Selected static foot assessments do not predict medial longitudinal arch motion during running.
Static assessments of the foot are commonly advocated within the running community to classify the foot with a view to recommending the appropriate type of running shoe. The aim of this work was to determine whether selected static foot assessment could predict medial longitudinal arch (MLA) motion during running. Fifteen physically active males (27 ± 5 years, 1.77 ± 0.04 m, 80 ± 10 kg) participated in the study. Foot Posture Index (FPI-6), MLA angle and rearfoot angle were measured in a relaxed standing position. MLA motion was calculated using the position of retro-reflective markers tracked by a VICON motion analysis system, while participants ran barefoot on a treadmill at a self-selected pace (2.8 ± 0.5 m.s(-1)). Bivariate linear regression was used to determine whether the static measures predicted MLA deformation and MLA angles at initial contact, midsupport and toe off. All three foot classification measures were significant predictors of MLA angle at initial contact, midsupport and toe off (p < .05) explaining 41-90 % of the variance. None of the static foot classification measures were significant predictors of MLA deformation during the stance phase of running. Selected static foot measures did not predict dynamic MLA deformation during running. Given that MLA deformation has theoretically been linked to running injuries, the clinical relevance of predicting MLA angle at discrete time points during the stance phase of running is questioned. These findings also question the validity of the selected static foot classification measures when looking to characterise the foot during running. This indicates that alternative means of assessing the foot to inform footwear selection are required.


Spylidone, a novel inhibitor of lipid droplet accumulation in mouse macrophages produced by Phoma sp. FKI-1840.
During our screening for microbial inhibitors of lipid droplet accumulation in macrophages, a new compound designated spylidone was isolated along with two structurally related known compounds, PF1052 and vermisporin, from the fermentation broth of Phoma sp. FKI-1840 by solvent extraction, silica gel column chromatography, ODS column chromatography and preparative HPLC. From the structure elucidation, spylidone has a spiro ring containing 2,4-pyrrolidinedione. Among the three compounds, only spylidone was found to inhibit lipid droplet accumulation in macrophages at 10 to approximately 50 microM without any cytotoxic effect.


Evaluation of time passed since death by examination of oxidative stress markers, histopathological, and molecular changes of major organs in male albino rats.
Recent biochemical, metabolic, and molecular profiles of various body fluids showed more accurate correlation to the postmortem interval than the traditional physical examination. Our study aimed to evaluate time passed since death in relation to oxidative stress markers, HMGB1 genetic expression, histopathological examination, and BCL2 immunohistochemical analysis in major organs (heart, kidney, and testis). Forty-two adult male rats were included and randomly divided into seven equal groups. After sacrification, the rodents were kept at room temperature and major organs were obtained at 0, 12, 24, 48, 72, 96, and 120 h. Malonaldehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH) tissue levels, High mobility group box 1 protein (HMGB1) gene expression, histopathological, and B cell lymphoma 2 (BCL2) immunohistochemical expressions were analyzed. Postmortem interval was correlated to different tissue levels of MDA, SOD, and GSH. HMGB1 showed enhanced postmortem gene expression with a peak at 48 h after death. Obvious time-dependent histopathological changes were observed in all the examined organs. Dilated spaces, extravasation, and fragmentation scores in heart specimens were higher at 96 and 120 h compared with the other groups. Renal changes in the form of shrunken glomeruli, loss of tubular epithelium, and hyalinization and testicular findings in the form of epithelial detachment, vacuolation, and loss of sperms started at 72 h postmortem. BCL2 expression began to decrease 24 h and became negative at 96 h after death. In conclusion, HMGB1 gene expression can be used for estimation of time passed since death as it shows time-dependent changes in the form of a progressive increase with a peak at 48 h then it begins to decline. Oxidants and antioxidants are correlated to PMI until 120 h after death. Histopathological changes in the heart, kidney, and testis are also time-dependent until the 5th day after death. BCL2 immunohistochemical expression begins to decline 24 h until 96 h after death when it becomes negative.


Socio-administrative conservation and collection practices of the sacred Thal Kedar forest, Uttarakhand, India.
The long-lasting association of humans with the forest is directly linked to the livelihood of natives without cultures, traditions, and beliefs. A survey conducted for the phytodiversity of the sacred Thal Kedar forest, Uttarakhand, India, reveals it as a center of spiritual approach and controlled by moral values rather than regulatory norms for conservation and sustainable benefits. Detailed investigation via group discussions, key informant interviews, observation of participants, and secondary data collection deciphers that the sacred forest plays a potential role in the food and health of the people, both at the local and regional levels. In the present survey, we found that local people are effectively controlled and guided to use all resources through moral duty, beliefs, and worship rituals, an inherited practice for ecological protection, and honesty to the Deity. Forest tourism based on holy baths, a current social demand, has been emerging as a sustainable job for local youths but requires stringent parallel administrative supervision along the established social norms to avoid any materialistic mind deeds to the sacred forest. The impact of climate change and the shift of various species to higher elevations is a matter of advanced strategy to the policymakers to preserve the floristic diversity of the sacred Thal Kedar forest.


Factors that influence the process of 51chromium labeling of human granulocytes isolated from blood by counterflow centrifugation.
The uptake of 51chromium by human granulocytes isolated from blood by counterflow centrifugation is influenced by the composition of the suspension medium, the incubation period, the temperature and the amount of 51chromium used. Counterflow centrifugation-elutriation isolated approximately 98 per cent of the granulocytes from the blood. Acid-citrate-dextrose (ACD) plasma, citrate-phosphate-dextrose (CPD) plasma and heparinized plasma as resuspension media produced similar labeling results, whereas phosphate-buffered saline resulted in three times greater uptake in 51chromium. The greatest uptake of 51chromium (4%) was achieved after incubation of 37 C for one hour in autologous plasma, and granulocyte integrity and metabolic function in vitro were not adversely affected.


Galanthamine in Alzheimer's disease : a new alternative to tacrine?
Galanthamine (galantamine), a tertiary alkaloid derived from the bulbs of the snowdrop and various Narcissus species, is a selective, centrally active and reversible inhibitor of acetylcholinesterase that is suitable for oral therapy. After a long period during which the investigational and clinical use of the drug was limited to anaesthesia and the treatment of peripheral paralysis syndromes in Eastern Europe, the molecule has now emerged as a promising lead substance for the treatment of cognitive decline in Alzheimer's disease.Galanthamine has similar therapeutic potential to tacrine, but has a significantly more favourable pharmacokinetic and toxicity profile. A chemical synthesis process on the required industrial scale of several tons per year has become available, removing a major obstacle to the development of the drug. Clinical trials published so far are, however, rather limited in terms of both design and patient number. The main reason for this is that there has been a lack of strong support for the drug within the pharmaceutical industry. However, the available data support the notion that this molecule, if properly developed, could be a peer for any second-generation cholinergic drug currently in clinical trials for the symptomatic treatment of Alzheimer's disease.


A Ni2+ (S = 1) Kagome compound templated by 1,4-diazacubane [corrected].
1,8-Diazacubane-templated nickel(II) sulfate with the Kagome structure prepared under solvothermal conditions exhibits interesting magnetic properties.


Examination of the horse with colic.
The purpose of this detailed description of the clinical examination of the colic patient is to arrive at a specific diagnosis. However, this is hardly ever possible, but the practitioner should be in the position to establish the suspicion of an intestinal obstruction or to rule out its presence during the course of the development. Single clinical findings should not be interpreted in isolation but in relation to one another, so that a false diagnosis is not made. All clinical findings should be documented, so that when repeated examinations are carried out, findings can be compared with one another. This is also important in the evaluation of the cause of the condition; also, it will be easier to discern the results of therapy.


Combined photoacoustic and acoustic imaging of human breast specimens in the mammographic geometry.
A photoacoustic volume imaging (PAVI) system was designed to study breast cancer detection and diagnosis in the mammographic geometry in combination with automated 3-D ultrasound (AUS). The goal of the work described here was to validate the design and evaluate its performance in human breast tissues for non-invasive imaging of deeply positioned structures covering such geometry. The good penetration of near-infrared light and high receiving sensitivity of a broad-bandwidth, 572-element, 2-D polyvinylidene fluoride (PVDF) array at a low center frequency of 1 MHz were used with 20 channel simultaneous acquisition. Pseudo-lesions filled with dilute blood were imaged in three human breast specimens at various depths up to 49 mm. With near-infrared light illumination and 256-sample averaging, the extrapolated maximum depth in imaging a 2.4-mm blood-rich lesion with a 3-dB contrast-to-noise ratio in a compressed breast was 54 mm. Three-dimensional photoacoustic volume image stacks of the breasts were co-registered with 3-D ultrasound image stacks, suggesting for the first time that PAVI, based on the intrinsic tissue contrast, can visualize tissue interfaces other than those with blood, including the inner skin surface and connective tissue sheets. With the designed system, PAVI revealed satisfactory imaging depth and sensitivity for coverage of the entire breast when imaged from both sides in the mammographic geometry with mild compression.


Ex vivo tissue slice culture system to measure drug-response rates of hepatic metastatic colorectal cancer.
The lack of predictive biomarkers or test systems contributes to high failure rates of systemic therapy in metastasized colorectal carcinoma, accounting for a still unfavorable prognosis. Here, we present an ex vivo functional assay to measure drug-response based on a tissue slice culture approach. Tumor tissue slices of hepatic metastases of nine patients suffering from colorectal carcinoma were cultivated for 72 h and treated with different concentrations of the clinically relevant drugs Oxaliplatin, Cetuximab and Pembrolizumab. Easy to use, objective and automated analysis routines based on the Halo platform were developed to measure changes in proliferative activity and the morphometric make-up of the tumor. Apoptotic indices were assessed semiquantitatively. Untreated tumor tissue slices showed high morphological comparability with the original "in vivo"-tumor, preserving proliferation and stromal-tumor interactions. All but one patients showed a dosage dependent susceptibility to treatment with Oxaliplatin, whereas only two patients showed responses to Cetuximab and Pembrolizumab, respectively. Furthermore, we identified possible non-responders to Cetuximab therapy in absence of RAS-mutations. This is the first time to demonstrate feasibility of the tissue slice culture approach for metastatic tissue of colorectal carcinoma. An automated readout of proliferation and tumor-morphometry allows for quantification of drug susceptibility. This strongly indicates a potential value of this technique as a patient-specific test-system of targeted therapy in metastatic colorectal cancer. Co-clinical trials are needed to customize for clinical application and to define adequate read-out cut-off values.


The NMDA receptor antagonist CPP suppresses long-term potentiation in the rat hippocampal-accumbens pathway in vivo.
Excitation of afferent fibres originating in the ventral subiculum of the hippocampus through stimulation of the fimbria elicits field potentials in the nucleus accumbens. When recorded in the dorsomedial aspect of the nucleus accumbens, the evoked field responses consisted of an early, negative-going component (N1) with a peak latency of 8-10 ms, followed by a second negative-going peak (N2) with a latency of 22-24 ms. The N1 response reflects monosynaptic activation of nucleus accumbens neurons; the N2 component appears to be polysynaptic in origin. In control rats, high-frequency stimulation of the fimbria (three trains at 250 Hz, 250 ms, delivered at 50 min intervals) resulted in a long-lasting potentiation of both the N1 and N2 components. The magnitude of potentiation exhibited by the polysynaptic N2 response was typically greater than that of the monosynaptically evoked N1 response. Following delivery of the first train, the amplitude of the N1 and N2 components was increased by approximately 20 and 50% respectively. Administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist 3-[(+-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP, 10 mg/kg i.p.) had no significant effects on the evoked nucleus accumbens responses. High-frequency stimulation failed to produce a significant increase in the amplitude of either the N1 or the N2 response when delivered 45-60 min after CPP administration. To test whether the suppressant effects of CPP were time-dependent, two further high-frequency trains were applied 90 and 180 min after administration of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)


A guideline for integrating dynamic areas of interests in existing set-up for capturing eye movement: Looking at moving aircraft.
Today, capturing the behavior of a human eye is considered a standard method for measuring the information-gathering process and thereby gaining insights into cognitive processes. Due to the dynamic character of most task environments there is still a lack of a structured and automated approach for analyzing eye movement in combination with moving objects. In this article, we present a guideline for advanced gaze analysis, called IGDAI (Integration Guideline for Dynamic Areas of Interest). The application of IGDAI allows gathering dynamic areas of interest and simplifies its combination with eye movement. The first step of IGDAI defines the basic requirements for the experimental setup including the embedding of an eye tracker. The second step covers the issue of storing the information of task environments for the dynamic AOI analysis. Implementation examples in XML are presented fulfilling the requirements for most dynamic task environments. The last step includes algorithms to combine the captured eye movement and the dynamic areas of interest. A verification study was conducted, presenting an air traffic controller environment to participants. The participants had to distinguish between different types of dynamic objects. The results show that in comparison to static areas of interest, IGDAI allows a faster and more detailed view on the distribution of eye movement.


The Landscape of CAR-T Cell Clinical Trials against Solid Tumors-A Comprehensive Overview.
CAR-T cells showed great potential in the treatment of patients with hematologic tumors. However, the clinical efficacy of CAR-T cells against solid tumors lags behind. To obtain a comprehensive overview of the landscape of CAR-T cell clinical trials against this type of cancer, this review summarizes all the 196 studies registered at clinicaltrials.gov. Special focus is on: (1) geographical distribution; (2) targeted organs, tumor entities, and antigens; (3) CAR transfer methods, CAR formats, and extra features introduced into the T cells; and (4) patient pretreatments, injection sites, and safety measurements. Finally, the few data on clinical outcome are reported. The last assessment of clinicaltrials.gov for the data summarized in this paper was on 4 August 2020.


Efficacy of antiepileptic tetramethylcyclopropyl analogues of valproic acid amides in a rat model of neuropathic pain.
Antiepileptic drugs (AEDs) are widely utilized in the management of neuropathic pain. The AED valproic acid (VPA) holds out particular promise as it engages a variety of different anticonvulsant mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but potentially life-threatening side effects: teratogenicity and hepatotoxicity. We have synthesized several tetramethylcyclopropyl analogues of VPA amides that are non-teratogenic, and are likely to be non-hepatotoxic, and that exhibit good antiepileptic efficacy. In the present study we have assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation (SNL) model of neuropathic pain. TMCA (2,2,3,3-tetramethylcyclopropanecarboxylic acid, 100-250 mg/kg), TMCD (2,2,3,3-tetramethylcyclopropanecarboxamide, 40-150 mg/kg), MTMCD (N-methyl-TMCD, 20-100 mg/kg), and TMCU (2,2,3,3-tetramethylcyclopropanecarbonylurea, 40-240 mg/kg) all showed dose-related reversal of tactile allodynia, with ED(50) values of 181, 85, 41, and 171 mg/kg i.p., respectively. All were more potent than VPA (ED(50)=269 mg/kg). An antiallodynic effect was obtained for TMCD, MTMCD and TMCU at plasma concentrations as low as 23, 6 and 22 mg/L, respectively. MTMCD was found to be non-toxic, non-sedative and equipotent to gabapentin, currently the leading AED in neuropathic pain treatment. Tetramethylcyclopropyl analogues of VPA amides have potential to become a new series of drugs for neuropathic pain treatment.


Hearing loss in patients with enlarged vestibular aqueduct: air-bone gap and audiological Bing test.
The Bing test is based on the principle that occlusion of the external auditory meatus improves the perception of bone-conducted sounds unless there is a conductive hearing impairment. An air-bone gap has been reported in patients with large vestibular aqueduct (LVA) syndrome without apparent middle ear dysfunction. We therefore performed the Bing test on nine patients with this syndrome to evaluate whether it is associated with an air-bone gap or middle ear dysfunction. Bone conduction thresholds did not change significantly during the Bing test in any patient. Because an air-bone gap is observed in patients with abnormal communication between the inner ear and cerebrospinal fluid through the LVA, dehiscent superior canal, or dilated inner ear meatus; we propose that a 'three windows' model (in which the abnormal communication provided by the enlarged endolymphatic duct and sac in LVA acts as the 'third window' for sound conductance) might explain the air-bone gap in such patients.


Multiple fish vertebra deformity in child with systemic lupus erythematosus: a case report.
We report an 11-year-old female patient with multiple fish vertebra deformity, which occurred in the course of treatment with corticosteroids for systemic lupus erythematosus (SLE). She was treated for SLE with predonisolone (30 mg per day) from April 2, 1996, and presented at our outpatient clinic for an osteoporosis check-up on April 27. She was 132 cm tall with-1.7 standard deviation of the average height, and X-ray examination revealed no evidence of osteoporosis in the spine. Bone mineral density (BMD) was 74.7% of the average BMD. Subsequently, she grew to 136 cm in September. However she began to have low back pain (LBP) from November, and received alfacalcidol. LBP deteriorated after pulse therapy with methylpredonisolone. In June 1997, X-ray examination revealed multiple fish vertebra deformity with 58.3% of the average BMD. Moreover her height had decreased to 131cm. She underwent combination therapy with elcatonin and alfacalcidol. In September 1999, she had no LBP nor progression of fish vertebra deformity. However she had no growth in height. Corticoseroids and SLE have multiple effects on bone metabolism, making the treatment of porosis complicated and difficult.


The reliability of hip scoring systems for total hip arthroplasty candidates: assessment by physical therapists.
Hip rating systems have been widely used in assessing severity of hip dysfunction but no uniform method has emerged. The current study was performed to determine the interobserver reliability of five different hip scores on patients with coxarthrosis. Test reliability among physical therapists for five commonly used hip scores. Thirty-five patients (48 hips) who had coxarthrosis and who were candidates for total hip arthroplasty were included in the study. Patients were evaluated preoperatively by three physical therapists using five different hip rating systems; the Harris Hip Score, the Iowa Hip Score, the Charnley Hip Score, the Merle d'Aubigne Hip Score and the American Academy of Orthopaedic Surgeons' Hip Score. The average age of the patients was 58.8 +/- 2.2 years (range 28-76 years). For all scores, an excellent interobserver reliability between the physical therapists were found (kappa = 0.77-0.95). The best correlation between first and second observer was on Harris Hip Score (kappa = 0.91), between second and third was on Merle d'Aubigne Hip Score (kappa = 0.95) and between first and third was on Iowa Hip Score (kappa = 0.87). There was an excellent interobserver reliability for all hip scores between the physical therapists, suggesting that all these hip scores are suitable for use by physical therapists.


Prediction of severe acute exacerbation using changes in breathing pattern of COPD patients on home noninvasive ventilation.
Acute exacerbation of COPD (AECOPD) is associated with poor outcome. Noninvasive ventilation (NIV) is recommended to treat end-stage COPD. We hypothesized that changing breathing pattern of COPD patients on NIV could identify patients with severe AECOPD prior to admission. This is a prospective monocentric study including all patients with COPD treated with long-term home NIV. Patients were divided in two groups: a stable group in which patients were admitted for the usual respiratory review and an exacerbation group in which patients were admitted for inpatient care of severe AECOPD. Data from the ventilator were downloaded and analyzed over the course of the 10 days that preceded the admission. A total of 62 patients were included: 41 (67%) in the stable group and 21 (33%) in the exacerbation group. Respiratory rate was higher in the exacerbation group than in the stable group over the 10 days preceding inclusion (18.2±0.5 vs 16.3±0.5 breaths/min, respectively) (P=0.034). For 2 consecutive days, a respiratory rate outside the interquartile limit of the respiratory rate calculated over the 4 preceding days was associated with an increased risk of severe AECOPD of 2.8 (95% CI: 1.4-5.5) (P<0.001). This assessment had the sensitivity, specificity, positive predictive, and negative predictive values of 57.1, 80.5, 60.0, and 78.6% respectively. Over the 10 days' period, a standard deviation (SD) of the daily use of NIV >1.0845 was associated with an increased risk of severe AECOPD of 4.0 (95% CI: 1.5-10.5) (P=0.001). This assessment had the sensitivity, specificity, positive predictive, and negative predictive values of 81.0, 63.4, 53.1, and 86.7%, respectively. Data from NIV can identify a change in breathing patterns that predicts severe AECOPD.


[Prognostic value of the ultrasonic determination of the degree of interstitial edema in patients with intermediate ejection fraction of the left ventricle after treating acute decompensation of heart failure].
Aim To study ultrasonic characteristics of lung tissue in patients with heart failure with left ventricular (LV) mid-range ejection fraction (HFmEF) and predictive value of these characteristics after reversing acute decompensated heart failure (ADHF).Material and methods Ultrasonic characteristics of lung tissue were studied by prospective observation in 71 patients (mean age, 65.2±3.6 years; men, 64.3 %) with HFmEF (LVEF from 40 to 49 %) following ADHF reversal. Semiquantitative evaluation of B-lines was performed by the E. Picano (2016) method at 5+2 days after hospitalization and on discharge from the hospital. The distance between B-lines was 3 mm (В3 lines) and 7 mm (В7 lines). Patients' catamnesis was studied for determining the predictive value of lung tissue ultrasonic characteristics for two years since the index hospitalization. Statistical analysis was performed using the McNemar's χ2 test (for evaluation of linked samples and of changes in the presence/absence of B-lines as determined by lung ultrasound examination (USE)) and the Wilcoxon test (for evaluation of quantitative changes). Differences were considered significant at p<0.05.Results B7-lines characteristic of interstitial component of pulmonary parenchymal edema prevailed in patients with HFmEF. В3-lines characteristic of alveolar edema were found in a small amount. In the anterior-superior segment, B7-lines predominated over B3-lines (80 % vs. 20 %, p<0.01) on the right; however, on the lest, significant differences were not observed (64 % vs. 36 %, p>0.05). In the anterior-inferior segment, В7-lines prevailed over В3-lines on the right (75 % vs. 25 %, p<0.05); however, on the left, the difference was not significant (67 % vs. 33 %, p=0.05). In the lateral superior segment on the right, В7-lines predominated over В3-lines (75 % vs. 25 %, p<0.01); in contrast, on the left, there were no differences (67 % vs. 33 %, p>0.05). In lateral-basal segments on both sides, significant differences were present (73 % vs. 27 % on the right, p<0.05; 72 % vs. 28 % on the lest, p<0.05). The results of lung ultrasound were also used for evaluation of the B-line predictive value in patients with ADHF and mid-range EF on discharge from the hospital after reversal of X-ray and clinical symptoms of pulmonary congestion. In the next two years, 35 patients (49.2 % of sample) were rehospitalized with signs of ADHF (39 hospitalizations, 1.1 hospitalizations per patient). The rehospitalized patients were divided into two subgroups, with an increased number of B-lines and small congestion on discharge (6-15 В-lines) and without signs of congestion (<5 В-lines). For patients with a minimal (small) congestion on pulmonary ultrasound but regression of clinical and X-ray congestion, the number of rehospitalizations was 25 vs. 11 in patients with the number of B7-lines <5. In the ROC-analysis, the area under the curve was 0.706, which corresponded to the expert assessment as "good". The position sensitivity was 78.6 % and the specificity was 79.7 %.Conclusion "Ultrasonic pulmonary edema syndrome" in patients with LV mid-range ejection fraction after reversing ADHF was characterized by predomination of the interstitial component, despite the absence of X-ray congestion, correlated with the blood level of NT-proBNP measured at the same time, and was associated with rehospitalizations.


Absent pedicle in the cervical spine.
2 cases of absent cervical pedicle are presented. It is important to be acquainted with this condition to be able to differentiate it from dumbbell tumour. Some other lesions which simulate it are briefly mentioned.


Coproducing and Implementing Person-Centered Key Performance Indicators in Ambulatory Cancer Nursing.
Policy advocates person-centered healthcare for people living with cancer. Although nurses and patients alike recognize that a good care experience cannot be measured solely by clinical outcomes, the difficulty in finding indicators that measure the delivery of effective person-centered care remains a challenge. The aim of this study was to explore the impact of a coproduced implementation project using the person-centered nursing key performance indicators to support the development of person-centered practice across ambulatory chemotherapy units. The study adopted an evaluation approach derived from work of the Medical Research Council. A mobile app was used to collect and analyze 3 cycles of data using 4 measurement tools, with the aim of informing quality improvement activities. Six implementation teams were recruited from chemotherapy units across a region in the United Kingdom. Qualitative interviews were used to evaluate the experience of participants. Data analysis revealed 4 themes: building relationships that nurture the care experience, inspiring nursing staff to flourish, shaping practice and service changes through the nature of the conversations, and becoming person-centered through coproduction. This study provides evidence of the value of implementing these person-centered key performance indicators using a model of coproduction in cancer nursing. The data generated by the key performance indicators offer valuable feedback to nurses that can inform the development of person-centered practice and contribute to an enhanced patient experience. This study provides an innovative and transferable approach for implementing relevant and appropriate key performance indicators within cancer nursing, which can contribute to developing person-centered cultures.


Initiation of Antiretroviral Therapy Before Pregnancy Reduces the Risk of Infection-related Hospitalization in Human Immunodeficiency Virus-exposed Uninfected Infants Born in a High-income Country.
Epidemiological studies conducted in low- and high-income countries showed that infants exposed to maternal human immunodeficiency virus (HIV) have a high risk of severe infections. Immune alterations during fetal life have been proposed as a possible mechanism. This prospective study assessed the relative risk of hospitalization for infection in HIV-exposed uninfected (HEU) infants as compared to HIV-unexposed (HU) infants born in a high-income country (HIC). Markers of monocyte activation and levels of pathogen-specific antibodies were measured at birth to identify correlates of infant susceptibility. There were 27 of 132 HEU infants and 14 of 123 HU infants hospitalized for infection during the first year of life (adjusted hazard ratio [aHR] 2.33, 95% confidence interval [CI] 1.10-4.97). Most of this increased risk was associated with the time of initiation of maternal antiretroviral therapy (ART). As compared to HU infants, the risk of hospitalization for infection of HEU infants was 4-fold higher when mothers initiated ART during pregnancy (aHR 3.84, 95% CI 1.69-8.71) and was not significantly increased when ART was initiated before pregnancy (aHR 1.42, 95% CI 0.58-3.48). The activation of newborn monocytes and the reduced transfer of maternal antibodies were most intense following ART initiation during pregnancy, and predicted the risk of infant hospitalization. These observations indicate that initiation of maternal ART before pregnancy reduces the susceptibility of HEU infants born in a HIC to severe infections, and that this effect could be related to the prevention of immune alterations during fetal life.


Intrahepatic venous and portal venous aneurysms examined by color Doppler flow imaging.
Thirteen cases with liver cystic lesions, which were suspected to communicate with intrahepatic vessels on the basis of ordinary sonography, were examined by color Doppler flow imaging. By this method, blood flow within the cystic lesion was detected in 5 of these cases, and the communication to the intrahepatic vessel confirmed. Information about the hemodynamics of aneurysms was obtained. Two of these lesions were diagnosed as an aneurysmal porta-hepatic venous fistula, another 2 as a portal venous aneurysm, and the remaining 1 as a hepatic venous aneurysm.


Ameliorative effect of different mesoporous bioactive glass materials in experimental tibial defects in rats.
Enhancing the bone healing procedure would resultantly improve the post-recovery life quality, as well as the speed with which the patient returns to their former life quality. Porous structures can provide a large surface area and abundant channels to facilitate mass transfer. To evaluate the application of mesoporous materials in the bone healing of surgically created defects on the tibiae of male adult Wistar rats. The defect areas were evaluated after implantation of 4 types of bioactive glass histopathologically and immunohistochemically. Fifty adult rats were divided into 5 groups including a control group without material. The used products were mesoporous bioactive glass (MBG), Cu-MBG, Zn-MBG, and Cu-Zn-MBG. Unicortical bone defects with a 3 mm diameter were performed in both tibiae of the animals and filled with 4 types of glass particles. The rats were then euthanized at 15 d and 30 d. Tibial samples were collected and the tissues forwarded for histological processing, and examined using light microscopy. Additionally, bone healing was evaluated by assessing the levels of bone morphogenetic protein BMP2, collagen 1, osteocalcin (OST), and vascular endothelial growth factor (VEGF) using immunohistochemical methods. Within the 15th day, all groups presented connective tissue septa; at the 30th day, the new bone formation was more intense in the Cu-Zn-MBG group. Additionally, BMP2, collagen 1, OST, and VEGF immune expression were more prominent in the Cu-Zn-MBG group. The study results indicated that MBG may be used for the repairing of bone defects. Cu-Zn-MBG may be the best choice for this purpose.


Indirect immobilization of recombinant proteins to a solid phase using the albumin binding domain of streptococcal protein G and immobilized albumin.
Immobilization of proteins to a solid phase leads to denaturation of the adsorbed molecules which may subsequently affect biological interactions. However, for many applications maintenance of the native structure is desired. Therefore, an indirect immobilization system was developed, based on binding of the albumin binding domain (ABP) of streptococcal protein G to rat serum albumin (RSA) precoated on a solid phase (RSA-microtiter plates). Escherichia coli vectors were adapted for production of recombinant protein fused to ABP and the 6 X His-tag. The expressed ABP tag was found to form homodimers. Plasmon resonance was used to study the interaction between an ABP fusion protein and immobilized RSA. Apparent on- and off-rates were calculated using a model for a bivalent analyte (k(a1) = 3.37 x 10(4) M(-1) s(-1), k(d1) = 1.23 x 10(-4) s(-1)). Thus, the stability of the ABP-RSA interaction can be explained by a slow off-rate. This was confirmed by chase experiments in an ELISA format. The ABP-RSA interaction remained stable after addition of different albumins. This immobilization system was used for the development of an ELISA to detect antibodies against Borna disease virus protein p40. The use of RSA-microtiter plates for indirect immobilization of ABP fusion protein was shown to be superior to direct adsorption on plastic. To obtain maximal antibody binding ten times less antigen was needed for indirect immobilization compared to direct adsorption. The binding capacity of the RSA-microtiter plates was determined to be about 0.8 pmol of monomeric ABP protein.


Advances in tryptophan hydroxylase-2 gene expression regulation: new insights into serotonin-stress interaction and clinical implications.
Serotonin (5-HT) modulates the stress response by interacting with the hormonal hypothalamic-pituitary-adrenal (HPA) axis and neuronal sympathetic nervous system (SNS). Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT biosynthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. While TPH2 genetic variance has been linked to numerous behavioral traits and disorders, findings on TPH2 gene expression have not only reinforced, but also provided new insights into, the long-recognized but not yet fully understood 5-HT-stress interaction. In this review, we summarize advances in TPH2 expression regulation and its relevance to the stress response and clinical implications. Particularly, based on findings on rhesus monkey TPH2 genetics and other relevant literature, we propose that: (i) upon activation of adrenal cortisol secretion, the cortisol surge induces TPH2 expression and de novo 5-HT synthesis; (ii) the induced 5-HT in turn inhibits cortisol secretion by modulating the adrenal sensitivity to ACTH via the suprachiasmatic nuclei (SCN)-SNS-adrenal system, such that it contributes to the feedback inhibition of cortisol production; (iii) basal TPH2 expression or 5-HT synthesis, as well as early-life experience, influence basal cortisol primarily via the hormonal HPA axis; and (iv) 5'- and 3'-regulatory polymorphisms of TPH2 may differentially influence the stress response, presumably due to their differential roles in gene expression regulation. Our increasing knowledge of TPH2 expression regulation not only helps us better understand the 5-HT-stress interaction and the pathophysiology of neuropsychiatric disorders, but also provides new strategies for the treatment of stress-associated diseases.


Crosstalk Between Vitamin D and p53 Signaling in Cancer: An Update.
It has now been convincingly shown that vitamin D and p53 signaling protect against spontaneous or carcinogen-induced malignant transformation of cells. The vitamin D receptor (VDR) and the p53/p63/p73 proteins (the p53 family hereafter) exert their effects as receptors/sensors that turn into transcriptional regulators upon stimulus. While the p53 clan, mostly in the nucleoplasm, responds to a large and still growing number of alterations in cellular homeostasis commonly referred to as stress, the nuclear VDR is transcriptionally activated after binding its naturally occurring biologically active ligand 1,25-dihydroxyvitamin D with high affinity. Interestingly, a crosstalk between vitamin D and p53 signaling has been demonstrated that occurs at different levels, has genome-wide implications, and is of high importance for many malignancies, including non-melanoma skin cancer. These interactions include the ability of p53 to upregulate skin pigmentation via POMC derivatives including alpha-MSH and ACTH. Increased pigmentation protects the skin against UV-induced DNA damage and skin photocarcinogenesis, but also inhibits cutaneous synthesis of vitamin D. A second level of interaction is characterized by binding of VDR and p53 protein, an observation that may be of relevance for the ability of 1,25-dihydroxyvitamin D to increase the survival of skin cells after UV irradiation. UV irradiation-surviving cells show significant reductions in thymine dimers in the presence of 1,25-dihydroxyvitamin D that are associated with increased nuclear p53 protein expression and significantly reduced NO products. A third level of interaction is documented by the ability of vitamin D compounds to regulate the expression of the murine double minute (MDM2) gene in dependence of the presence of wild-type p53. MDM2 has a well-established role as a key negative regulator of p53 activity. Finally, p53 and its family members have been implicated in the direct regulation of the VDR. This review gives an update on some of the implications of the crosstalk between vitamin D and p53 signaling for carcinogenesis in the skin and other tissues, focusing on a genome-wide perspective.


Characterization of methicillin resistant Staphylococcus aureus strains among inpatients and outpatients in a referral hospital in Tehran, Iran.
Methicillin resistant Staphylococcus aureus is one of the most common causes of a variety of infections ranging from wound infections to urinary tract infections (UTI) in hospital and community. In this study during 3 years we characterized the antibiotic resistance patterns of 491 hospital acquired MRSA and community associated MRSA strains by the guidelines of clinical and laboratory standard institute. A combination of high resolution PhP typing method and SCCmec typing were used for clonal dissemination of isolates. Among all 491 MRSA strains, diverse PhP types consisting of 29 common types (CTs) and 4 single types (STs) and also 2 different SCCmec types (III and IVa) were detected. In addition, 18 CTs were common among CA- and HA-MRSA strains and the presence of all 4 STs was limited to HA-MRSA strains. All isolates were resistant to penicillin and high level resistance was observed against ciprofloxacin, erythromycin, tobramycin and kanamycin and the rate of resistance to most of the antibiotic tested among HA-MRSA was significantly higher than CA-MRSA isolates. Moreover, all isolates showed susceptibility to linezolid, vancomycin and quinupristin-dalfopristin and very low resistance to fusidic acid, nitrofurantoin and chloramphenicol were detected. Our findings illustrated the increasing rate of clonal dissemination and persistence of highly antibiotic resistant CA-MRSA strains in Tehran hospitals, and also indicated the important role of the hospitals as the reservoir of MRSA strains.


Genome-wide analysis of acute leukemia and clonally related histiocytic sarcoma in a series of three pediatric patients.
Pediatric histiocytic sarcoma (HS) clonally related to anteceding leukemia is a rare malignancy with poor outcome. We performed a molecular characterization of HS and the corresponding leukemia by methylation arrays and whole-exome sequencing and found a variety of aberrations in both entities with deletions of CDKN2A/B as a recurrent finding. Furthermore, data from genome-wide mutation analysis from one patient allowed the reconstruction of a sequence of tumorigenesis of leukemia and HS lesions including the acquisition of a putatively activating KRAS frameshift deletion (p.A66fs). Our results provide an insight into the genetic landscape of pediatric HS clonally related to anteceding leukemia.


Identification and Quantitation of Malonic Acid Biomarkers of In-Born Error Metabolism by Targeted Metabolomics.
Malonic acid (MA), methylmalonic acid (MMA), and ethylmalonic acid (EMA) metabolites are implicated in various non-cancer disorders that are associated with inborn-error metabolism. In this study, we have slightly modified the published 3-nitrophenylhydrazine (3NPH) derivatization method and applied it to derivatize MA, MMA, and EMA to their hydrazone derivatives, which were amenable for liquid chromatography- mass spectrometry (LC-MS) quantitation. 3NPH was used to derivatize MA, MMA, and EMA, and multiple reaction monitoring (MRM) transitions of the corresponding derivatives were determined by product-ion experiments. Data normalization and absolute quantitation were achieved by using 3NPH derivatized isotopic labeled compounds 13C2-MA, MMA-D3, and EMA-D3. The detection limits were found to be at nanomolar concentrations and a good linearity was achieved from nanomolar to millimolar concentrations. As a proof of concept study, we have investigated the levels of malonic acids in mouse plasma with malonyl-CoA decarboxylase deficiency (MCD-D), and we have successfully applied 3NPH method to identify and quantitate all three malonic acids in wild type (WT) and MCD-D plasma with high accuracy. The results of this method were compared with that of underivatized malonic acid standards experiments that were performed using hydrophilic interaction liquid chromatography (HILIC)-MRM. Compared with HILIC method, 3NPH derivatization strategy was found to be very efficient to identify these molecules as it greatly improved the sensitivity, quantitation accuracy, as well as peak shape and resolution. Furthermore, there was no matrix effect in LC-MS analysis and the derivatized metabolites were found to be very stable for longer time. Graphical Abstract .


A modular molecular tweezer designed using CAVEAT.
A pair of water-soluble molecular tweezers designed using the computer program CAVEAT were prepared and their binding to an N-ethylquinolinium cation was demonstrated by 1H NMR spectroscopy.


Cryopolymerization-enabled self-wrinkled polyaniline-based hydrogels for highly stretchable all-in-one supercapacitors.
Conductive polymer hydrogels are attractive due to their combination of high theoretical capacitance, intrinsic electrical conductivity, fast ion transport, and high flexibility for supercapacitor electrodes. However, it is challenging to integrate conductive polymer hydrogels into an all-in-one supercapacitor (A-SC) simultaneously with large stretchability and superior energy density. Here, a self-wrinkled polyaniline (PANI)-based composite hydrogel (SPCH) with an electrolytic hydrogel and a PANI composite hydrogel as the core and sheath, respectively, was prepared through a stretching/cryopolymerization/releasing strategy. The self-wrinkled PANI-based hydrogel exhibited large stretchability (∼970%) and high fatigue resistance (∼100% retention of tensile strength after 1200 cycles at a 200% strain) ascribing to the formation of the self-wrinkled surfaces and the intrinsic stretchability of hydrogels. Upon cutting off the edge connections, the SPCH could directly work as an intrinsically stretchable A-SC maintaining high energy density (70 µW h cm-2) and stable electrochemical outputs under a stretchability of 500% strain and a full-scale bending of 180°. After 1000 cycles of 100% strain stretching and releasing processes, the A-SC device could deliver highly stable outputs with high capacitance retention of 92%. This study might provide a straightforward method for fabricating self-wrinkled conductive polymer-based hydrogels for A-SCs with highly deformation-tolerant energy storage.


Is Lipoprotein(a) Clinically Actionable with Today's Evidence? The Answer is Yes.
Lipoprotein(a) is an independent risk factor for cardiovascular disease. We review the ongoing shifts in consensus guidelines for the testing and management of Lp(a) and provide insight into whether current evidence suggests that awareness and testing of Lp(a) is clinically actionable. GWAS and Mendelian randomization studies have established causal links between elevated Lp(a) and forms of CVD, including CAD and calcific aortic valve disease. Testing of Lp(a) identifies patients with similar risk to that of heterozygous FH, enhances risk stratification in patients with borderline/intermediate risk as determined through traditional factors, and facilitates the assessment of inherited CVD risk through cascade screening in patients with known family history of elevated Lp(a). Reductions in Lp(a) through non-targeted therapies including PCSK9 inhibition and lipoprotein apheresis have demonstrated reductions in ASCVD risk that are likely attributable to lowering Lp(a). Targeted therapies to potently lower Lp(a) are in clinical development. Lp(a) is actionable, and can be used to identify high risk patients for primary prevention and their family members through cascade screening, and to guide intensification of therapy in primary and secondary prevention of ASCVD.


Short latency somatosensory evoked potentials in infants.
Short latency somatosensory evoked potentials (SEPs) to unilateral median nerve electrical stimulation were recorded from normal infants at birth and at 2, 4, 6, 8, 10 and 12 months of age. Three channels were recorded: Erb's point-Fz; C II (over 2nd cervical vertebra)-Fz; contralateral C' (2 cm posterior to C3 or C4)-Fz. Sweep time = 50 msec. At birth, the C II potential was seen in all infants; the Erb's point and C' potentials were seen in two-thirds. All older infants had well developed potentials at all sites. The mean latency of the Erb's point potential was stable over time. The latency of the C II potential decreased with maturation. At C', 4 components were seen, the latencies of which decreased with maturation: N1, P1, N2 and P2. The duration of N1 and P1 decreased with maturation. Standard deviations were relatively small for latencies and large for amplitudes. SEPs were adversely affected by using the 60 c/sec filter. Increasing the low frequency filter from 1 to 30 c/sec changed SEP, particularly in younger infants. Abnormal SEPs were seen in prematures surviving periventricular hemorrhage.


Amodiaquine-induced fulminant hepatitis.
Three patients suffered from fulminant hepatitis within 23, 59 and 22 weeks after having ingested a total dose of 16, 26 and 15 g, respectively, of amodiaquine for the prophylaxis of malaria. Amodiaquine administration was continued for 44, 21 and 25 days after the onset of jaundice, respectively. One patient underwent emergency orthotopic liver transplantation and survived. The other two died. Fulminant hepatitis threatens patients in whom amodiaquine administration is protracted for several months and not interrupted when jaundice occurs.


[Study on the high-affinity IgE receptor beta gene polymorphism and its association with the susceptibility to allergic asthma in Han nationality of Hubei province].
To determine whether 2 polymorphism sites of the high-affinity IgE receptor beta (Fc epsilon RI beta) gene were associated with allergic asthma in Han nationality of Hubei province in China. DNA and clinical data were obtained from allergic asthma patients and were compared with those from a group of healthy control subjects. The subjects were genotyped for the -109C/T and a coding variant Glu237Gly in Fc epsilon RI beta gene by polymerase chain reaction-restriction fragment length polymorphism. (1) The genotype frequencies were 0.403 for -109T/T, 0.491 for -109T/C and 0.106 for -109C/C in allergic asthma patients in a Chinese population. No significant difference in the distribution of -109C/T polymorphism was found between allergic asthma patients and healthy control subjects; however, a homozygosity for the -109T allele was associated with increased total plasma IgE levels in patients with allergic asthma (F=7.523, P<0.01). (2) The frequency of Gly237Gly genotype was 0.051 in patient group, and 0.020 in control group. The allele frequencies of Gly237 in the patients and control were 0.236 and 0.136 respectively. There was a significant association between Gly/Gly genotype and allergic asthma. Among allergic asthma patients Gly237Gly was significantly associated with high IgE. These data suggested that the Gly237Gly genotype of the Fc epsilon RI beta gene conferred genetic susceptibility to allergic asthma in Chinese, which affected the total plasma IgE levels in the allergic asthma patients. And a homozygosity for the -109T allele was associated with increased total plasma IgE.


rDNA subtypes and their transcriptional expression in zebrafish at different developmental stages.
Eukaryotic 18S, 5.8S and 28S rRNAs are processed from a single transcript transcribed from the 45S rDNA gene, which is normally tandemly arrayed over hundred copies in a genome. Recently, a maternal (M) subtype and a somatic (S) subtype of rDNA were identified in zebrafish, with M-subtype on chromosome 4 and S-subtype on chromosome 5. It appears that the M-subtype is only expressed in eggs whilst the expression of the S-subtype is coupled with the initiation of zygotic gene expression. In this report, we identified three novel but transcriptionally inactive 18S variants in zebrafish genome with chromosome location different from the M- and S-subtype, suggesting translocation of 18S rDNA fragment during zebrafish evolution. Furthermore, we confirmed that the unfertilized eggs only have the M-subtype transcripts while brain, heart and liver have only the S-subtype transcripts. Both the M- and S-subtype transcripts were detected in female gonad. Our results support that the expression of different subtypes of rDNA is differentially regulated to meet the requirement for 'specialized ribosomes' during different developmental stages.


Smooth Muscle Sirtuin 1 Blocks Thoracic Aortic Aneurysm/Dissection Development in Mice.
Advancing age is the major risk factor for thoracic aortic aneurysm/dissection (TAAD). However, the causative link between age-related molecules and TAAD remains elusive. Here, we investigated the role of Sirtuin 1 (SIRT1, also known as class III histone deacetylase), the best studied member of the longevity-related Sirtuin family, in TAAD development in vivo. We used male smooth muscle-specific SIRT1 transgenic (ST-Tg) mice, smooth muscle-specific SIRT1 knockout (ST-KO) mice, and their wild-type (WT) littermates on a C57BL/6J background to establish a TAAD model induced by oral administration of 3-aminopropionitrile fumarate (BAPN). We analyzed the incidence and fatality rates of TAAD in the groups. We examined matrix metallopeptidase 2 (MMP2) and MMP9 expression in aortas or cultured A7r5 cells via western blotting and real-time polymerase chain reaction (PCR). We performed chromatin immunoprecipitation (ChIP) to clarify the epigenetic mechanism of SIRT1-regulated MMP2 expression in vascular smooth muscle cells (VSMCs). BAPN treatment markedly increased the incidence of TAAD in WT mice but caused less disease in ST-Tg mice. Moreover, ST-KO mice had the highest BAPN-induced TAAD fatality rate of all the groups. Mechanistically, SIRT1 overexpression resulted in lower MMP2 and MMP9 expression after BAPN treatment in both mouse aortas and cultured A7r5 cells. The downregulation of BAPN-induced MMP2 expression by SIRT1 was mediated by deacetylation of histone H3 lysine 9 (H3K9) on the Mmp2 promoter in the A7r5 cells. Our findings suggest that SIRT1 expression in SMCs protects against TAAD and could be a novel therapeutic target for TAAD management.


Detoxification of oxalic acid by pseudomonas fluorescens strain pfMDU2: implications for the biological control of rice sheath blight caused by Rhizoctonia solani.
Rhizoctonia solani isolates varying in their virulence were tested for their ability to produce oxalic acid (OA) in vitro. The results indicated that the virulent isolates produced more OA than the less virulent isolates. In order to isolate OA-detoxifying strains of Pseudomonas fluorescens, rhizosphere soil of rice was drenched with 100 mM OA and fluorescent pseudomonads were isolated from the OA-amended soil by using King's medium B. These isolates were tested for their antagonistic effect towards growth of R. solani in vitro. Among them P. fluorescens PfMDU2 was the most effective in inhibiting the mycelial growth of R. solani. P. fluorescens PfMDU2 was capable of detoxifying OA and several proteins were detected in the culture filtrate of PfMDU2 when it was grown in medium containing OA. To investigate whether the gene(s) involved in OA-detoxification resides on the plasmids in P. fluorescens PfMDU2, a plasmid-deficient strain of P. fluorescens was generated by plasmid curing. The plasmid-deficient strain (PfMDU2P-) failed to grow in medium containing OA and did not inhibit the growth of R. solani. Both PfMDU2 and PfMDU2P- were tested for their efficacy in controlling sheath blight of rice under greenhouse conditions. Seed treatment followed by soil application of rice with P. fluorescens strain, PfMDU2, reduced the severity of sheath blight by 75% compared with the control, whereas PfMDU2P- failed to control sheath blight disease.


A randomised, phase II study of nintedanib or sunitinib in previously untreated patients with advanced renal cell cancer: 3-year results.
This exploratory study evaluated the safety/efficacy of nintedanib or sunitinib as first-line therapy in patients with advanced renal cell carcinoma (RCC). Ninety-six patients were randomised (2:1) to either nintedanib (200 mg twice daily) or sunitinib (50 mg kg(-1) once daily (4 weeks on treatment; 2 weeks off)). Primary endpoint was progression-free survival (PFS) at 9 months. P-values reported are descriptive only; the study was not powered for such comparisons. Progression-free survival at 9 months was comparable between nintedanib and sunitinib (43.1% vs 45.2%, respectively; P=0.85). Median PFS was 8.4 months in each group (hazard ratio (HR), 1.12; 95% confidence interval (CI): 0.70-1.80; P=0.64). Median overall survival was 20.4 and 21.2 months for nintedanib and sunitinib, respectively (HR, 0.92; 95% CI: 0.54-1.56; P=0.76). Overall incidence of any grade adverse events (AEs) was comparable (90.6% vs 93.8%); AEs grade ⩾ 3 were lower with nintedanib than sunitinib (48.4% vs 59.4%). Nintedanib was associated with lower incidences of some AEs typical of antiangiogenic tyrosine kinase inhibitors (TKIs): hypertension, hypothyroidism, hand-foot syndrome, cardiac disorders and haematological abnormalities. In patients with advanced RCC, nintedanib has promising efficacy and similar tolerability to sunitinib, and a manageable safety profile with fewer TKI-associated AEs.


Dextromethorphan as a novel nonopioid adjunctive agent for pain control with medication abortion: A randomized controlled trial.
To evaluate efficacy and satisfaction of dextromethorphan as a non-narcotic adjuvant to current analgesic regimens for medication abortion. We conducted a randomized, double-blinded, placebo-controlled trial. We randomized eligible participants (N = 156) 1:1 to adjunctively take dextromethorphan (loading dose 60 mg and two subsequent 30 mg doses at 2 and 5 hours after misoprostol administration) or placebo combined with usual-care nonsteroidal anti-inflammatory medications ± opioids for pain. Participants reported pain scores and satisfaction using a secure texting application at 2, 5, 8, and 24 hours after misoprostol administration. Our primary outcome was worst pain score and total analgesic use. Baseline demographics of enrolled participants were similar between randomization arms. Worst pain scores for participants receiving dextromethorphan versus placebo (8.0 vs 7.0, p = 0.06) did not differ. Total milligram usage of ibuprofen (800 mg vs 610 mg, p =.62), acetaminophen (1000 mg vs 1300 mg, p = 0.62), and opioids (10 mg vs 15 mg, p = 0.51) did not differ between the randomization groups. Participants randomized to placebo were significantly more likely to be satisfied with their pain control (91% vs 75%, p = 0.02). Dextromethorphan used adjunctively with standard analgesics did not reduce pain associated with medication abortion. Participants who received dextromethorphan reported decreased satisfaction with their pain control. Dextromethorphan used adjunctively with commonly used analgesic regimens did not reduce medication abortion associated pain. Many participants did not use analgesics as counseled, and nearly 25% used no analgesia during medication abortion.


Feasibility study and determination of prerequisites of telecare programme to enhance patient management in lung transplantation: a qualitative study from the perspective of Iranian healthcare providers.
Non-adherence to treatment plans, follow-up visits and healthcare advice is a common obstacle in the management of lung transplant patients. This study aims to investigate experts' views on the needs and main aspects of telecare programmes for lung transplantation. A qualitative study incorporating an inductive thematic analysis. Lung transplant clinic and thoracic research centre. Clinicians: four pulmonologists, two cardiothoracic surgeons, two general physicians, two pharmacotherapists, one cardiologist, one nurse and one medical informatician. This study adopted a focus group discussion technique to gather experts' opinions on the prerequisites and features of a telecare programme in lung transplantation. All interviews were coded and combined into main categories and themes. Thematic analysis was performed to extract the key concepts using ATLAS.Ti. Ultimately, all extracted themes were integrated to devise a conceptual model. Ten focus groups with 13 participants were conducted. Forty-six themes and subthemes were extracted through the thematic analysis. The main features of the final programme were extracted from expert opinions through thematic analysis, such as continuous monitoring of symptoms, drug management, providing a specific care plan for each patient, educating patients module, creating an electronic medical record to collect patient information, equipping the system with decision support tools, smart electronic prescription and the ability to send messages to the care team. The prerequisites of the system were summarised in self-care activities, clinician's tasks and required technologies. In addition, the barriers and benefits of using a telecare system to enhance the quality of care were determined. Our investigation recognised the main factors that must be considered to design a telecare programme to provide ideal continuous care for lung transplant patients. Users should further explore the proposed model to support the development of telecare interventions at the point of care.


Identification of molecular recognition of Langmuir-Blodgett monolayers using surface-enhanced Raman scattering spectroscopy.
A facile and effective approach for SERS identification of molecular recognition in Langmuir-Blodgett monolayers on smooth substrates was developed by spreading Ag nanoparticles on ordered alkyl chains in the monolayers, which acted as a spacer layer to separate analytes of interest from direct contact with active substrates.


In vitro antioxidant and anti-inflammatory activities of Jaceosidin from Artemisia princeps Pampanini cv. Sajabal.
Oxidized low-density lipoprotein (oxLDL) plays a key role in the inflammatory processes of atherosclerosis. Jaceosidin isolated from the methanolic extracts of the aerial parts of Artemisia princeps Pampanini cv. Sajabal was tested for antioxidant and anti-inflammatory activities. Jaceosidin inhibited the Cu(2+)-mediated LDL oxidation with IC(50) values of 10.2 microM in the thiobarbituric acid-reactive substances (TBARS) assay as well as the macrophage-mediated LDL oxidation. The antioxidant activities of jaceosidin were exhibited in the conjugated diene production, relative electrophoretic mobility, and apoB-100 fragmentation on copper-mediated LDL oxidation. Jaceosidin also inhibited the generation of reactive oxygen species (ROS) concerning in regulation of NF-kappaB signaling. And jaceosidin inhibited nuclear factor-kappa B (NF-kappaB) activity, nitric oxide (NO) production, and suppressed expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages.


Standardization of 152Eu.
152Eu was standardized within the frame of a BIPM international comparison. The solution was prepared and bottled by PTB. The ampoules were measured at BIPM in the SIR ionization chambers and then dispatched to the participating laboratories. In the Radionuclide Metrology Laboratory of IFIN-HH, the solution was standardized using a coincidence method with "beta-efficiency extrapolation" by foil absorption. A simple 4pi beta-gamma-coincidence system was used, with NaI(Tl) and 4piPC detectors. No significant impurities were found apart for 0.5% 154Eu. To obtain linear extrapolation plots, a "gamma-window" of 180-1500 keV was chosen. Dead-times of 10 micros were used. A combined uncertainty of 0.24% was obtained, mainly from the extrapolation procedure component.


Potential of right to left ventricular volume ratio measured on chest CT for the prediction of pulmonary hypertension: correlation with pulmonary arterial systolic pressure estimated by echocardiography.
To investigate the correlation of right ventricular (RV) to left ventricular (LV) volume ratio measured by chest CT with pulmonary arterial systolic pressure (PASP) estimated by echocardiography. 104 patients (72.47 ± 13.64 years; 39 male) who had undergone chest CT and echocardiography were divided into two groups (hypertensive and normotensive) based upon an echocardiography-derived PASP of 25 mmHg. RV to LV volume ratios (RV(V)/LV(V)) were calculated. RV(V)/LV(V) was then correlated with PASP using regression analysis. The Area Under the Curve (AUC) for predicting pulmonary hypertension on chest CT was calculated. In the hypertensive group, the mean PASP was 46.29 ± 14.42 mmHg (29-98 mmHg) and there was strong correlation between the RV(V)/LV(V) and PASP (R = 0.82, p < 0.001). The intraobserver and interobserver correlation coefficients for RV(V)/LV(V) were 0.990 and 0.892. RV(V)/LV(V) was 1.01 ± 0.44 (0.51-2.77) in the hypertensive and 0.72 ± 0.14 (0.52-1.11) in the normotensive group (P <0.05). With 0.9 as the cutoff for RV(V)/LV(V), sensitivity and specificity for predicting pulmonary hypertension over 40 mmHg were 79.5 % and 90 %, respectively. The AUC for predicting pulmonary hypertension was 0.87 RV/LV volume ratios on chest CT correlate well with PASP estimated by echocardiography and can be used to predict pulmonary hypertension over 40 mmHg with high sensitivity and specificity.


Latent tuberculosis infection in transplant candidates: a systematic review and meta-analysis on TST and IGRA.
The diagnostic accuracy of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST) for latent tuberculosis infection (LTBI) in transplant candidates is uncertain. Pubmed, Embase and Cochrane library were searched to identify relevant studies. Quality of included studies was assessed with RevMan5 software (via GUADAS2 checklist). Accuracy measures of IGRAs and TST assays (sensitivity, specificity and others) were pooled with random effects model. Data were analyzed by STATA and Meta-DiSc. Twenty-eight studies were selected for full review, and 16 were included in the final analysis. The pooled sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) for TST were 46% [95% confidence interval (CI) 38-54%], 86% (95% CI 75-93%), 46.3% (95% CI 40-52), 88.7% (95% CI 87-89), 3.3 (95% CI 1.6-6.4), 0.63 (95% CI 0.52-0.77) and 5 (95% CI 2-12), respectively. For QFT-G, the pooled sensitivity, specificity, PPV, NPV, PLR, NLR, and DOR were 58% (95% CI 41-73%), 89% (95% CI 77-95%), 72.7% (95% CI 68-76), 80.6% (95% CI 78-82), 5.3 (95% CI 2.0-14.0), 0.47 (95% CI 0.30-0.75) and 11 (95% CI 3-46), respectively. Likewise, for T-SPOT.TB, the pooled sensitivity, specificity, PPV, NPV, PLR, NLR, and DOR were 55% (95% CI 40-70%), 92% (95% CI 87-95%), 60.4% (95% CI 47-72), 90.2% (95% CI 86-92), 6.7 (95% CI 4.0-11.1), 0.52 (95% CI 0.31-0.85) and 16 (95% CI 7-37), respectively. IGRAs were more sensitive and specific than the TST with regard to the diagnosis of LTBI in the transplant candidates. They have added value and can be complementary to TST.


The role of the CRISPR-Cas system in cancer drug development: Mechanisms of action and therapy.
The recent emergence of gene editing using Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated system (Cas) tools and advances in genomics and proteomics has revolutionized drug discovery and personalized medicine. The CRISPR-Cas system has enabled gene and cell-based therapies, screening for novel drug targets, a new generation of disease models, elucidation of drug resistance mechanisms, and drug efficacy testing. Here, we summarized recent investigations and strategies involved in cancer-related drug discovery using the CRISPR-Cas system. CRISPR-Cas-mediated gene editing has shown great potential in the development of next generation drugs for treatment of Mendelian disorders and various cancer types. In this review, we focused on the impact of the CRISPR-Cas system in drug discovery and its application to biomarker identification and validation, high-end target genes, and breakthrough anticancer cell therapies. We also highlighted the role of CRISPR-Cas in precision disease modeling and functional drug screening.


Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor.
Human cannabinoid type 1 (CB1) G-protein coupled receptor is a potential therapeutic target for obesity. The previously predicted and experimentally validated ensemble of ligand-free conformations of CB1 [Scott, C. E. et al. Protein Sci. 2013 , 22 , 101 - 113 ; Ahn, K. H. et al. Proteins 2013 , 81 , 1304 - 1317] are used here to predict the binding sites for known CB1-selective inverse agonists including rimonabant and its seven known derivatives. This binding pocket, which differs significantly from previously published models, is used to identify 16 novel compounds expected to be CB1 inverse agonists by exploiting potential new interactions. We show experimentally that two of these compounds exhibit inverse agonist properties including inhibition of basal and agonist-induced G-protein coupling activity, as well as an enhanced level of CB1 cell surface localization. This demonstrates the utility of using the predicted binding sites for an ensemble of CB1 receptor structures for designing new CB1 inverse agonists.


Radiation induced height impairment in pediatric Hodgkin's disease.
To quantitate the impairment in skeletal growth from radiation treatment, we reviewed height measurements among children with Hodgkin's disease irradiated at Stanford University Medical Center between 1965 and 1986. One hundred and twenty-four children with Hodgkin's disease, in whom long-term follow-up data were available, became the subjects for this analysis. They all had baseline height measurements within 1 year of radiation treatment, a final height measurement beyond age 15 for boys and 13 for girls, and a minimum time interval between baseline and final measurement of 2 years. A baseline and final percent height, as compared to a reference standard, was calculated for each patient. The difference between these two figures was used to assess height impairment. The study group was divided into age and treatment groups and a comparative analysis between these groups was performed. Height impairment was most severe among children who were given high dose radiation to the entire spine when pre-pubertal in age. These patients demonstrated a 7.7% (p < 0.0001) average height impairment, which equates to a height loss of 13 cm or two standard deviations of the U.S. population mean. Pubertal and post-pubertal patients given similar heavy treatment as well as pre-pubertal patients given light treatment also demonstrated some impairment of skeletal growth, however, the loss was not deemed clinically significant. Comparison of standing versus sitting height impairment did not show evidence of disproportionate final growth impairment. Treatment regimens that use low doses of radiation for pediatric Hodgkin's disease are thus not associated with clinically significant impairment of skeletal growth, as measured by standing and sitting heights.


Some studies of the oedematogenic action of the venom of funnel-web spiders (Atrax species).
The ability of the venoms of Atrax infensus and two other funnel-web spider species to induce oedema in rats was investigated and it was found that all Atrax venoms tested caused strong Evans blue leakage from adjacent blood vessels when injected subcutaneously. This dye leakage did not diminish significantly either when the neurotoxin in the venom was first neutralized by pre-mixing with a rat serum protein preparation or when the sensory nerves supplying an area of skin were severed 4 days prior to its envenomation. The pattern and speed of Evans blue extravasation caused by female A. infensus venom resembled that for histamine and for 5-hydroxytryptamine, and pretreatment with an antihistamine-antiserotonin mixture caused essentially complete blockade of the oedematogenic action of this venom, although neither inhibitory drug was very effective when used individually. It was concluded that this venom induces local oedema in rats mainly by causing mast cell degranulation. In confirmation of this, the mast cells in the rat skull periosteal membranes were found to be extensively degranulated by exposure to the venom. Surprisingly, whole-rat envenomation, using very large doses of venom, produced little dye leakage even though obvious symptoms of neurotoxic action were observed.


Thyrotropin-releasing hormone release is enhanced in hippocampal slices after electroconvulsive shock.
Hippocampal thyrotropin-releasing hormone (TRH) release was examined after seizures were induced by electroconvulsive shock (ECS). Rat hippocampal slices taken 12, 24, or 48 h after 3 days of alternate-day ECS treatment or sham-ECS treatment were stimulated with potassium with or without calcium in a superfusion system containing in-line charcoal adsorbent to concentrate TRH. Released TRH and tissue TRH were measured by radioimmunoassay. The TRH content of hippocampal slices was increased fivefold over sham-ECS levels 12, 24, and 48 h after ECS, but this was not associated with an increase in basal TRH release. Potassium-stimulated TRH release was significantly elevated over basal release 12, 24, and 48 h after ECS. Potassium-stimulated calcium-dependent TRH release increased linearly after ECS, reaching its highest level 48 h after seizure. Thus, although enhanced calcium-dependent TRH release was associated with elevated tissue levels, this relationship was not proportional in that tissue TRH was elevated to the same extent at all times after ECS, whereas potassium-evoked calcium-dependent TRH release increased gradually over time after seizure. These results suggest that postictal elevations in TRH are associated with an enhanced capacity for release that develops as a result of a time-dependent shift of TRH from a storage compartment ot a readily releasable pool. The observed elevation in stimulated TRH release may be relevant to seizure-induced modulation of TRH receptors in vivo.


Hepatitis E and pregnancy: current state.
Hepatitis E virus (HEV) is responsible for more than 50% of acute viral hepatitis cases in endemic countries. Approximately 2 billion individuals live in hepatitis E-endemic areas and, therefore, are at risk of infection. According to World Health Organization, HEV causes about 20.1 million infections and 70 000 deaths every year. In developing countries with poor sanitation, this disease is transmitted through contaminated water and is associated with large outbreaks, affecting hundreds or thousands of people. In developed countries, autochthonous cases of HEV have been increasingly recognized in the past several years. Hepatitis E virus typically causes an acute, self-limiting illness similar to other acute viral hepatitis, such as hepatitis A or B, with about 0.2% to 1% mortality rate in the general population. However, the course of hepatitis E in pregnancy is different than the mild self-constraining infection described in other populations. During pregnancy, HEV infection can take a fulminant course, resulting in fulminant hepatic failure, membrane rupture, spontaneous abortions, and stillbirths. Studies from various developing countries have shown a high incidence of HEV infection in pregnancy with a significant proportion of pregnant women progressing to fulminant hepatitis with a fatality rate of up to 30%. The present review will highlight new aspects of the HEV infection and pregnancy.


A surgical approach to lymphedema.
An approach to the management of lymphedema of the extremity is described. Current surgical procedures for this condition are evaluated and it is emphasized that no cure for this difficult problem exists. Available data indicate that physiologically designed procedures which attempt to reconstruct lymph flow are unsuccessful. Currently, subcutaneous excision beneath skin flaps is the most desirable procedure.


CXT: a programme for analysis of linear dynamic systems in the frequency domain.
In this paper, the computer programme CXT (CompleX Tools for Linear Dynamic System Analysis), using the frequency response method, is described and exemplified. The method is based on the approximation of the frequency response of the linear or linearised dynamic system, measured or calculated from input-output measurements, by the frequency model of the system transfer function in the form of the ratio of two frequency-dependent polynomials. The form of the programme is sufficiently general to permit application in many areas, e.g., in modelling linear or linearised dynamic biological systems consisting of several subsystems arranged in serial and/or parallel fashion, with or without time delays. The programme is a menu-driven software taking data from a keyboard or disk file to produce outputs on a screen, printer, or disk file in tables and plots. The programme can run interactively or in an automatic tutorial mode, under DOS and/or WINDOWS. Numerical examples are taken from pharmacokinetics and indocyanine green liver function tests.


Noninvasive Evaluation of Varying Pulse Pressures in vivo Using Brachial Sphymomanometry, Applanation Tonometry, and Pulse Wave Ultrasound Manometry.
The routine assessment and monitoring of hypertension may benefit from the evaluation of arterial pulse pressure (PP) at more central locations (e.g. the aorta) rather solely at the brachial artery. Pulse Wave Ultrasound Manometry (PWUM) was previously developed by our group to provide direct, noninvasive aortic PP measurements using ultrasound elasticity imaging. Using PWUM, radial applanation tonometry, and brachial sphygmomanometry, this study investigated the feasibility of noninvasively obtaining direct PP measurements at multiple arterial locations in normotensive, pre-hypertensive, and hypertensive human subjects. Two-way ANOVA indicated a significantly higher aortic PP in the hypertensive subjects, while radial and brachial PP were not significantly different among the subject groups. No strong correlation (r2 < 0.45) was observed between aortic and radial/brachial PP in normal and pre-hypertensive subjects, suggesting that increases in PP throughout the arterial tree may not be uniform in relatively compliant arteries. However, there was a relatively strong positive correlation between aortic PP and both radial and brachial PP in hypertensive subjects (r2 = 0.68 and 0.87, respectively). PWUM provides a low-cost, non-invasive, and direct means of measuring the pulse pressure in large central arteries such as the aorta. When used in conjunction with peripheral measurement devices, PWUM allows for the routine screening of hypertension and monitoring of BP-lowering drugs based on the PP from multiple arterial sites.


Cross-trait assortative mating is widespread and inflates genetic correlation estimates.
The observation of genetic correlations between disparate human traits has been interpreted as evidence of widespread pleiotropy. Here, we introduce cross-trait assortative mating (xAM) as an alternative explanation. We observe that xAM affects many phenotypes and that phenotypic cross-mate correlation estimates are strongly associated with genetic correlation estimates (R2=74%). We demonstrate that existing xAM plausibly accounts for substantial fractions of genetic correlation estimates and that previously reported genetic correlation estimates between some pairs of psychiatric disorders are congruent with xAM alone. Finally, we provide evidence for a history of xAM at the genetic level using cross-trait even/odd chromosome polygenic score correlations. Together, our results demonstrate that previous reports have likely overestimated the true genetic similarity between many phenotypes.


Fate and transport of atorvastatin and simvastatin drugs during conventional wastewater treatment.
This research investigates the environmental behavior of two widely prescribed cholesterol-lowering statin drugs that are expected to be present at significant concentrations in wastewater influents, namely: atorvastatin and simvastatin. Batch biodegradation experiments suggest that both statins are well degraded during secondary treatment, and removal rates exhibit a substrate-enhancement model reflecting elements of both first-order behavior and cometabolism. Resulting biodegradation parameters are used in conjunction with literature sorption parameters to construct a mass-balance model of statin concentrations during conventional treatment. Model results exhibit excellent accuracy compared to measurements from a medium-sized WWTP in the Southeastern USA. Influent concentrations of 1.56 μg L(-1) and 1.23 μg L(-1) were measured for atorvastatin and simvastatin. Results also suggest that 85-90% of each drug is removed during conventional treatment, with sorption accounting for less than 10% of overall removal. Expected effluent concentrations are orders of magnitude less than previously reported ecotoxicity thresholds for both drugs. Overall, results suggest statin active ingredients do not pose a significant environmental threat. It is recommended that future work characterize the fate of statin metabolites and that the same mass-balance modeling approach be used to assess other highly-prescribed pharmaceutical drugs.


Purification of human protease nexin.
Addition of several arginine-specific serine proteases to culture medium conditioned by fibroblasts results in the proteases being taken into sodium dodecyl sulfate-stable complexes with a secreted factor termed protease nexin (PN) (Baker, J. B., Low, D. A., Simmer, R. L., and Cunningham, D. D. (1980) Cell 21, 37-45). PN not only inhibits these degradative enzymes but also mediates their binding, internalization, and degradation by the cells (Low, D. A., Baker, J. B., Koonce, W. C., and Cunningham, D. D. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 2340-2344). Here we describe a simple procedure for purifying milligram quantities of PN from serum-free medium conditioned by human foreskin cells. Accumulation of PN in the medium is increased by using high density microcarrier cultures supplemented with epidermal growth factor and bovine serum albumin. Application of ultrafiltration-concentrated medium to a heparin-Sepharose column followed by extensive washing of the column with buffer containing 0.2 M NaCl and elution with buffer containing 1.0 M NaCl results in the recovery of 60-90% of the input PN in a form that is 90-97% pure. This preparation can be further purified by hydrophobic chromatography on octyl-agarose. Purified PN has a molecular mass of approximately 51 kilodaltons. On nonequilibrium pH gradient electrophoresis it migrates as five bands with isoelectric points between 7.5 and 7.8. Purified PN exhibits all the properties attributed to PN in culture medium. These include: 1) formation of sodium dodecyl sulfate-stable complexes with thrombin, urokinase, and plasmin; 2) inhibition of protease activity; 3) heparin-enhanced inhibition of thrombin; and 4) cellular binding of protease-PN complexes in a heparin-sensitive reaction. When thrombin-PN complexes are dissociated with 1 M hydroxylamine a smaller form of PN (approximately 46 kilodaltons) is detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, indicating that the complexed PN is proteolytically modified.


Inositol supplementation in respiratory distress syndrome.
According to preliminary results inositol (INO) is an important nutrient to immature preterm infants (J Pediatr 1987; 110:604). However, it is absent in nutrition of critically ill very low birth weight infants. In a present randomized double blind trial INO or glucose (70-100 mg/kg/day) was given to altogether 230 preterm infants (gestation 24 to 31 w, mean 27.8 w, mean BW 1,106 g) with RDS during 5 neonatal days. Two more courses during the first month were given, if the infant remained respirator-dependent and did not tolerate breast milk. INO-supplemented infants tended to have a milder respiratory course during the first week than those on glucose. The surviving INO-treated infants had a lower incidence of bronchopulmonary dysplasia (BPD) than the controls (p less than 0.01). No infant receiving INO had severe retinopathy (gr 4), whereas of the surviving placebo treated infants 8.8% became blind (p less than 0.005). Inositol promotes endothelial cell growth, enhances glucocorticoid-mediated lung epithelial cell differentiation, and may serve as an antioxidant. INO should be seriously considered as a nutrient during compromised neonatal transition of very low birth weight infants.


Morphological and functional changes in the tight junctions of the bile canaliculi induced by bile duct ligation.
Thin sections after bile duct ligation showed that the depth of tight junctions appeared to increase and that the distance between individual punctate contacts appeared to become irregular and wider than in controls. The freeze fracture replicas clearly demonstrated these changes in the tight junction morphology. Changes were noted most conspicuously in the tight junction three weeks after ligation. Measurements of the junctional morphology in control and ligated specimens showed that the junctional depth had increased two fold in the latter, whereas the number of strands had scarcely changed. Lanthanum tracer experiments showed that the tight junctions did not permit the passage of the tracer in normal nor ligated rats. It was concluded that the mechanism of obstructive jaundice could not be related to changes in junctional morphology causing increased junctional permeability.


Use of liquid concentrated growth factor in the management of necrotic tissue after facial vascular complications induced by hyaluronic acid injection.
HA fillers may induce facial vascular embolism. The resulting tissue ischemia and necrosis are severe iatrogenic complications for which no effective treatments are available. This single-center case series studied the use of liquid CGF in the management of facial tissue necrosis due to HA injection. All 12 patients with facial tissue necrosis (2 mild, 3 moderate, 7 severe) were previously treated with hyaluronidase injection in outside hospitals. They received a routine injection of hyaluronidase (dose of 400-1500 U) at the site of ischemia immediately after admission to the authors' hospital, but CGF was also injected. CGF injection was repeated once weekly until wound healing. Efficacy was assessed at 4 weeks (mean, 24.08 days). No patient experienced wound expansion or aggravation or infection at the sites of necrosis. A complete healing rate of 91.67% was noted at the 4-week follow-up. No scarring was evident in patients with mild to moderate necrosis. Those with moderate necrosis exhibited varied degrees of scarring after recovery, and scarring was evident in those with severe necrosis. No severe adverse effects occurred. CGF promoted the healing of ischemic and necrotic tissue wounds induced by facial vascular embolism following injection of HA fillers. CGF should be considered as a nonsurgical treatment method for vascular embolism following HA filler injection.


Multiple mutations in the aglycone binding pocket to convert the substrate specificity of dalcochinase to linamarase.
Dalcochinase from Dalbergia cochinchinensis Pierre and linamarase from Manihot esculenta Crantz are β-glucosidases which share 47% sequence identity, but show distinct substrate specificities in hydrolysis and transglucosylation. Previously, three amino acid residues of dalcochinase, namely I185, N189 and V255, were identified as being important for determining substrate specificity. In this study, kinetic analysis of the ensuing double and triple mutants of dalcochinase showed that only those containing the 185A mutation could appreciably hydrolyze linamarin as well as transfer glucose to 2-methyl-2-propanol. So, the space provided by the I185A mutation appeared to be a prerequisite for accommodation of the aglycone moiety containing three substituents at the carbinol carbon. However, quantitative analysis of the energy parameters revealed mostly antagonistic interactions between these mutations. In addition, the N189F mutant showed a potential for use in enzymatic synthesis of alkyl glucosides via transglucosylation and reverse hydrolysis reactions. Thus, substitution of only 2-3 key residues in the aglycone binding pocket of dalcochinase could convert its specificities to that of linamarase, as well as to be suitable for any chosen hydrolytic or synthetic applications.


Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Piragliatin, a Glucokinase Activator, and Glyburide, a Sulfonylurea, in Type 2 Diabetic Patients.
A glucokinase activator and a sulfonylurea might be coprescribed to synergize treatment success for type 2 diabetes (T2D). This clinical pharmacology study was designed to investigate the potential glucose-lowering effect or pharmacodynamic (PD), pharmacokinetic (PK), and safety/tolerability interactions between piragliatin and glyburide in T2D patients already taking glyburide but not adequately controlled. This was an open-label, multiple-dose, 3-period, single-sequence crossover design: on days -1, 6, and 12, PD and PK samples were drawn with glyburide alone (period 0), piragliatin + glyburide (period 1), and piragliatin alone (period 2) treatments. The glucose-lowering effect, including fasting plasma glucose (FPG), of piragliatin was more pronounced when it was administered concomitantly with glyburide as compared to piragliatin or glyburide administered alone. However, this enhancement cannot be explained by a potential PK interaction between piragliatin and glyburide. Other than hypoglycemia, there were no clinically relevant safety findings. Thus, the enhanced PD effect warrants further investigation to define the optimal dose combination between glucokinase activators and sulfonylureas with regard to efficacy, safety, and tolerability.


Extracranial metastases of high-grade glioma: the clinical characteristics and mechanism.
This presentation of two cases and literature review discusses the epidemiology, clinical manifestations, pathogenesis, diagnosis, treatment, and prognosis of high-grade glioma with extracranial metastases. A retrospective analysis of the clinical features of two cases of malignant glioma, including metastatic sites, pathological data, and treatment methods, and a literature review was performed. Two patients developed extracranial metastases within 1 year after surgery for primary glioma. One patient developed cervical lymph node and bone metastases while the other developed bone metastases, and both patients died within 2 months after the diagnosis of the extracranial metastasis. Extracranial metastases may develop from malignant gliomas. According to the literature, the most common extracranial site is intraspinal (along the neural axis), followed by the vertebrae, lungs, liver, and lymph nodes. The complex metastatic mechanism remains unclear, and the prognosis is very poor, with a survival duration of less than 6 months.


Fairness and generalisability in deep learning of retinopathy of prematurity screening algorithms: a literature review.
Retinopathy of prematurity (ROP) is a vasoproliferative disease responsible for more than 30 000 blind children worldwide. Its diagnosis and treatment are challenging due to the lack of specialists, divergent diagnostic concordance and variation in classification standards. While artificial intelligence (AI) can address the shortage of professionals and provide more cost-effective management, its development needs fairness, generalisability and bias controls prior to deployment to avoid producing harmful unpredictable results. This review aims to compare AI and ROP study's characteristics, fairness and generalisability efforts. Our review yielded 220 articles, of which 18 were included after full-text assessment. The articles were classified into ROP severity grading, plus detection, detecting treatment requiring, ROP prediction and detection of retinal zones. All the article's authors and included patients are from middle-income and high-income countries, with no low-income countries, South America, Australia and Africa Continents representation.Code is available in two articles and in one on request, while data are not available in any article. 88.9% of the studies use the same retinal camera. In two articles, patients' sex was described, but none applied a bias control in their models. The reviewed articles included 180 228 images and reported good metrics, but fairness, generalisability and bias control remained limited. Reproducibility is also a critical limitation, with few articles sharing codes and none sharing data. Fair and generalisable ROP and AI studies are needed that include diverse datasets, data and code sharing, collaborative research, and bias control to avoid unpredictable and harmful deployments.


Associations between social integration, participation and productivity loss among persons with chronic pain: a registry based cross sectional study.
To examine associations between factors of social inclusion and participation and productivity loss in employed persons with chronic pain, assessed for an interprofessional pain rehabilitation programme. We hypothesized that factors of social inclusion and participation and work related social factors are significantly associated with productivity when experiencing chronic pain and we expected a moderate effect. Cross-sectional study using data collected prospectively in an interprofessional patient registry for chronic pain. The primary end point was productivity loss, measured with the iMTA Productivity Costs Questionnaire. We included data from 161 individuals. To be included, persons had to be 18 years old or older, in paid work, and had to have a medical diagnosis of chronic pain syndrome with actual or potential tissue damage. In addition, participants had to have indicators of significant impairments in psychosocial functions. Linear regression analysis showed that a highly stressful professional situation, frequent problems regarding the compatibility of the family and job and not being Swiss were associated with a significantly higher total productivity loss. Similar results were found for productivity loss in paid work. However, problems concerning the compatibility of the family and job did not reach the significance level for productivity loss in paid work. The results of this study underscore the importance of factors of social inclusion and participation for interprofessional rehabilitation programmes to manage chronic pain especially when focussing on productivity loss.


Peroxidase-like Activity of Metal-Organic Framework [Cu(PDA)(DMF)] and Its Application for Colorimetric Detection of Dopamine.
A metal-organic framework (MOF) [Cu(PDA)(DMF)] was synthesized under mild mixed solvothermal conditions. It is constructed by 1,10-phenanthroline-2,9-dicarboxylic acid (H2PDA) and Cu2+ ions. The complex exhibits high peroxidase-like activity and can catalytically oxidize the colorless substrate 3,3',5,5'-tetramethylbenzidine to a blue product in the presence of H2O2. However, the peroxidase-like activity of [Cu(PDA)(DMF)] can be potently inhibited in the presence of dopamine. Based on this phenomenon, the colorimetric detection of dopamine was demonstrated with good selectivity and high sensitivity. [Cu(PDA)(DMF)] showed good stability and robust catalytic activity, which has been employed in the detection of dopamine in human urine and pharmaceutical samples.


Feasibility of Automated Three-Dimensional Rotational Mechanics by Real-Time Volume Transthoracic Echocardiography: Preliminary Accuracy and Reproducibility Data Compared with Cardiovascular Magnetic Resonance.
Three-dimensional (3D) speckle-tracking echocardiography (STE) for myocardial strain imaging may be superior to two-dimensional STE, especially with respect to rotational mechanics. Automated strain measurements from nonstitched 3D STE may improve work flow and clinical utility. The aim of this study was to test the feasibility of model-based 3D STE for the automated measurement of voxel circumferential strain (Ecc) and myocardial rotation. Thirty-five individuals (12 healthy volunteers, 12 patients with dilated cardiomyopathy, and 11 patients with hypertensive left ventricular [LV] hypertrophy) were prospectively studied. The latter two groups did not have significant coronary artery disease on coronary arteriography. Tagged cardiovascular magnetic resonance (CMR) and feature-tracking CMR were used as reference standards. Regional (apex and mid left ventricle) and slice (within a region) Ecc and rotation were measured by real-time volume transthoracic echocardiography (nonstitched) using an automated algorithm. Compared with both CMR techniques, apical and mid-LV Ecc (concordance correlation coefficients [CCCs], 0.84-0.95 and 0.48-0.68) and rotation (CCCs, 0.70-0.95 and 0.42-0.68) showed excellent, good, and moderate agreement, respectively. At the LV base, rotation showed poor agreement with CMR methods (CCC, 0.04-0.21), consistent with previous descriptions, but calculated LV twist showed moderate to good correlation with CMR techniques (CCC, 0.61-0.84). However, the 95% CI for measurements between techniques was wide, emphasizing the challenges in comparing voxel deformation by 3D echocardiography with CMR, compounded by differences in approaches to measuring deformation, and matching regional and slice measurements between techniques. Reproducibility (n = 10, including test-retest variability) of automated 3D strain and rotation measurements was good to excellent (coefficient of variation < 10%) and was comparable with that of CMR methods (coefficient of variation < 10%) in the same patients. The data from this study show that automated measurements of voxel rotational mechanics by real-time volume transthoracic echocardiography is feasible and comparable with tagged CMR and feature-tracking CMR strain measurements, albeit with wide limits of agreement, emphasizing the differences between the modalities. Furthermore, this automated 3D speckle-tracking echocardiographic approach shows excellent reproducibility, including test-retest variability, comparable with that of the CMR methods.