. Two healthy volunteers each received a single 400 mg oral dose of racemic clinafloxacin (alone) and with oral administration of 1 gm probenecid separated by a 1‐week washout period between treatments. With probenecid coadministration, the increase in AUC0‐∞; was 75% and 83% for R‐clinafloxacin and was 71% and 75% for S‐clinafloxacin in each subject, respectively. Probenecid increased the total exposure (AUC) of both R‐clinafloxacin and S‐clinafloxacin, although it had no stereo‐selective effects on the disposition of either enantiomer. The antimicrobial potency of the isomers was also evaluated. In vitro susceptibility testing showed that the two compounds were comparable in their inhibitory activities, as all MICs were within twofold for each organism tested. These results demonstrate that in addition to their similar antimicrobial potency, R‐ and S‐clinafloxacin have nearly identical disposition characteristics and are eliminated by similar mechanisms that display no apparent enantioselectivity in man.
The Effect of a High‐Fat Meal on the Oral Bioavailability of the Immunosuppressant Sirolimus (Rapamycin)
Authors: Zimmerman James J. , Ferron Geraldine M. , Lim Heng‐Keang , Parker Vernon
Published: September 2022

The bioavailability of an oral nonaqueous solution of sirolimus was compared under fasting conditions and after a high‐fat meal in a randomized, two‐way crossover pharmacokinetic study. Healthy volunteers were administered a 15 mg single dose of sirolimus on two occasions, once while fasting and once after consumption of a high‐fat breakfast. Whole blood concentrations of sirolimus were assayed by using a validated method with high‐performance liquid chromatography/tandem mass spectrometric detection. Sirolimus was absorbed more slowly when administered after a high‐fat meal than when administered after fasting, as shown by statistically significant reductions in peak concentration (Cmax) and the ratio of Cmax to the area under the curve (AUC), and lengthening of the time to peak concentration. The oral availability of sirolimus was increased to a modest extent (35%) and in a uniform manner when administered with a high‐fat meal; the geometric mean ratio of the fed/fasting AUC values was 1.35, with a 90% confidence interval of 1.26 to 1.46. Food had no effect on the terminal half‐life of sirolimus (mean values of 67 to 68 hours). The 35% increase in AUC obtained after a high‐fat meal appears small relative to the intersubject and intra‐subject variabilities observed in clinical trials. However, to minimize unnecessary fluctuations in trough whole blood sirolimus concentrations, it is advisable that sirolimus be administered consistently in individual patients, either with or without meals.
Effect of Disulfiram‐Mediated CYP2E1 Inhibition on the Disposition of Vesnarinone
Authors: Frye Reginald F. , Tammara Brinda , Cowart T. Douglas , Bramer Steven L.
Published: September 2022

Vesnarinone is an orally administered inotropic agent that is metabolized in vitro by the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1. The purpose of this study was to assess the contribution of CYP2E1 activity to the disposition of vesnarinone in humans by characterizing the pharmacokinetics before and after disulfiram‐mediated CYP2E1 inhibition. The pharmacokinetics of vesnarinone 60 mg were determined in normal healthy volunteers (N = 7) before and after daily disulfiram administration (250 mg). Chlorzoxazone 250 mg was also administered before, during, and after disulfiram administration to serve as a positive control for CYP2E1 inhibition. Disulfiram treatment decreased 6‐hydroxychlorzoxazone formation clearance by nearly 95% but effected only a modest decrease in vesnarinone apparent oral clearance (5.7 ± 1.0 vs. 5.0 ± 0.5 ml/min; p = 0.022). In contrast to the modest effect on the parent drug, disulfiram treatment substantially increased plasma concentrations of the primary metabolite OPC‐18692. The Cmax of OPC‐18692 was increased approximately 7‐fold, and the area under the plasma concentration‐time curve was increased 18‐fold (2.9 ± 0.9 vs. 53.7 ± 33.2 μg•h/ml; p = 0.006). The results indicate that CYP2E1 inhibition has only a modest, clinically insignificant effect on vesnarinone disposition but markedly increases plasma concentrations of the OPC‐18692 metabolite. The pharmacological properties of this metabolite have not been fully defined; thus, the clinical importance of this observation depends on whether this metabolite contributes to any of the toxicity associated with vesnarinone administration.
Collaboration between teachers and educational-psychological service counsellors
Authors: Jortveit Maryann
Published: September 2022

This qualitative study examines cross-professional collaboration between Educational-Psychological Service (EPS) counsellors and school teachers who have pupils with special needs in their class. Research shows that EPS counsellors spend much time writing assessment reports, that they do not have much presence in school and that there is a power imbalance between the collaborating parties. The collaboration may be experienced as imbalanced because the teacher is dependent on the EPS counsellors’ expertise and assessment reports for special teaching resources to be made available for pupils. Six teachers have been interviewed about their collaboration with EPS staff. The thematically analysed findings show that the teachers generally have good collaboration with the counsellors and trust them. However, they feel vulnerable because their teaching is being assessed, and they depend on the EPS report’s recommendations for resources. The informants feel that the typical signs of an equal collaboration relationship are when the partners have a good dialogue and mutual trust. A role clarification between the collaboration parties is needed, where there is trust, acknowledgement and mutual respect. This will in turn inspire a collaboration that leads to changes in the teaching situation and to special teaching measures for the pupils with special needs.
Diversified Treatment Options of Adult Stem Cells for Optic Neuropathies
Authors: Tan Shaoying , Yao Yao , Yang Qichen , Yuan Xiang-Ling , Cen Ling-Ping , Ng Tsz Kin
Published: September 2022

Optic neuropathies refer to a group of ocular disorders with abnormalities or dysfunction of the optic nerve, sharing a common pathophysiology of retinal ganglion cell (RGC) death and axonal loss. RGCs, as the retinal neurons in the central nervous system, show limited capacity in regeneration or recovery upon diseases or after injuries. Critically, there is still no effective clinical treatment to cure most types of optic neuropathies. Recently, stem cell therapy was proposed as a potential treatment strategy for optic neuropathies. Adult stem cells, including mesenchymal stem cells and hematopoietic stem cells, have been applied in clinical trials based on their neuroprotective properties. In this article, the applications of adult stem cells on different types of optic neuropathies and the related mechanisms will be reviewed. Research updates on the strategies to enhance the neuroprotective effects of human adult stem cells will be summarized. This review article aims to enlighten the research scientists on the diversified functions of adult stem cells and consideration of adult stem cells as a potential treatment for optic neuropathies in future clinical practices.
Contestation and participation: Concepts, measurement, and inference
Authors: Alexandra Boese Vanessa , Charles Wilson Matthew
Published: September 2022

Contestation and participation are commonly viewed as two main constituent dimensions of electoral democracy. How exactly have these two dimensions been conceptualized and measured in the literature? Are they empirically observable and do they matter for democratic development and stability? This article answers the first of these questions and considers their implications for the second by reviewing the literature on these two dimensions. We discuss three issues that affect conclusions about dimensions of democracy and their relevance for understanding democratic development: First, conceptual ambiguities—substantive overlap between the two concepts—obscure the meanings of each of the two dimensions. Such ambiguities led to a second issue, which is a concept-measurement mismatch. The conceptual contributions were never really met with an empirical equivalent that would allow us to properly measure the two dimensions. Scholars continue to invoke theoretical understandings from the 1950s, 1960s, and 1970s, but represent them using measures that were not explicitly concerned with measuring them, which presents the third issue of concept reification. As a result of these three issues, inferences about how democracy has developed and its relevance for democratic stability or for transitions to democratic rule is potentially obscured. Based on these issues, we provide three suggestions for future research concerning the concepts of contestation and participation.
All-cause and cause-specific mortality rates for Kisumu County: a comparison with Kenya, low-and middle-income countries
Authors: Waruiru Wanjiru , Oramisi Violet , Sila Alex , Onyango Dickens , Waruru Anthony , Mwangome Mary N. , Young Peter W. , Muuo Sheru , Nyagah Lilly M. , Ollongo John , Ngugi Catherine , Rutherford George W.
Published: September 2022

Background

Understanding the magnitude and causes of mortality at national and sub-national levels for countries is critical in facilitating evidence-based prioritization of public health response. We provide comparable cause of death data from Kisumu County, a high HIV and malaria-endemic county in Kenya, and compared them with Kenya and low-and-middle income countries (LMICs).

Methods

We analyzed data from a mortuary-based study at two of the largest hospital mortuaries in Kisumu. Mortality data through 2019 for Kenya and all LMICs were downloaded from the Global Health Data Exchange. We provided age-standardized rates for comparisons of all-cause and cause-specific mortality rates, and distribution of deaths by demographics and Global Burden of Disease (GBD) classifications.

Results

The all-cause age-standardized mortality rate (SMR) was significantly higher in Kisumu compared to Kenya and LMICs (1118 vs. 659 vs. 547 per 100,000 population, respectively). Among women, the all-cause SMR in Kisumu was almost twice that of Kenya and double the LMICs rate (1150 vs. 606 vs. 518 per 100,000 population respectively). Among men, the all-cause SMR in Kisumu was approximately one and a half times higher than in Kenya and nearly double that of LMICs (1089 vs. 713 vs. 574 per 100,000 population). In Kisumu and LMICs non-communicable diseases accounted for most (48.0 and 58.1% respectively) deaths, while in Kenya infectious diseases accounted for the majority (49.9%) of deaths. From age 10, mortality rates increased with age across all geographies. The age-specific mortality rate among those under 1 in Kisumu was nearly twice that of Kenya and LMICs (6058 vs. 3157 and 3485 per 100,000 population, respectively). Mortality from injuries among men was at least one and half times that of women in all geographies.

Conclusion

There is a notable difference in the patterns of mortality rates across the three geographical areas. The double burden of mortality from GBD Group I and Group II diseases with high infant mortality in Kisumu can guide prioritization of public health interventions in the county. This study demonstrates the importance of establishing reliable vital registry systems at sub-national levels as the mortality dynamics and trends are not homogeneous.
A coarse-to-fine cascade deep learning neural network for segmenting cerebral aneurysms in time-of-flight magnetic resonance angiography
Authors: Chen Meng , Geng Chen , Wang Dongdong , Zhou Zhiyong , Di Ruoyu , Li Fengmei , Piao Sirong , Zhang Jiajun , Li Yuxin , Dai Yakang
Published: September 2022

Background

Accurate segmentation of unruptured cerebral aneurysms (UCAs) is essential to treatment planning and rupture risk assessment. Currently, three-dimensional time-of-flight magnetic resonance angiography (3D TOF-MRA) has been the most commonly used method for screening aneurysms due to its noninvasiveness. The methods based on deep learning technologies can assist radiologists in achieving accurate and reliable analysis of the size and shape of aneurysms, which may be helpful in rupture risk prediction models. However, the existing methods did not accomplish accurate segmentation of cerebral aneurysms in 3D TOF-MRA.

Methods

This paper proposed a CCDU-Net for segmenting UCAs of 3D TOF-MRA images. The CCDU-Net was a cascade of a convolutional neural network for coarse segmentation and the proposed DU-Net for fine segmentation. Especially, the dual-channel inputs of DU-Net were composed of the vessel image and its contour image which can augment the vascular morphological information. Furthermore, a newly designed weighted loss function was used in the training process of DU-Net to promote the segmentation performance.

Results

A total of 270 patients with UCAs were enrolled in this study. The images were divided into the training (N = 174), validation (N = 43), and testing (N = 53) cohorts. The CCDU-Net achieved a dice similarity coefficient (DSC) of 0.616 ± 0.167, Hausdorff distance (HD) of 5.686 ± 7.020 mm, and volumetric similarity (VS) of 0.752 ± 0.226 in the testing cohort. Compared with the existing best method, the DSC and VS increased by 18% and 5%, respectively, while the HD decreased by one-tenth.

Conclusions

We proposed a CCDU-Net for segmenting UCAs in 3D TOF-MRA, and the obtained results show that the proposed method outperformed other existing methods.
The association between ROS1 rearrangement and risk of thromboembolic events in patients with advanced non-small cell lung cancer: a multicenter study in China
Authors: Yi Jiawen , Chen Huang , Li Jie , Jiang Xingran , Xu Yan , Wang Mengzhao , Wang Zheng , Zhai Zhenguo , Ren Yanhong , Zhang Yuhui
Published: September 2022

Background

According to several studies, ROS1 rearrangement is associated with thrombotic risk in non-small cell lung cancer (NSCLC). However, there is no clear understanding of the predictors and prognostic impact of thromboembolic events (TEEs) in patients with advanced ROS1 rearrangement NSCLC.

Methods

A total of 47 newly diagnosed advanced NSCLC patients with ROS1 rearrangement from four Chinese hospitals were retrospectively included and were evaluated for TEEs incidence, characteristics, predictors, as well as response to therapies and overall survival (OS).

Results

Of the 47 enrolled patients, 23.4% (n = 11) patients developed TEEs. Among them, 7 of 11 patients (64%) developed pulmonary embolism (PE), and 5 patients (45%) experienced recurrent TEEs. In multivariate analysis, D-dimer was associated with the occurrence of TEEs in ROS1 rearranged NSCLC (HR 1.16, 95% CI 1.08–1.23, P < 0.001). Median progression-free survival (PFS) after first-line ROS1 tyrosine kinase inhibitors (TKIs) therapy was significantly longer in patients without TEEs than in those developing TEEs (26 months vs. 12 months, P = 0.0383). Furthermore, patients with TEEs had a shorter OS period than those without TEEs (29.8 months vs. not estimable, P = 0.0647).

Conclusion

The results of this multicenter study indicated that advanced NSCLC patients with ROS1 rearrangement were more likely to experience PE and TEEs recurrence. And patients with TEEs tended to have a worse prognosis. Furthermore, an elevated D-dimer level suggested a hypercoagulable state in NSCLC patients with ROS1 rearrangement.
A unified scheme for the benchmarking of upper limb functions in neurological disorders
Authors: Longatelli Valeria , Torricelli Diego , Tornero Jesús , Pedrocchi Alessandra , Molteni Franco , Pons José L. , Gandolla Marta
Published: September 2022

Background

In neurorehabilitation, we are witnessing a growing awareness of the importance of standardized quantitative assessment of limb functions. Detailed assessments of the sensorimotor deficits following neurological disorders are crucial. So far, this assessment has relied mainly on clinical scales, which showed several drawbacks. Different technologies could provide more objective and repeatable measurements. However, the current literature lacks practical guidelines for this purpose. Nowadays, the integration of available metrics, protocols, and algorithms into one harmonized benchmarking ecosystem for clinical and research practice is necessary.

Methods

This work presents a benchmarking framework for upper limb capacity. The scheme resulted from a multidisciplinary and iterative discussion among several partners with previous experience in benchmarking methodology, robotics, and clinical neurorehabilitation. We merged previous knowledge in benchmarking methodologies for human locomotion and direct clinical and engineering experience in upper limb rehabilitation. The scheme was designed to enable an instrumented evaluation of arm capacity and to assess the effectiveness of rehabilitative interventions with high reproducibility and resolution. It includes four elements: (1) a taxonomy for motor skills and abilities, (2) a list of performance indicators, (3) a list of required sensor modalities, and (4) a set of reproducible experimental protocols.

Results

We proposed sixmotor primitivesas building blocks of most upper-limb daily-life activities and combined them into a set of functionalmotor skills. We identified the main aspects to be considered during clinical evaluation, and grouped them into tenmotor abilitiescategories.For each ability, we proposed a set ofperformance indicatorsto quantify the proposed ability on a quantitative and high-resolution scale. Finally, we defined the procedures to be followed to perform the benchmarking assessment in a reproducible and reliable way, including the definition of the kinematic models and the target muscles.

Conclusions

This work represents the first unified scheme for the benchmarking of upper limb capacity. To reach a consensus, this scheme should be validated with real experiments across clinical conditions and motor skills. This validation phase is expected to create a shared database of human performance, necessary to have realistic comparisons of treatments and drive the development of new personalized technologies.
Polyclonal evolution of Fanconi anemia to MDS and AML revealed at single cell resolution
Authors: Chang Lixian , Cui Zejia , Shi Deyang , Chu Yajing , Wang Bichen , Wan Yang , Ma Qiuyi , Zhang Ranran , Li Haoyuan , Cheng Xuelian , Cheng Tao , Zhu Xiaofan , Li Cheng , Yuan Weiping
Published: September 2022

Background

Fanconi anemia (FA) is a rare disease of bone marrow failure. FA patients are prone to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, the molecular clonal evolution of the progression from FA to MDS/AML remains elusive.

Methods

Herein, we performed a comprehensive genomic analysis using an FA patient (P1001) sample that transformed to MDS and subsequently AML, together with other three FA patient samples at the MDS stage.

Results

Our finding showed the existence of polyclonal pattern in these cases at MDS stage. The clonal evolution analysis of FA case (P1001) showed the mutations of UBASH3A, SF3B1, RUNX1 and ASXL1 gradually appeared at the later stage of MDS, while the IDH2 alteration become the dominant clone at the leukemia stage. Moreover, single-cell sequencing analyses further demonstrated a polyclonal pattern was present at either MDS or AML stages, whereas IDH2 mutated cell clones appeared only at the leukemia stage.

Conclusions

We thus propose a clonal evolution model from FA to MDS and AML for this patient. The results of our study on the clonal evolution and mutated genes of the progression of FA to AML are conducive to understanding the progression of the disease that still perplexes us.
New insights into municipal biowaste derived products as promoters of seed germination and potential antifungal compounds for sustainable agriculture
Authors: Fragalà Ferdinando , Castello Ivana , Puglisi Ivana , Padoan Elio , Baglieri Andrea , Montoneri Enzo , Vitale Alessandro
Published: September 2022

Background

Municipal biowaste management may generate a negative impact on the environment; therefore, their biomasses could be valorised as an alternative feedstock to fossils to produce high performance compounds useful for agricultural applications. The main objective of this study was to evaluate the potential agricultural applications of bioproducts (BPs) obtained by alkaline hydrolysis of the solid anaerobic digestate of municipal biowastes (ADMBW) and of one oxidized (ozonized) product (ADMBW BP OX). Both products were chemically characterized and used for agricultural in vitro assays.

Results

BP preparations were tested for their potential effect as enhancers of seed germination process using five concentrations (1, 10, 100, 1000, and 5000 mg L−1) and three different species: cress (Lepidium sativum), tomato (Solanum lycopersicum), and lettuce (Lactuca sativa L.). At this aim several germination indices were calculated to establish the priming effect of these substances on the selected seeds. Moreover, the potential in vitro antifungal effects of BPs at three concentrations (100, 1000, and 5000 mg L−1) on many dangerous fungal phytopathogens of economically important cultivated crops were evaluated and compared to Benzothiadiazole, one of the most-used plant disease suppressants. Results show that these ADMBW derived BPs exert a seed specie-specific positive effect on germination process, inducing better performances in the several calculated indices at all the concentration tested, except for the ADMBW BP OX 5000 mg L−1, which showed at the highest concentration a strong phytotoxic effect on tomato seeds.

Conclusions

The fungicidal potency of ADMBW BP OX was for the first time clearly demonstrated on multiple targets as Botrytis cinerea, Sclerotinia sclerotiorum, Monilia sp., Sclerotium rolfsii, and Phytophthora nicotianae, by calculating their relative EC50 and, when it was possible, also EC95 and MIC values. These results are of great impact in the actual historical moment, as from a biowaste as DMBW, which is worldwide constantly produced, may be possible to obtain agrochemicals and fertilizers without the usual feedstocks, which are more and more expensive.

Graphical Abstract
Prevalence of overweight and obesity and associated factors among people living with HIV attending a tertiary care clinic in Uganda
Authors: Nalugga Esther Alice , Laker Eva , Nabaggala Maria Sarah , Ddungu Ahmed , Batte Charles , Piloya Theresa , Bongomin Felix
Published: September 2022

Background:

Overweight and obesity are significantly increasing among people living with HIV (PLWH), contributing to the risk of major adverse cardio-metabolic events. However, little is known on its prevalence among PLWH in sub-Saharan Africa. In this study, we report the prevalence and factors associated with overweight and obesity among PLWH in a large tertiary HIV clinic in Kampala, Uganda.

Methods:

A cross-sectional, retrospective review of electronic database of all PLWH that attended the Adult Infectious Diseases Institute clinic between November 2018 and April 2019 was conducted. Demographic, body mass index (BMI) [kg/m2] and clinical variables were extracted. Based on BMI, nutritional status was classified as undernutrition (< 18.5kg/m2), normal (≥ 18.5 < 25kg/m2), overweight (≥ 25 < 30kg/m2) and obesity (≥ 30kg/m2). Poisson regression analysis was performed to determine factors associated with overweight and obesity.

Results:

Overall, 7,818 participants were included in the analysis, 64% (n = 4,976) were female, with a median age of 44 years (interquartile range (IQR): 36–51) and a median BMI of 24.2 (IQR: 21.2–28.1). The prevalence of overweight and obesity combined was 46% (55% female versus 30% male), obesity 18.2% (24.6% female versus 7.1% male) and overweight 27.8% (30.4% female versus 22.9% male). Factors associated with overweight and obesity were: Females (adjusted prevalence ratio [aPR]: 1. 8, 95%CI:1.69–1.87), age category 25—59 years (aPR: 1.9, 95%CI: 1.63–2.24) and ≥ 60 years (aPR: 1.8, 95%CI:1.49–2.12); duration on antiretroviral therapy (ART) for 6—10 years (aPR: 1.1, 95%CI:1.08–1.18), CD4 count 200–500 (aPR:0.08, 95%CI:0.01–0.15) and > 500 (aPR:0.46, 95%CI:0.39–0.54) and having at least one noncommunicable disease (NCD) (aPR: 1.1, 95%CI:1.07–1.18).

Conclusion

There is a high burden of overweight and obesity among PLWH in Uganda. Nutrition and weight management programs particularly targeting high risk groups such as females and persons with underlying NCDs should be integrated into HIV care.
On singularity points in elastic orthorhombic media
Authors: Stovas Alexey , Roganov Yuriy , Roganov Vyacheslav
Published: September 2022

The analysis of singularity points in anisotropic models of low symmetry is very important for seismic modelling and seismic data processing. Ray tracing: the group velocity vector dramatically changes the orientation in vicinity of singularity point. Seismic amplitudes: the relative geometrical spreading of seismic wave tends to zero in singularity point. Seismic wave polarization: the polarization vectors dramatically change in vicinity of singularity point. Multiarrival: one of the waves has triplication associated with singularity point, another wave has a lacuna.The singularity points are considered for elastic anisotropic model with orthorhombic symmetry. The conditions for the presence of singularity points are derived depending on location of these points, in symmetry plane and in-between the symmetry planes. The explicit equations for images of the singularity points in group velocity domain are derived. The conditions for different types of degeneracy of these images are defined. We also perform the analysis of interaction of the group velocity images of different singularity points.
Real-World Cost of Pediatric Acute Lymphoblastic Leukemia Care Among Commercially Insured Individuals in the United States: Effect of Era and Age at Diagnosis
Authors: Turcotte Lucie M. , Watson Dave , Tanner Lynn , Hoover Alex , Gilchrist Laura , Finch Mike , Messinger Yoav H.
Published: September 2022

PURPOSE:

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Five-year survival is approaching 90%. In efforts to further improve outcomes, it is critical to consider the cost of ALL care.

MATERIALS AND METHODS:

Commercial insurance data from OptumLabs Data Warehouse were used to identify patients with ALL, age 1-30 years, diagnosed in 1993-2017 in the United States, with 36 months of continuous insurance coverage. Patients treated with hematopoietic cell transplantation were excluded. Inpatient and outpatient utilization and cumulative reimbursements (inflation-adjusted to December 2020) were computed 8 and 36 months from diagnosis and stratified by age (1-9, 10-12, and ≥ 13 years) as proxies for National Cancer Institute risk groups. Regression models were constructed to assess associations with demographic and clinical characteristics.

RESULTS:

Among 927 patients (median age, 6 years; interquartile range, 3-12 years; 43% female), individuals age ≥ 10 years had 23-25 more inpatient days and 22 more outpatient encounters compared with younger patients. The 36-month median cost was $394,000 (USD) (interquartile range, $256,000-$695,000 [USD]), and 64% of the total cost was incurred during the initial 8 months. The 36-month cost was 1.5-fold higher for those age 10-12 years and 1.7-fold higher for those age ≥ 13 years compared with 1-9 years. The cost for those diagnosed in 2013-2017 was 70% higher compared with 1993-2002, and was not different on the basis of sex, race, or ethnicity.

CONCLUSION:

Older age was associated with higher utilization and cost, and the cost of treatment increased significantly over time. These data provide valuable benchmarks for future studies examining the cost-benefit of ALL therapy modifications.
Azoles resistance of candida species causing vulvo-vaginitis in reproductive age women at a tertiary care setting
Authors: Zaman Ronaq , Ullah Ihsan , Adeeb Humera , Arif Ambreen
Published: September 2022

Objectives: To study prevalence and resistance pattern to azoles of candida species causing vulvovaginitis in reproductive age women.

Methods: Samples were collected from Hayatabad Medical Complex from November 2018 to May 2019. This cross-sectional study was conducted at the department of Microbiology, Institute of Pathology and Diagnostic Medicine, Khyber Medical University Peshawar, Pakistan. A total of 369 high vaginal swabs were collected. Candida was isolated by vaginal swabs inoculation on Sabouraud’s dextrose agar (SDA). Colonies on SDA were inoculated on Candida CHROM agar to identify candida species. Wet film microscopy and Gram staining were performed. Biochemical identification was done with 20C AUX. Antifungal susceptibility testing was done by disc diffusion and broth micro-dilution methods to find the resistance pattern of azole drugs. Fluconazole, Clotrimazole, Miconazole, Voriconazole and Itraconazole were the azoles drugs used.

Results: Among 43%(n=158) positive candida cases, 44%(n=85) were non pregnant women while 41%(n=73) were pregnant. The Candida species distribution of 158 isolates was as follow; Candida albicans (C. albicans) 46.2%(n=73), Candida krusei (C. krusei) 29.1%(n=46), Candida parapsilosis (C. parapsilosis) 19%(n=30) and Candida glabrata (C. glabrata) 5.7%(n=9). Overall Candida isolates were highly resistant 72%(n=113) to Fluconazole while least resistant 21.5 % (n=34) to Itraconazole.

Conclusion: C. albicans is the most prevalent specie involved in Vulvovaginal candidiasis. Candida species were found to be least resistant to Itraconazole followed by Voriconazole, Miconazole, Clotrimazole and Fluconazole.

doi: https://doi.org/10.12669/pjms.38.8.5984

How to cite this:Zaman R, Ullah I, Adeeb H, Arif A. Azoles resistance of candida species causing vulvo-vaginitis in reproductive age women at a tertiary care setting. Pak J Med Sci. 2022;38(8):---------. doi: https://doi.org/10.12669/pjms.38.8.5984

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Greece 2.0, Health Economics and Outcome Research and the Rise of Artificial Intelligence: Another Missed Opportunity or it's Time for Brilliance?
Authors: Fylatos Dimitrios , Efthymiou Iris Panagiota , Sidiropoulos Symeon , Emmanouil-Kalos Alkinoos , Vozikis Athanassios
Published: September 2022

The EU National Recovery and Resilience Plan "Greece 2.0" includes, among other priorities, a framework to promote and reform the health system, with a focus on digitalization of health and the use of information technology applications. Greece 2.0 may offer a chance to address the current scarcity of high-quality, reliable data sources, which is limiting the spread and impact of health economics and outcomes research (HEOR). We also suspect that the use of artificial intelligence (AI) in HEOR will play an important role in Greece's health-care reform and that it will be critical for making real-world data-driven decisions, reducing policy uncertainty. Greece has a once-in-a-lifetime chance to start from scratch and potentially build data-centric AI systems that prioritise data quality over quantity and are built on scalable, flexible, and governable data collection. This commentary explains and critically considers the significance of developing and funding an innovative plan for using AI in HEOR as part of the Greece 2.0 framework. It also discusses ethical issues and the larger role of HEOR in health-care reform.