FSH and ovarian response: spontaneous recovery of pituitary-ovarian activity during the pill-free period vs. exogenous recombinant FSH during high-dose combined oral contraceptives.
Compare spontaneous recovery of pituitary-ovarian activity during the pill-free period following the correct use of low-dose oral contraceptives and subsequent ovarian function during the administration of exogenous recombinant FSH (recFSH) after switching to continued Lyndiol (2.5 mg lynestrenol + 0.05 mg ethinyl-oestradiol) medication. Prospective, randomized, group-comparative, single-centre study. Following the monitoring of the pill-free period (week 1) and subsequent treatment with Lyndiol (for a total of 5 weeks), all subjects were randomly allocated to one of four groups receiving daily FSH injections for 1 week [75, 150, 225 IU recFSH or 150 IU purified urinary FSH (uFSH)] during the fourth week of Lyndiol use. Thirty-six healthy volunteers aged 18-39 years, prestudy oral contraceptive use for at least 3 months, cycle length between 24 and 35 days. Serum FSH, LH and oestradiol (E2) concentrations as well as transvaginal ultrasound assessment of the number and diameter of follicles > 2 mm were used to monitor pituitary ovarian function. At the start of the pill-free period following the prestudy contraceptive medication, 67% of the women presented with LH and FSH levels < 1 IU/l and only one follicle > 10 mm was observed. Initial levels of LH and FSH correlated (P < 0.05) with the extent of pituitary-ovarian activity during the pill-free period. At the end of the pill-free period a follicle > 10 mm had emerged in one subject only. During the first 3 days of Lyndiol use, seven women (19%) eventually showed at least one follicle > 10 mm. During combined exogenous FSH and Lyndiol administration, LH levels remained completely suppressed (< or = 0.5 IU/l) in all women studied. FSH levels and number and size of follicles increased with increasing doses of exogenous FSH in a dose-dependent manner. E2 levels remained low in all groups (< 150 pmol/l). During the week following FSH administration, FSH levels and E2 levels decreased gradually while the number of follicles > 10 mm still increased. We have confirmed that dominant follicles > 10 mm are present at the end of the pill-free period and during the first days after resumption of pill intake. Once follicles > 10 mm arose at the end of the pill-free period, continued use of Lyndiol did not reduce follicle diameters. One week of Lyndiol reduces pituitary-ovarian activity to levels observed after 3 weeks of low-dose pills. FSH administration during Lyndiol resulted in dose-dependent follicle growth despite extremely low LH levels. E2 secretion (56 +/- 51 pmol/l) occurred to a limited and variable extent along with extremely low serum LH concentrations. Recovery of pituitary-ovarian activity at the end of the pill-free period is comparable to FSH levels and follicle dynamics following 7 days of 75-150 IU/l recFSH.


lncRNA EZR‑AS1 knockdown represses proliferation, migration and invasion of cSCC via the PI3K/AKT signaling pathway.
Although long non‑coding RNAs (lncRNAs) have been implicated in various human cancer types, the role of lncRNA ezrin antisense RNA 1 (EZR‑AS1) in cutaneous squamous cell carcinoma (cSCC) remains unclear. The present study aimed to investigate the effect of lncRNAEZR‑AS1 on cSCC and identify the underlying molecular mechanisms. EZR‑AS1 expression was measured in cSCC tissue and cells detected using reverse transcription‑quantitative PCR. Gain‑of‑function assays were performed in A431 cells, which have a relatively low expression of EZR‑AS1, while loss‑of‑function assays were performed in SCC13 and SCL‑1 colon cancer cells, which have a relatively high expression of EZR‑AS1. Cell viability, proliferation, migration, invasion and apoptosis were assessed using MTT, plate cloning, wound healing, Transwell and flow cytometry assays, respectively. EZR‑AS1 mRNA expression levels were significantly upregulated in cSCC tissues and cells compared with adjacent healthy tissues and HaCaT cells, respectively. Compared with the small interfering RNA (si)‑negative control (NC) group, si‑EZR‑AS1 significantly inhibited SCC13 and SCL‑1 cell proliferation, migration and invasion, but promoted cell apoptosis. By contrast, compared with the pc‑NC group, EZR‑AS1 overexpression significantly enhanced A431 cell proliferation, migration and invasion, but inhibited cell apoptosis. Moreover, focal adhesion kinase (FAK) was identified as a target of EZR‑AS1, and EZR‑AS1 knockdown significantly decreased FAK expression compared with the si‑NC group. Moreover, EZR‑AS1 knockdown significantly downregulated the protein expression levels of phosphorylated (p)‑PI3K/PI3K and p‑AKT/AKT in cSCC cells compared with the si‑NC group. The PI3K agonist 740Y‑P significantly reversed si‑EZR‑AS1‑mediated effects on SCC13 and SCL‑1 cell proliferation, migration, invasion and apoptosis. In conclusion, the present study demonstrated that si‑EZR‑AS1 inhibited cSCC cell proliferation, migration and invasion, and promoted cell apoptosis, potentially via regulating the PI3K/AKT signaling pathway. Therefore, the present study provided novel insights into the diagnosis and treatment of cSCC.


Successful single-visit endodontics during Operation Desert Shield.
This article reports on the incidence of success following single-visit endodontic therapy. Non-surgical endodontic therapy was performed on 210 teeth in 167 patients who were rapidly deployed during the initial stages of Operation Desert Shield. Upon their return, 97 patients were recalled for follow-up evaluation. This study evaluated 102 teeth. The recall rate was 58% with a success rate of 89%.


Influence of acidified fluoride gel on abrasion resistance of eroded enamel.
The objective of the study was to evaluate the abrasion resistance of eroded enamel brushed with an acidified fluoride gel. Each enamel specimen was prepared from one of 64 bovine incisors. The specimens were embedded in acrylic resin, ground flat, polished and subsequently covered with a tape exposing an area of 1.8x10.0 mm in the center of the enamel specimens. The samples were alternatingly stored in a demineralizing solution (5 min) and a remineralizing solution (1min) four times. An acidic soft drink (Sprite Light(R)) served as a demineralizing solution and artificial saliva was used as a remineralizing solution. After each remineralization the specimens were brushed in an automatic brushing machine (2,000 strokes, 2.5 N load) and subsequently stored again in saliva (1 min). A mixture of artificial saliva (5 ml) with a gel (1 ml) based on the formulation of Elmex(R) gelée (Wybert, Lörrach, Germany) served as an abrasive slurry. Thirty seconds after brushing, the slurry was removed from the specimens by rinsing with destilled water. For each of 16 specimens the following gels (A-D) were used: gels A (pH 7.0) and B (pH 4.5) were unfluoridated; gels C (pH 7.0) and D (Elmex gelée; pH 4.5) contained 1.25% F-. After two cycles the specimens were kept in the saliva for 8 h. Finally the tape was removed and the abrasion was determined profilometrically. The following values (mean +/- SD) were obtained and statistically analyzed by analysis of variance and Wilcoxon two-sample tests (p</=0.01): gel A, 0.96+/-0.24 microm; B, 1.58+/-0.32 microm; C, 0. 71+/-0.23 microm; D, 0.25+/-0.08 microm. The differences between all experimental groups were statistically significant. It is assumed that treatment of enamel erosions with an acidified fluoride gel results in a higher abrasion resistance compared to gels which are either unfluoridated or neutral.


Reversible acidochromism of a benzoxazole based scaffold and construction of reconfigurable dual output molecular logic gates.
This report explores the reversible acidochromism of a benzoxazole-based scaffold (BPP), which is highly sensitive to the acid-base in the liquid and gas phases. With the addition of acid, the solution of BPP changes its color from yellow to pink fuchsia due to the transformation of its imine into quinonoid form. Colour change is completely reversible in the presence of the base, confirming the reversible acidochromic behavior of the present BPP system. Further, a paper strips-based test kit has been demonstrated for the practical utility of the present acidochromic BPP to identify a trace amount of acid-base in solution and gas-phase, respectively. The mechanistic aspect of detection of acid-base and colorimetric change in the presence of acid-base have been explored by density functional theoretical investigations and 1H NMR experiments. Moreover, we have constructed a reconfigurable dual-output combinatorial logic circuit by utilizing the spectral shift between two wavelengths at 404 nm and 552 nm, respectively, and colorimetric change of the BPP in the presence and absence of acid-base.


The c-Rel transcription factor limits early interferon and neuroinflammatory responses to prevent herpes simplex encephalitis onset in mice.
Herpes simplex virus type 1 (HSV-1) is the predominant cause of herpes simplex encephalitis (HSE), a condition characterized by acute inflammation and viral replication in the brain. Host genetics contribute to HSE onset, including monogenic defects in type I interferon signaling in cases of childhood HSE. Mouse models suggest a further contribution of immune cell-mediated inflammation to HSE pathogenesis. We have previously described a truncating mutation in the c-Rel transcription factor (RelC307X) that drives lethal HSE in 60% of HSV-1-infected RelC307X mice. In this study, we combined dual host-virus RNA sequencing with flow cytometry to explore cell populations and mechanisms involved in RelC307X-driven HSE. At day 5 postinfection, prior to HSE clinical symptom onset, elevated HSV-1 transcription was detected together with augmented host interferon-stimulated and inflammatory gene expression in the brainstems of high-responding RelC307X mice, predictive of HSE development. This early induction of host gene expression preceded pathological infiltration of myeloid and T cells in RelC307X mice at HSE onset by day 7. Thus, we establish c-Rel as an early regulator of viral and host responses during mouse HSE. These data further highlight the importance of achieving a balanced immune response and avoiding excess interferon-driven inflammation to promote HSE resistance.


Large differences in CO2 emissions from two dairy farms on a drained peatland driven by contrasting respiration rates during seasonal dry conditions.
Drained peatlands are major sources of CO2 to the atmosphere, yet the effects of land management and hydrological extremes have been little-studied at spatial scales relevant to agricultural enterprises. We measured fluxes of CO2 using the eddy covariance (EC) technique at two adjacent dairy farms on a drained peatland in Aotearoa New Zealand with remaining peat depths 5.5-8 m. One site (SD) had shallow surface drains and mean water table depth (WTD) -657 mm, while the other site (BD) had deep field border drains and mean WTD -838 mm. Net ecosystem CO2 production (NEP) was similar at the two sites when the soils were moist but diverged during late-summer drying, with site BD having 4.56 t C ha-1 greater CO2 emission than site SD over the four-month dry period. Soil drying reduced gross primary production (GPP) at both sites, while ecosystem respiration (ER) was reduced at site SD but not at site BD. The low dry season respiration rates at site SD contributed to near-zero annual NEP, while higher respiration rates at site BD led to annual CO2 loss of -4.95 ± 0.59 t C ha-1 yr-1. Accounting for other imports and exports of carbon, annual net ecosystem carbon balances were -2.23 and -8.47 t C ha-1 yr-1 at sites SD and BD, respectively. It is likely that the contrasting dry season respiration rates resulted from differences in soil physical properties affecting soil moisture vertical redistribution and availability to plants and microbes rather than from the relatively small differences in WTD. These differences could be caused by soil physical disturbances during pasture renewal or paddock recontouring, or time since initial drainage. Therefore, improved soil management might provide practical mitigation against excessive CO2 emissions during dry conditions, including droughts.


Perceptions of being a registered nurse (PRN): development and validation of a survey tool.
Nursing students enter nursing programs with idealistic perceptions of what it is to be a nurse. Upon graduation, many find these perceptions mismatched with the actual nurse's role. This can lead to discontentment in their chosen career. These issues highlight the importance of nursing students developing an understanding of the nurse's role during their undergraduate nursing education. One way to accomplish this is to assess perceptions and address them accordingly during the nursing program. Survey tools assessing perceptions of nursing exist but lack contemporary and multicultural foci. To develop a feasible, valid, and reliable survey tool to identify nursing students' perceptions of being a nurse. In Phase 1, a literature review and Nominal Group Technique meetings were used to generate primary survey items. Phase 2 included a pre-pilot and online pilot testing of the Perceptions of being a Registered Nurse (PRN) survey tool with 797 nursing students across all year levels at three Australian Universities. The 34-item PRN survey tool uses a five-point Likert scale to measure nursing students' perceptions of nursing, including factors influencing a nurse's well-being, attributes and qualities of nurses, the role of the nurse, and nursing professionalism. The Item-Content validity index was high (> 0.78), and the inter-item correlation validity was identified by Pearson's product-moment coefficient of r = .712. Internal reliability was confirmed with a Cronbach's alpha = 0.83. Based upon the participation completion rate, the survey tool was deemed applicable and feasible. The majority of respondents believed that nurses have altruistic attributes; however, perceptions of nursing varied significantly when rating factors influencing the physical, emotional, and social well-being of a nurse. In later stages of training, respondents were more likely to agree that nursing is physically and emotionally demanding and that nurses experience social isolation due to shift work, finding it difficult to achieve a work-life balance. The PRN survey tool was found to be valid, reliable, and feasible. Future use and outcomes from PRN assessments may lead to changes to nursing curricula that enhance nursing students' perceptions of nursing.


Triphalangeal thumb and brachy-ectrodactyly syndrome. Confirmation of autosomal dominant inheritance.
Two patients with triphalangeal thumbs-ectrodactyly syndrome are described. The first case is a 4-year-old female with triphalangeal thumbs, preaxial polydactyly with rudimentary polydactyly of the 3rd finger of the right hand and ectro-syndactyly of feet. Her stillborn sister had triphalangeal thumbs and ectrodactyly of feet. The mother has triphalangeal thumbs, brachy-syndactyly of the left foot and ectro-syndactyly of the right one. The maternal grandmother has syndactyly of 1st, 2nd, 3rd toes and hypoplasia of the 3rd toe on the right foot. The second case is sporadic and shows triphalangeal thumbs, preaxial polydactyly of the right hand and bilateral lobster-claw feet. Our observations confirm the variability of clinical expression and support the autosomal dominant inheritance of the syndrome.


Cyclic alternating pattern analysis in REM sleep behavior disorder.
Rapid eye movement (REM) sleep behavior disorder (RBD) is a type of REM parasomnia characterized by complex motor activity during REM sleep. In this study, cyclic alternating pattern (CAP) in patients with idiopathic RBD was analyzed to evaluate the expression of arousal instability of NREM sleep. A total of 31 idiopathic RBD patients and age- and gender-matched 21 control subjects were consecutively recruited. Conventional sleep polysomnographic recording parameters and CAP parameters were compared between RBD and the control group. The number of CAP cycles (120.13 ± 113.56, p = 0.007), CAP sequences (20.9 ± 18.15, p < 0.001), CAP index (25.14 ± 24.44, p = 0.017), and CAP rate (24.07 ± 13.22, p = 0.016) were all significantly higher in RBD patients compared to the control group. The increase in CAP sequences was observed in phase A2 and A3 subtypes while phase A1 subtype was significantly lower in RBD patients. A significant positive correlation was observed between disease duration with total CAP time (r = 0.289, p = 0.042) and A3 index (r = 0.32, p = 0.024). There was a negative correlation between the age and A1 index (r = -0.4491, p = 0.0001). To our knowledge this is the first polysomnographic clinical study which evaluated CAP parameters in RBD. Increased CAP rate found may be considered as a sign showing that NREM sleep may also be affected in RBD patients. Therefore, CAP analysis may be important to enlighten the pathogenesis of parasomnias.


Juvenile Ocular Myasthenia Gravis: Presentation and Outcome of a Large Cohort.
Isolated ocular myasthenia gravis (MG) is sparingly common in children relative to adults, ranging from 71% to 93% of all children with MG. We aimed to characterize the ocular manifestations and outcomes in children with isolated ocular MG. Medical records of consecutive 62 subjects less than 15 years of age with ocular MG, were retrospectively reviewed. Demographic data, presenting ocular features, types and variabilities of duction limitation, MG confirmatory tests, types of and responses to treatment, and generalized MG conversion were reviewed. Mean age at onset and follow-up time were 49 months (range, one to 173 months) and 95 months (range, six to 226 months), respectively. Female-to-male ratio was 1.5:1. Initially, ptosis was found in 60 subjects (96.8%), while duction limitation was observed in 28 subjects (45.2%). Total ophthalmoparesis was the most common type of duction limitation. Variability of duction limitation was found in 68% of subjects during the follow-up. Pyridostigmine alone was the most common medication used (48.4%); ptosis was more responsive to therapy than duction limitation. Conversion to generalized MG occurred in 19.4% of subjects, with a mean interval to conversion of nine months after symptom onset. Most conversions (91.7%) occurred in the first two years. Ptosis was more responsive to treatment than duction limitation. Thus other treatment modalities, as well as strabismic amblyopia screening, should be considered in children with prolonged duction limitation that is refractory to medication. In contrast with adults, a much lower proportion of children converted to generalized MG. This may explain the higher prevalence of isolated ocular MG among the juvenile population.


Post-exposure rabies treatment in pigs.
A rabid dog invaded a Thai pig farm and severely mauled 11 adult pigs. This offered an opportunity to study efficacy of a human type post-exposure vaccine regimen with and without rabies immunoglobulin. A commercial veterinary tissue culture rabies vaccine and equine rabies immune globulin were used. All pigs survived for 1 year following the exposure. All animals developed detectable rabies neutralizing antibodies on day 7 and levels over 0.5IU/ml on day 14. This small study suggests that post-exposure rabies treatment using a proven human regimen, applied to valuable farm animals, can be safe and effective.


Corrigendum: A novel approach to utilizing the essential public health functions in Ireland's health system recovery and reform.
[This corrects the article DOI: 10.3389/fpubh.2023.1074356.].


Inhibitory effect of a Pichia anomala killer toxin on Pneumocystis carinii infectivity to the SCID mouse.
A Pichia anomala killer toxin has been demonstrated to have a specific inhibitory effect on the in vitro attachment of Pneumocystis carinii. The results presented herein show that this yeast toxin is also effective against P. carinii infectivity in reducing parasite colonization in the lungs of SCID mice. The specificity of this inhibitory effect was controlled using a monoclonal antibody neutralizing the killer properties of the yeast toxin.


Autophagic and apoptotic cell death in amniotic epithelial cells.
The aim of this paper is to determine if autophagic cell death is associated with apoptosis and whether it participates in the process of term amniotic rupture. Forty pieces of fresh term amnions, including twenty from a position near the margin of the placentas and twenty from the margin of the naturally ruptured part of the placentas in term gestation were collected, respectively. The amnions were examined by scanning electron microscopy (SEM) and amniotic epithelial (AE) cells were examined by transmission electron microscopy (TEM). Autophagic and apoptotic cell death (PCD) were assayed by laser scanning confocal microscopy (LSCM) or flow cytometry using monodansylcadaverin (MDC) and propidium iodide (PI) stain. BCL(2) and BAX were examined by immunoblotting. Under SEM the amniotic epithelia appeared normal in the position near the placenta. They had an atrophied appearance in the margin of their natural broken parts. In the AE cells PCD was divided into three subtypes by TEM: autophagic cell death with positive stains of MDC and PI; apoptotic cell death; and the mixed type. Quantitative detection showed that there were more death cells, including autophagic and apoptotic, in the AE cells near the ruptured parts than near the placentas. An increased expression of BAX and a decreased expression of BCL(2) protein in the AE cells near the broken margin were observed. Apoptotic and autophagic cell death by the intrinsic pathway are the basic event in the AE cell and they are involved in the cause of membrane rupture of the human amnion in term gestation.


Curcumin analog 1, 5-bis (2-trifluoromethylphenyl)-1, 4-pentadien-3-one exhibits enhanced ability on Nrf2 activation and protection against acrolein-induced ARPE-19 cell toxicity.
Curcumin, a phytochemical agent in the spice turmeric, has received increasing attention for its anticancer, anti-inflammatory and antioxidant properties. However, application of curcumin has been limited due to its insolubility in water and poor bioavailability both clinically and experimentally. In addition, the protective effects and mechanisms of curcumin in eye diseases have been poorly studied. In the present study, we synthesized a curcumin analog, 1, 5-bis (2-trifluoromethylphenyl)-1, 4-pentadien-3-one (C3), which displayed improved protective effect against acrolein-induced toxicity in a human retinal pigment epithelial cell line (ARPE-19). At 5 μM, curcumin completely protected against acrolein-induced cell oxidative damage and preserved GSH levels and mitochondrial function. Surprisingly, C3 displayed a complete protective effect at 0.5 μM, which was much more efficient than curcumin. Both 0.5 μM C3 and 5 μM curcumin induced Nrf2 nuclear translocation and Nrf2 target genes transcription similarly. Experiments using Nrf2 siRNA showed that the protective effects of curcumin and C3 were eliminated by Nrf2 knockdown. Additionally, both curcumin and C3 activated the PI3/Akt pathway, however, Nrf2 activation was independent of this pathway, and therefore, we hypothesized that both curcumin and C3 activated phase II enzymes via directly disrupting the Nrf2/Keap1 complex and promoting Nrf2's nuclear translocation. Since acrolein challenge of ARPE-19 cells has been used as a model of smoking and age-related macular degeneration (AMD), we concluded that the curcumin analog, C3, may be a more promising drug candidate for its potential application for the prevention and treatment of eye diseases, such as AMD.


Association between balance recovery during inpatient rehabilitation and gait without physical assistance in severe subacute post-stroke patients.
Studies that analyze gait without physical assistance recovery post-stroke are scarce. There are few of the studies that analyze longitudinally the recovery of balance during the subacute post-stroke inpatient rehabilitation. The aim of the study was to analyze the association between balance recovery during subacute stroke inpatient rehabilitation and gait without physical assistance achievement. Secondarily, to analyze the association between balance at admission of inpatient rehabilitation and gait without physical assistance achievement. An observational, longitudinal, and retrospective cohort study was conducted. Subacute stroke subjects with an admission Berg Balance Scale below or equal to 4 points were included (n = 164). Two logistic regression models were developed. Model 1 analyzes the association between balance recovery during inpatient rehabilitation and gait without physical assistance at discharge. Model 2 analyzes the association between balance at the admission and gait without physical assistance at discharge. Of 164 severe post-stroke patients, 60 (36.5%) achieved gait without physical assistance. Although the two models developed a statistically significant association (p < 0.001), Model 1 evinced better discrimination performance (Model 1: area below the curve was of 0.987 -CI 95%: 0.975-0.998- vs. Model 2: area below the curve 2 was of 0.705 -CI 95%: 0.789-0.601-). Balance recovery during rehabilitation was strongly associated with gait without physical assistance achievement at the time of discharge in severe subacute post-stroke patients. The longitudinal analysis of motor recovery in severe subacute post-stroke patients may be helpful in the decision making process during inpatient rehabilitation.


Granulomatous sialadenitis of the major salivary glands. A clinicopathological study of 57 cases.
Fifty-seven of 469 major salivary glands excised for various reasons were found to contain granulomas. The aetiologies were tuberculosis (eight parotid, one sublingual), sarcoidosis (two parotid), calculous duct obstruction (34 submandibular), carcinomatous duct obstruction (four submandibular, one sublingual) and undetermined (four submandibular, three parotid). The tuberculous glands showed caseation in the majority of cases but two cases consisted predominantly of discrete granulomas with minimal necrosis. The sarcoid granulomas were typically non-caseating but a few were centrally necrotic. The cases of calculous and carcinomatous duct obstruction contained single to multiple small granulomas which contained mucin and were related to ruptured ducts. It is suggested that the frequency of calculi and the mixture of serous and mucous acini in the submandibular gland account for the distribution of obstructive granulomas. This study establishes calculous sialadenopathy as a major cause of granulomatous sialadenitis.


Pretreatment Multiparametric MRI-Based Radiomics Analysis for the Diagnosis of Breast Phyllodes Tumors.
Preoperative pathological grading assessment is important for patients with breast phyllodes tumors (PTs). To develop and validate a clinical-radiomics model based on multiparametric MRI and clinical information for the pretreatment differential diagnosis of PTs. Retrospective. A total of 216 patients with PTs, 133 in the training cohort (55 benign PTs [BPTs] and 78 borderline/malignant PTs [BMPTs]) and 83 in the validation cohort (28 BPTs and 55 BMPTs). 1.5 T and 3 T; T2-weighted imaging (T2WI), precontrast T1-weighted imaging (T1WI) and dynamic contrast-enhanced T1-weighted imaging (DCE-T1WI). A total of 3138 radiomics features were computed to decode the imaging phenotypes of PTs. To build the classification models, the following workflow was followed: minimum-maximum scaling normalization method, recursive feature elimination based on ridge regression (Ridge-RFE), synthetic minority oversampling technique, and support vector machine classifier. We established several models based on the statistically significant features (Ridge-RFE selected) of each sequence to distinguish BPTs from BMPTs, including precontrast T1WI model, DCE-T1WI phase 1 model, T1WI feature fusion model, T2WI model, T1WI + T2WI model, clinical feature model, conventional MRI characteristics model, and combined clinical-radiomics model. Univariate analysis was utilized to compare variables between the BPT and BMPT groups. The receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic performance of these models. In the training cohort, the clinical-radiomics model had excellent diagnostic efficiency, with an area under ROC (AUC) of 0.91 ± 0.02 (95% CI: 0.87-0.94). In the validation cohort, the AUCs were 0.79 ± 0.05 (95% CI: 0.70-0.87) for the combined model and 0.77 ± 0.05 (95% CI: 0.67-0.85) for the radiomics model. Compared with conventional MRI characteristics, radiomics features extracted from multiparametric MRI are helpful for improving the accuracy of differentiating the pathological grades of PTs preoperatively. The model based on radiomics and clinical information is expected to become a potential noninvasive tool for the assessment of PTs grades. 4 TECHNICAL EFFICACY: Stage 2.


Mosaicism in XX males.
Three males with a 46,XX karyotype are described. In two of them, evidence of a Y-containing line was found. In the first case, 1 of 500 lymphocyte metaphases was 48,XXY. In the second, 1 of 400 oral mucosa cells contained a Y body. The proportion of low-grade XX/XXY mosaics found among XX males now stands at about 17%.


Public health issues in geriatric dentistry in the United States.
The aging United States population living in the new millennium has dental needs that are very different and more complex than those experienced by previous older adult cohorts during the twentieth century. The type of dental care to be provided for older Americans goes way beyond emergency care, extractions and denture care. Dental caries is still clearly a public health problem for subgroups of older Americans, such as those of lower socioeconomic status, with dementia, who are homebound and who are institutionalized. These are also the subgroups experiencing greater barriers to accessing dental care. Stakeholders, including dental professionals and the dental benefits industry, need to work together to develop innovative dental financing programs that will increase older Americans access to dental care.


Depression of evoked potentials in rat thalamic ventro-basal complex and somatosensory cortex after reticular stimulation.
Experiments on unanesthetized rats immobilized with D-tubocurarine showed that electrical stimulation (100/sec) of the central gray matter and the mesencephalic and medullary reticular formation considerably depressed potentials in the somatic thalamic relay nucleus and somatosensory cortex evoked by stimulation of the forelimb or medial lemniscus. The mean threshold values of the current used for electrical stimulation of these structures did not differ significantly and were 70 (20--100), 100(20--120), and 120 (50--200) muA, respectively. On comparison of the amplitude-temporal characteristics of inhibition of evoked potentials during electrical stimulation of the above-mentioned structures by a current of twice the threshold strength, no significant differences were found. Immediately after the end of electrical stimulation the amplitude of the cortical evolved potential and the post-synpatic components of the thalamic evoked potential was 50--60% (P less than 0.01) below the control values. The duration of this depression varied from 0.5 to 1 sec. An increase in the intensity of electrical stimulation of brain-stem structures to between three and five times the threshold led to depression of the presynaptic component of the thalamic evoked potential also. Depression of the evoked potential as described above was found with various ratios between the intensities of conditioning and testing stimuli.


Tetralogy of fallot in addition to anomalous aortic origin of a coronary artery in a 1-year-old boy: a case report.
Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital heart disease, characterized by the coronary artery inappropriately originates from the aorta. It is usually classified according to the sinus where the coronary artery arises from, while anomalous origin of the right coronary being the most common type. In this case report, we described a rare case of Tetralogy of Fallot (TOF) in a 1-year-old boy, who also had the anomalous right coronary artery that originated from the left coronary sinus without an intramural segment. Besides TOF repair, lateral pulmonary translocation was undertaken in order to avoid risks of myocardial ischemia. We successfully completed a one-stage operation consisting of TOF repair and pulmonary artery translocation in a 1-year-old boy. We advocated early operation of pulmonic translocation for AAOCA patients without an intramural segment instead of unroofing procedure.


Genetic toxicology: web resources.
Genetic toxicology is the scientific discipline dealing with the effects of chemical, physical and biological agents on the heredity of living organisms. The Internet offers a wide range of online digital resources for the field of Genetic Toxicology. The history of genetic toxicology and electronic data collections are reviewed. Web-based resources at US National Library of Medicine (NLM), including MEDLINE, PUBMED, Gateway, Entrez, and TOXNET, are discussed. Search strategies and Medical Subject Headings (MeSH) are reviewed in the context of genetic toxicology. The TOXNET group of databases are discussed with emphasis on those databases with genetic toxicology content including GENE-TOX, TOXLINE, Hazardous Substances Data Bank, Integrated Risk Information System, and Chemical Carcinogenesis Research Information System. Location of chemical information including chemical structure and linkage to health and regulatory information using CHEMIDPLUS at NLM and other databases is reviewed. Various government agencies have active genetic toxicology research programs or use genetic toxicology data to assist fulfilling the agency's mission. Online resources at the US Food and Drug Administration (FDA), the US Environmental Protection Agency (EPA), the National Institutes of Environmental Health Sciences, and the National Toxicology Program (NTP) are outlined. Much of the genetic toxicology for pharmaceuticals, industrial chemicals and pesticides that is performed in the world is regulatory-driven. Regulatory web resources are presented for the laws mandating testing, guidelines on study design, Good Laboratory Practice (GLP) regulations, and requirements for electronic data collection and reporting. The Internet provides a range of other supporting resources to the field of genetic toxicology. The web links for key professional societies and journals in genetic toxicology are listed. Distance education, educational media resources, and job placement services are also available online in the field of genetic toxicology. As molecular biology and computational tools improve, new areas within genetic toxicology such as structural activity relationship analysis, mutational spectra databases and toxicogenomics, now have resources online as well.


Clinical and computed tomography characteristics of non-small cell lung cancer with ALK gene rearrangement: Comparison with EGFR mutation and ALK/EGFR-negative lung cancer.
The study was conducted to evaluate the clinical and computed tomography (CT) findings of non-small cell lung cancer (NSCLC) patients to distinguish between ALK gene rearrangement, EGFR mutation, and non-ALK/EGFR (no genetic abnormalities). We enrolled 201 patients with primary NSCLC who had undergone molecular testing for both ALK gene rearrangement and EGFR mutation. The clinical features and CT findings of the main lesion and associated pulmonary abnormalities were investigated. Female gender (P = 0.0043 vs. non-ALK/EGFR), young age (P = 0.0156 vs. EGFR), and a light or never smoking history (P = 0.0039 vs. non-ALK/EGFR) were significant clinical characteristics of NSCLC with ALK gene rearrangement. The significant CT characteristics compared to NSCLC with EGFR mutation were a large mass (P = 0.0155), solid mass (P = 0.0048), and no air bronchogram (P = 0.0148). A central location (P = 0.0322) and lymphadenopathy (P = 0.0353) were also more frequently observed. Coexisting emphysema was significantly less frequent in NSCLC patients with ALK gene rearrangement (P = 0.0135) than non-ALK/EGFR. NSCLC with ALK gene rearrangement was more likely to develop in younger women with a light or never smoking history. The characteristic CT findings of NSCLC with ALK gene rearrangement were a large solid mass, less air bronchogram, a central location, and lymphadenopathy.


Structure of thymidylate kinase from Ehrlichia chaffeensis.
The enzyme thymidylate kinase phosphorylates the substrate thymidine 5'-phosphate (dTMP) to form thymidine 5'-diphosphate (dTDP), which is further phosphorylated to dTTP for incorporation into DNA. Ehrlichia chaffeensis is the etiologic agent of human monocytotropic erlichiosis (HME), a potentially life-threatening tick-borne infection. HME is endemic in the United States from the southern states up to the eastern seaboard. HME is transmitted to humans via the lone star tick Amblyomma americanum. Here, the 2.15 Å resolution crystal structure of thymidylate kinase from E. chaffeensis in the apo form is presented.


[Amputation after traumatic lesion of the popliteal artery-avoidable or inevitable? (author's transl)].
Each serious injury of the joint of the knee involves the possibility of an additional lesion of the popliteal artery. Among the arterial injuries the traumatic lesions of the popliteal artery with a frequency of up to 20% are of great importance. Failure to recognize or estimate them correctly may result in a high rate of amputations. In addition, three own cases were critically analysed.


Effects of N,N,N',N'-ethylenediaminetetramethylene phosphonic acid on cortical bone remodeling in the adult dog.
Phosphonic acids are of interest because of their potential usefulness in the treatment of disorders of bone and mineral metabolism, as a treatment for dental calculus, and as skeletal imaging agents. The effects of oral doses of N,N,N',N'-ethylenediaminetetramethylene phosphonic acid (EDITEMPA) on cortical bone remodeling and histology of adult dogs were determined. After treatment for 3 and 6 months, there were dose-related changes observed in cortical bone as measured using histomorphometric methods. With higher doses, EDITEMPA treatment resulted in the accumulation of osteoid due to impaired or delayed mineralization of bone. There was an increased mineralized and osseous tissue porosity suggesting an early increase in bone resorption perhaps due to an increased activation of bone remodeling.


Development of postoperative velopharyngeal function in patients with cleft palate.
Patients with a cleft palate often experience a velopharyngeal dysfunction known as velopharyngeal insufficiency (VPI). The purpose of this study was to examine the development of velopharyngeal function (VPF) following primary palatoplasty and the factors that are linked to it. A retrospective study was conducted to examine the medical records of patients who had cleft palate, with or without cleft lip (CP ± L) and underwent palatoplasty at a Tertiary Affiliated Hospital between 2004 and 2017. Postoperative evaluation of VPF was conducted at two follow-up times (T1, T2) and was classified as either normal VPF, mild VPI, or moderate/severe VPI. The consistency of VPF evaluations between the two time points was then assessed, and patients were categorized into either the consistent or inconsistent group. The study collected and analyzed data on gender, cleft type, age at operation, follow-up duration, and speech records. The study included 188 patients with CP ± L. Out of these, 138 patients (73.4%) showed consistent VPF evaluations, while 50 patients (26.6%) showed inconsistent VPF evaluations. Among those with VPI at T1 (91 patients), 36 patients (39.6%) had normal VPF at T2. The rate of VPI decreased from 48.40% at T1 to 27.13% at T2, whereas the rate of normal VPF increased from 44.68% at T1 to 68.09% at T2. The consistent group had a significantly younger age at operation (2.90 ± 3.82 vs 3.68 ± 4.02), a longer duration of T1 (1.67 ± 0.97 vs 1.04 ± 0.59), and a lower comprehensive score of speech performance (1.86 ± 1.27 vs 2.60 ± 1.07) than the inconsistent group. It has been verified that there are changes in the development of VPF over time. Patients who underwent palatoplasty at a younger age were more likely to have confirmed VPF diagnosis at the first evaluation. The duration of follow-up was identified as a critical factor that affects the confirmation of VPF diagnosis.


Derivation of a subtype-specific biochemical signature of endometrial carcinoma using synchrotron-based Fourier-transform infrared microspectroscopy.
Endometrial carcinoma consists of endometrioid (type I) and serous papillary (SP; type II) subtypes; a rarer form is malignant mixed müllerian tumours (MMMT; type II/mixed). We set out to determine whether one might be able to biochemically signature these subtypes using Fourier-transform infrared (FTIR) microspectroscopy and distinguish non-tamoxifen associated from tamoxifen-associated cases. Paraffin-embedded blocks were obtained from non-tamoxifen associated cases reported as endometrioid (n=7), SP (n=4) or MMMT (n=4). From tamoxifen-associated cases, endometrioid (n=1), SP (n=3) and MMMT (n=4) blocks were retrieved; benign tissues (n=3) were also analysed. Exploiting synchrotron-based radiation, sections (10-microm thick) on BaF(2) windows were interrogated through a 10 microm x 10 microm aperture. Point spectra were derived from >or=10 locations in each of six glandular elements per tissue; a further 20 stromal spectra were obtained. Following normalisation to Amide I, average spectra (1800-900 cm(-1)) per gland or stroma were analysed for variance using principal component analysis (PCA) and linear discriminant analysis (LDA). In scores plots, segregation of spectra from different subtypes or benign tissues was noted and it proved possible to distinguish tamoxifen-associated cases. In the PCA-LDA loadings plots, the wavenumbers that highlighted variance for benign or endometrioid carcinoma tissues were in the protein region (1800-1480 cm(-1)) whereas those contributing most to SP or MMMT segregation were primarily in the DNA/RNA region (1425-900 cm(-1)) of the vibrational spectrum. Our results suggest that the application of FTIR microspectroscopy is a powerful new approach in disease diagnosis and characterisation.


Crescentic glomerulonephritis with anti-GBM antibody but no glomerular deposition.
Anti-glomerular basement membrane (GBM) antibodies are highly specific for Goodpasture's or anti-GBM disease, in which they are generally directed against the non-collagenous (NC1) domain of the alpha 3 chain of type IV collagen(α3(IV)), and less commonly, toward the α 4(IV) or α 5(IV) chains, which form a triple helical structure in GBM and alveolar basement membrane (ABM). Alterations in the hexameric structure of the NC1 (α3 (IV)), allows novel epitopes to be exposed and an immune response to develop, with subsequent linear antibody deposition along the GBM, leading to a crescentic glomerulonephritis. Positive anti-GBM antibodies are assumed to be pathogenic and capable of binding GBM in vivo, especially in the context of rapidly progressive glomerulonephritis. We have investigated patients with circulating anti-GBM antibodies, reactive to α3 (IV) and human GBM by immunoassays and Western blotting respectively, with focal necrotising crescentic glomerulonephritis but no linear GBM antibody deposition on immunohistochemistry. Three out of four were also ANCA positive. Despite not binding native GBM, patients' sera showed linear binding to primate glomeruli by indirect immunofluorescence, in the 2 cases tested. Following treatment, significant improvements in kidney function were found in 3/4 patients. We present four patients with crescentic glomerulonephritis and circulating anti-GBM antibodies, but no glomerular binding. These novel findings, demonstrate that in some patients anti-GBM antibodies may not bind their own GBM. This has important implications for clinical diagnosis, suggesting that histological confirmation of kidney injury by anti-GBM antibodies should be obtained, as non-binding GBM antibodies may be associated with significant renal recovery.


A comparative study of audiological outcomes and compliance between the Osia system and other bone conduction hearing implants.
To examine the subjective and objective audiological benefits of the Osia system compared to devices commonly implanted prior to the introduction of this system. Osia recipients with either conductive hearing loss (CHL/MHL) (n = 9) or single-sided deafness (SSD) (n = 8) who underwent surgery from February 2021 to March 2022 were prospectively recruited. The audiological outcomes and usage rate of Osia implantees were compared with those of retrospectively recruited patients implanted with other devices (n = 50). The subjective satisfaction of the Osia implantees was also evaluated through questionnaires. All users of the Osia system were classified as regular users. In the CHL/MHL group, the effective gain of the Osia system (11.1 ± 14.9 dB) surpassed that of the Baha and Bonebridge (- 2.7 ± 12.6 dB) at 2 kHz (p = 0.01, Mann-Whitney U test). Among the devices, the Osia system tended to tolerate the worst bone conduction thresholds, up to the level of 61 dB. In the SSD group, the functional gain of Osia at 4 kHz (37.5 ± 3.1 dB) was higher than that of the Baha and Bonebridge group (26.9 ± 3.0 dB) (p = 0.05, Mann-Whitney U test). The Osia system yielded larger audiological gain than the Baha Attract and Bonebridge devices, especially at high frequencies, leading to substantially higher compliance. The Osia system tended to have the strongest tolerance to aggravated bone conduction thresholds among the available transcutaneous bone conduction hearing implants. Therefore, the Osia system could potentially be a good option for CHL/MHL patients with bone conduction thresholds of 50 dB HL or more, as well as patients with SSD.


In utero ischemic injury: sonographic diagnosis and medicolegal implications.
The antenatal diagnosis of fetal neurologic injury has profound medical and legal implications. We report a case of antenatally diagnosed intracranial lesions including parenchymal hemorrhage in an otherwise physically normal infant. Computerized tomography in the newborn period demonstrated diffused ischemic damage with secondary cystic changes in addition to intracranial hemorrhage.


[Risk factors for failure of scleral buckling in rhegmatogenous retinal detachment. A Moroccan series].
To evaluate risk factors for failure of scleral buckling in rhegmatogenous retinal detachment (RRD) in an adult Moroccan population. A retrospective study of 432 eyes of 422 patients undergoing scleral buckling (SB) for primary RRD between 2001 and 2009 was carried out. Statistical analysis of risk factors for failure was performed using binary logistic regression. Mean patient age was 43 ± 15 years, and 45.4% were myopic. The median recurrence was at 10 months. The final failure rate was 22.5%. Univariate analysis shows that significant risk factors for failure were extent of RRD ≥ 3 quadrants (P<0.001), advanced PVR (P<0.001) and worsening PVR postoperatively (P<0.001). In the multivariate model, the only significant risk factor for failure was the worsening postoperative PVR (P<0.001). Our findings suggest that worsening of PVR after surgery is the major risk factor for failure of SB in RRD. Thus, it is necessary to recognize the risk factors contributing to PVR and to plan the most appropriate, earliest and least traumatic surgical treatment of RRD.


Establishment of a gastric cancer cell line with high microsatellite instability, OCUM-13, derived from Borrmann type-2 primary tumor.
Gastric cancer (GC) with microsatellite instability (MSI) has been reported to be sensitive to immunotherapy, however some of GC cases with MSI remain resistant to immunotherapy. Cancer cell lines showing MSI might be useful for the analysis of mechanisms of immunotherapy, while only a few GC cell lines with MSI are available so far. In this study, we established a unique GC cell line with MSI, OCUM-13, from a primary GC with abundant tumor-infiltrating lymphocytes. MSI assay indicated that OCUM-13 cells as well as the primary tumor showed a band shift in more than 3 of 5 microsatellite loci, suggesting that OCUM-13 did have high MSI. The subcutaneous inoculation of OCUM-13 cells into mice performed tumor formation. Insulin-like growth factor 1 receptor inhibitor decreased the growth of OCUM-13 cells. The newly established cell line with MSI, OCUM-13, might be useful for the analysis of cancer therapy for GC with MSI.


Comparison of agreement in asthmagen exposure assessments between rule-based automatic algorithms and a job exposure matrix in healthcare workers in Australia and Bhutan.
Assessment of occupational exposures is an integral component of population-based studies investigating the epidemiology of occupational diseases. However, all the available methods for exposure assessment have been developed, tested and used in high-income countries. Except for a few studies examining pesticide exposures, there is limited research on whether these methods are appropriate for assessing exposure in LMICs. The aim of this study is to compare a task-specific algorithm-based method (OccIDEAS) to a job-specific matrix method (OAsJEM) in the assessment of asthmagen exposures among healthcare workers in a high-income country and a low- and middle- income country (LMIC) to determine an appropriate assessment method for use in LMICs for future research. Data were obtained from a national cross-sectional survey of occupational asthmagens exposure in Australia and a cross-sectional survey of occupational chemical exposure among Bhutanese healthcare workers. Exposure was assessed using OccIDEAS and the OAsJEM. Prevalence of exposure to asthmagens and inter-rater agreement were calculated. In Australia, the prevalence was higher for a majority of agents when assessed by OccIDEAS than by the OAsJEM (13 versus 3). OccIDEAS identified exposures to a greater number of agents (16 versus 7). The agreement as indicated by κ (Cohen's Kappa coefficient) for six of the seven agents assessed was poor to fair (0.02 to 0.37). In Bhutan, the prevalence of exposure assessed by OccIDEAS was higher for four of the seven agents and κ was poor for all the four agents assessed (-0.06 to 0.13). The OAsJEM overestimated exposures to high-level disinfectants by assigning exposures to all participants from 10 (Bhutan) and 12 (Australia) ISCO-88 codes; whereas OccIDEAS assigned exposures to varying proportions of participants from these ISCO-codes. There was poor to fair agreement in the assessment of asthmagen exposure in healthcare workers between the two methods. The OAsJEM overestimated the prevalence of certain exposures. As compared to the OAsJEM, OccIDEAS appeared to be more appropriate for evaluating cross-country exposures to asthmagens in healthcare workers due to its inherent quality of assessing task-based determinants and its versatility in being adaptable for use in different countries with different exposure circumstances.


Acute multiple gastric ulcers in the pyloric antrum.
Acute prepyloric hemorrhagic erosions occasionally progress to symmetrical ulcers. Cytomegalic inclusion bodies were frequently seen, a history of alimentary allergens, excessive alcohol intake or coffee drinking was common. Hyperchlorhydria which decreased spontaneously was found in 89% during the acute attack.


Detection and typing of human herpesviruses by multiplex polymerase chain reaction.
A new approach to simultaneous detection and typing of related agents by the multiplex polymerase chain reaction (PCR) is described. The reaction was been applied to human herpesviruses by nested amplification of fragments of the DNA polymerase genes. During the first amplification, primers were used as two equimolar mixtures of non-degenerate oligonucleotides, aligning the 3'-ends with selected consensus regions, and their 5'-ends with the non-related sequences of each herpesvirus to be amplified. The specific fragments obtained were the substrate for a second, multiplex reaction for which primers were designed to produce different-size fragments for each related virus. The results showed high specificity for the detection and typing of the human herpesviruses with known sequences and no amplification of human DNA, in spite of the presence of the same consensus regions within human DNA polymerase alpha. It is concluded that this new approach would be useful for the differential diagnosis of herpesviruses, as well as for other groups of agents with conserved regions in their genomes and causing similar syndromes.


Structural variation of lignin-carbohydrate complexes (LCC) in Chinese quince (Chaenomeles sinensis) fruit as it ripens.
Chinese quince (Chaenomeles sinensis) fruits are rich in lignin, and too sour, astringent and woody to be eaten raw. More than 50 % of lignin in plant cell walls is covalently associated with carbohydrates to form lignin-carbohydrate complexes (LCC). In this study, LCC preparations were extracted from fruits harvested on the 15th day of the month from May-October 2019. A variety of chemical and instrumental analytical approaches were used to characterize the LCC fractions, including HPAEC, TGA, GPC, FT-IR, and 2D HSQC NMR. Antioxidant activities were evaluated by DPPH radical scavenging assays. Results showed that the LCC fractions from October fruits had better thermal stability and homogeneity. NMR results revealed that the lignin-lignin linkages in LCC-AcOH preparations included β-O-4', β-β' and β-5', but β-5' linkages were not present in LCC preparations. And the NMR signals of carbohydrate confirmed the presence of lignin-pectin complexes, which was consistent with sugar analysis. All LCC preparations showed good antioxidant activity, among which Björkman LCC from October fruits showed best. This study will facilitate understanding the chemical bonds of LCC macromolecules in the plant cell wall. More specifically, it provides information critical for specific industrial applications of quince fruits.


Presence of Cytomegalovirus in urine and blood of pregnant women with primary infection might be associated with fetal infection.
Cytomegalovirus (CMV) congenital infection can result from primary infection, reinfection or reactivation among pregnant women. The risk of vertical transmission is much higher in case of primary infection, and the transmission rate increases with gestational age. However there are still many questions about maternal markers that can predict whether the virus will be transmitted to the fetus. To investigate the relationship between the presence and the quantity of CMV in urine and blood of women presenting a primary CMV infection during pregnancy and the presence of congenital infection in their offspring. Detection and quantification of CMV DNA was performed on 150 urine samples and 114 blood samples from 150 pregnant women with proven CMV primary infection. Transmission rate was 36.7% (55/150). A statistically significant association was found between the presence of CMV in maternal urine and newborn infection (OR 2.03 95%CI 1.03-3.99). A clearly significant association was found between the presence of CMV in maternal blood and newborn infection (OR 3.14 95% CI 1.38-7.16). Taking into consideration those samples that are positive for CMV in maternal urine, the median value of viral load was significantly higher in those patients who transmitted to offspring (P=0.015). No significant association between viral load in maternal blood and newborn infection was observed. The presence of CMV in maternal urine and maternal blood correlated to the transmission of CMV to offspring in our cohort. The median viral load in urine is higher in women who transmitted. These markers may help to identify pregnant women at risk to transmit to the fetus.


Treatment With Adjuvant Abemaciclib Plus Endocrine Therapy in Patients With High-risk Early Breast Cancer Who Received Neoadjuvant Chemotherapy: A Prespecified Analysis of the monarchE Randomized Clinical Trial.
Patients selected to receive neoadjuvant chemotherapy (NAC) are usually those at higher risk of relapse, and there is a need to find better therapeutic options for these patients. To determine the efficacy and safety outcomes for patients with hormone receptor (HR)-positive, ERBB2 (formerly HER2)-, high-risk early breast cancer enrolled in the randomized clinical trial monarchE who received NAC. The monarchE randomized clinical trial was a multicenter, phase 3, open-label study that evaluated adjuvant treatment with abemaciclib plus endocrine therapy (ET) compared with ET alone in patients with HR+, ERBB2-, and node-positive early breast cancer who were at high risk of recurrence. Patients were recruited between July 2017 and August 2019 from 603 sites in 38 countries. This subgroup analysis was performed with primary outcome data, with a cutoff date of July 8, 2020. Enrolled patients were randomized (1:1) to receive standard of care ET for at least 5 years with or without treatment with abemaciclib (150 mg, twice daily) for 2 years (treatment period) or until criteria were met for discontinuation. Prior chemotherapy (NAC vs adjuvant vs none) was a stratification factor in monarchE, and and a prespecified exploratory analysis included outcomes in patients who received NAC. The data presented in this article are from the primary outcome analysis (395 invasive disease-free survival [IDFS] events; cutoff date, July 8, 2020; median follow-up 19 months [IQR, 15.6-23.9 months]). Invasive disease-free survival (the primary end point of monarchE) and distant relapse-free survival (DRFS) were evaluated using the Cox proportional hazard model and Kaplan-Meier method. Of the 5637 patients (mean [SD] age, 49.9 [10.6] years; 2046 women [99.5%]; 462 Asian [22.8%], 54 Black [2.7%], and 1473 White participants [70.8%]) enrolled in monarchE, 2056 (37%) received treatment with NAC. In this subgroup, treatment with abemaciclib and ET demonstrated clinically meaningful benefit in IDFS (hazard ratio, 0.61; 95% CI, 0.47-0.80) and DRFS (hazard ratio, 0.61; 95% CI, 0.46-0.81), which corresponded with an absolute improvement of 6.6% in 2-year IDFS rates and 6.7% in 2-year DRFS rates. A consistent treatment benefit was observed across subgroups of pathological breast tumor size or number of positive lymph nodes at surgery. In the randomized clinical trial monarchE, treatment with adjuvant abemaciclib combined with ET demonstrated a clinically meaningful improvement in IDFS and DRFS for patients with HR+, ERBB2-, node-positive, high-risk early breast cancer who received NAC before trial enrollment. ClinicalTrials.gov Identifier: NCT03155997.


Discovery of a novel bicyclic compound, DS54360155, as an orally potent analgesic without mu-opioid receptor agonist activity.
We synthesized derivatives of a natural alkaloid, conolidine, and evaluated these derivatives in the acetic acid-induced writhing test and formalin test in ddY mice after oral administration. As a result, we identified (5S)-6-methyl-1,3,4,5,6,8-hexahydro-7H-2,5-methano[1,5]diazonino[7,8-b]indol-7-one sulfate salt, 15a (DS54360155), with a unique and original bicyclic skeleton, as an analgesic more potent than conolidine. Moreover, 15a did not exhibit mu-opioid receptor agonist activity.


HuanglianGanjiang Tang alleviates DSS-induced colitis in mice by inhibiting necroptosis through vitamin D receptor.
HuanglianGanjiang Tang (HGT) is a classic prescription of traditional Chinese medicine (TCM) recorded in Dan Xi Xin Fa, which was used to alleviate manifestations like diarrhea, abdominal pain and hemafecia. In current clinical practices, HGT is adopted for the treatment of ulcerative colitis (UC) and affords good curative effect. However, the underlying mechanism deserves further elucidation. UC is a hard-to-curable and easy-to-recurrent inflammatory disease. This study is to evaluate the potential therapeutics and explore the molecular mechanism of HGT on UC in the mouse model. The components of HGT extracts were identified by HPLC. The colitis of mice was induced by 3% (w./v.) dextran sulfate sodium (DSS). The HGT decoction was prepared through boiling and centrifuging. The mice were given HGT decoction via oral gavage (0.34 g/ml & 0.68 g/ml; 5 ml/kg b.w.). The protective role of HGT on colitis mice was evaluated by body weight change, colon length, disease activity index (DAI) and histological scores. The expressions of necroptosis-related and vitamin D receptor (VDR)-related proteins were measured by Western blot, RT-qPCR and immunofluorescence. HGT could significantly reduce the loss of body weight and colon length in colitis mice, and alleviated the DAI and histological scores. Mechanically, HGT also promoted the expression of E-cadherin, Occludin, ZO-1 and VDR, and reduced the level of intestinal inflammatory cytokines, such as, IL-6, IL-1β and TNF-α. Besides, HGT downregulated the protein level of p-RIPK3, p-RIPK1 and p-MLKL while upregulated the protein level of Caspase-8 in colon tissue compared to the model group. Our study addressed that HGT can alleviate DSS-induced colitis of mice through inhibiting colonic necroptosis by upregulating the level of VDR.


Need of education for dry powder inhaler storage and retention - a patient-reported survey.
Dry powder inhalers (DPIs) are the most commonly used devices in asthma treatment in the Nordic countries. As new DPIs become available, patients are likely to be exposed to more than one type of device, with variable optimal handling. The aim was to examine real life storage and retention of multidose DPIs in patients with asthma. This patient-reported survey on real life storage and retention of DPIs included asthma patients using multidose DPIs. Basic patient characteristics, information on inhaler use and storage, check of expiry date, and concurrent inhaler use was examined using an on line questionnaire. A total of 738 patients were included with a median age of 41 years, out of which 83 % were women. Sixty-three per cent reported storage conditions pre-defined as risk locations for their maintenance inhaler and 38 % of the responding patients had more than one maintenance inhaler in use at the same time. Two thirds of the study population checked inhaler expiry date less than monthly or not at all. Use after expiry date was frequently reported. Two thirds of the patients had not received information on DPI storage, either from their doctor and/or nurse or at the pharmacy. This patient reported survey indicates that two thirds of the patients store their inhaler devices in suboptimal conditions, and only a minority had received instruction regarding inhaler handling. Non awareness of inhalers' expiry dates and use of more than one maintenance inhaler simultaneously was common. As inhaler mishandling may impact device functionality, improved communication and patient education is needed.


Unexpected, dramatic improvement in atrioventricular conduction during pacemaker implantation for apparent complete heart block.
We describe the case of a 29-year-old man with complete heart block after aortic and mitral valve surgery for bacterial endocarditis. Prior to pacemaker implantation, the patient had sinus bradycardia with third degree atrioventricular (AV) block. During testing of the atrial lead, the patient manifested intact AV conduction with a constant PR interval, which was robust up to 120 beats/min. This case represents a dramatic example of unexpected, improved AV conduction, perhaps a result of loss of Phase IV block.


Global charcoal mobilization from soils via dissolution and riverine transport to the oceans.
Global biomass burning generates 40 million to 250 million tons of charcoal every year, part of which is preserved for millennia in soils and sediments. We have quantified dissolution products of charcoal in a wide range of rivers worldwide and show that globally, a major portion of the annual charcoal production is lost from soils via dissolution and subsequent transport to the ocean. The global flux of soluble charcoal accounts to 26.5 ± 1.8 million tons per year, which is ~10% of the global riverine flux of dissolved organic carbon (DOC). We suggest that the mobilization of charcoal and DOC out of soils is mechanistically coupled. This study closes a major gap in the global charcoal budget and provides critical information in the context of geoengineering.


Displacement of the superior sagittal sinus associated with a brain tumor.
A 13-year-old girl with an 11 1/2-year history of seizures, was found to have a brain tumor and contralateral displacement of the superior sagittal sinus and falx. The rarity and possible mechanisms of sagittal sinus displacement are discussed.


Analysis of rye grains and rye meals for ergot alkaloids.
Due to the exceptionally hot and dry summer in 2003 the ergot of that harvest was rather small and could only be separated from normal grain with increased efforts. Based on a clean-up procedure of Wolffet al. (1) and of Kluget al. (2), a HPLC-FLD-method for the determination of 12 ergot alkaloids (6 "In"-, 6 "Inin"-forms) was established and modified. Actually reference substances are commercially available only for 5 selected alkaloids. Because of the instability of the alkaloids a new standard preparation procedure was tested and implemented. The maximum allowed impurity with ergot (0.05%=1000 μg alkaloids/kg) was exceeded in samples of harvest 2003. Except for one sample, all exceedings were detected in conventionally grown products, unlike organically grown products.


New insight into tricuspid valve anatomy from 100 hearts to reappraise annuloplasty methodology.
Prosthetic ring annuloplasty plays an important role in tricuspid valve repair. However, discussions regarding the appropriate suturing technique for rigid annuloplasty rings in patients with tricuspid valve anatomical variations are lacking. We aimed to clarify the diversity and pattern of tricuspid valve morphology. We analyzed tricuspid valve morphology and measured leaflet dimensions in 100 autopsy hearts, which were classified into three groups based on the number of posterior leaflet scallops: single scallop (PLS1) (n = 52), two scallops (PLS2) (n = 42), and three scallops (PLS3) (n = 5). One heart without posterior leaflet was excluded from the statistical analysis. Demographic characteristics were compared between PLS1, PLS2, and PLS3. The linear trends of proportions of each leaflet between PLS1, PLS2, and PLS3 were assessed using linear regression analysis. Median proportion (interquartile range) of the posterior annular length out of the entire annular perimeter in PLS1, PLS2, and PLS3 was 26% (22-31%), 37% (33-40%), and 45% (42-49%), respectively. Linear regression analysis showed a significant increasing trend (p for trend < 0.001) of the posterior leaflet annulus proportion from PLS1 to PLS3. Accordingly, the anterior and septal annulus proportions significantly decreased from PLS1 to PLS3. Approximately half of the tricuspid valve has multiple posterior leaflet scallops. The proportion of the posterior leaflet annular length to the tricuspid valve annulus perimeter increases as the number of posterior leaflet scallops increases. These morphologic variations will be fundamental for future discussion about the pathology of a dilated tricuspid valve and methodology of prosthetic ring annuloplasty.


Subthreshold transpupillary thermotherapy in Chinese patients with myopic choroidal neovascularization: one- and two-year follow up.
To perform a safety and efficacy study of subthreshold transpupillary thermotherapy (TTT) in Chinese patients with choroidal neovascularization (CNV) secondary to pathologic myopia. In a prospective study, patients with subfoveal or juxtafoveal CNV secondary to high myopia underwent subthreholdTTT with fixed treatment and follow-up protocols. From October 2002 to July 2005, 12 and 24 months of follow up were completed for 21 eyes and 13 eyes respectively. The mean best-corrected visual acuities (BCVA) were maintained at the baseline level at 1 and 2 years. Seventy-two per cent of eyes and 63% of eyes had stable or improved BCVA at 12 and 24 months.Thirty-four per cent and 39% of eyes had a moderate gain in vision (improved by three or more lines) at 12 and 24 months respectively.The average number of subthreshold TTT treatments was 1.7. The major complication of subthresholdTTT included laserrelated low-grade retinal pigment epithelium atrophy in two eyes of young patients with clear lenses. The final VA was significantly associated with pretreated VA (r = 0.614, P = 0.003).The final VA improvement was significantly associated with pretreatment VA in negative correlation (r=-0.731, P = 0.0002, Person correlation test). Subthreshold TTT in Chinese patients with pathologic myopia and subfoveal or juxtafoveal CNV generally maintained vision at 1- and 2-year follow up. Using decreased power of subthreshold TTT, especially in the younger patients with a clear lens, is suggested.


Compensating patients in trials: Perspectives from an ethical committee versus sponsor.
According to European clinical research legislation, no undue influence, including financial incentives, should be used to encourage participation in clinical trials. Financial compensation should be based on the inconvenience experienced by patients and is determined by the sponsor. The objective of this study was to assess the adequacy of patients' financial compensation by obtaining an external ethical opinion compared to the actual compensation provided. We randomly selected and reviewed 50 clinical drug trials, including 25 academic and 25 industry-sponsored studies. An external ethics group consisting of three members from French ethics committees, blinded to the actual compensation and the sponsor, retrospectively reviewed the study characteristics and assessed whether financial compensation was appropriate. Cohen's Kappa test measured agreement between actual compensation and the ethics group's opinion, and the McNemar test measured discrepancies. There was no agreement between the actual financial compensation and the ethics group's opinion (K = -.07; 95% CI = [-.16-.02]). More discrepancies were found in favour of financial compensation according to the ethics group than provided by sponsors (12 vs. 2, p = .016). The ethics group recommended financial compensation in 12 out of 50 studies (24%), which were studies with a higher number of additional visits (p = .004) and were more frequently sponsored by industry (p = .008). Sponsors only provided financial compensation in 2 out of 50 studies (4%). Patients are rarely compensated despite the perceived inconvenience. Both sponsors and ethics members struggle to determine the need for financial compensation, indicating a need for more precise recommendations for both parties.


A comparison of Biobrane vs. homograft for coverage of contaminated burn wounds.
An evaluation was made comparing homograft to Biobrane for the coverage of excised burn wounds using a rat model which had been contaminated with 1 x 10(5) Pseudomonas aeruginosa 1244. The homograft and Biobrane were then covered with either silver sulphadiazine cream, a 5 per cent mafenide acetate solution, or no topical antibacterial agent. Five days later the wounds were examined to determine the percentage of graft take. The homograft was found to have a superior graft take in this model. It is therefore recommended that a surgeon using Biobrane for the first time ensures the wound is at least as free of bacterial contamination as he would if he were using homograft.


Fungal empyema thoracis in cancer patients.
Fungal empyema thoracis (FET) is a rare life-threatening infection. We sought to describe the clinical characteristics of FET in a large academic cancer center. We conducted a retrospective chart review of all cancer patients who had a fungal isolate from the pleural fluid culture between 1/2005 and 8/2013. A total of 106 fungal isolates were identified in 97 patients. Yeasts accounted for 62% of the isolates whereas 38% were identified as molds. The most frequent pathogens were Candida spp. (58%) and Aspergillus spp. (12%). All patients with Aspergillus and 83% with Candida met criteria for proven fungal disease. Compared to the Aspergillus group, Candida FET was associated with recent abdominal or thoracic surgical procedures (44% vs. 0%, p = 0.01). Overall, 6-week mortality was high, with no significant differences between Candida and Aspergillus (31% vs. 45%, respectively [p = 0.48]). Only 1 out of 11 patients with uncommon molds died at 6 weeks, despite only 2 of them received appropriate antifungal therapy. Development of FET carries a high mortality in cancer patients. A history of a recent surgical procedure is a risk factor for FET due to Candida. Isolation of uncommon molds is likely to represent a contamination of the pleural fluid.


Effects of carotenoids on cells.
When added to cells, carotenoids display a variety of properties, including inhibition of mutagenesis, genotoxicity, malignant transformation, and growth of tumor cells. In addition, carotenoids increase cell-cell communication, and may have direct effects as cellular antioxidants.


The effect of vitamin E treatment during preovulatory period on reproductive performance of goats following estrous synchronization using intravaginal sponges.
The objectives of this study were to investigate whether the use of intravaginal sponge for estrous synchronization of goats causes oxidative stress, and to examine the effect of administering vitamin E during preovulatory period on reproductive performance of estrous synchronized goats. Estrus was synchronized in 36 non-lactating adult does using intravaginal sponges containing 30 mg of fluorogestane acetate (FGA) for 14 days. All females received 500 IU of eCG at the sponge withdrawal. The goats were allocated at random to two groups balanced for breed, age and body weight. Treatment group (n=18) received 200mg of vitamin E i.m. at the time of sponge removal and again at the time of second artificial insemination. The other 18 goats (control) were administered 1 ml of physiological saline instead of vitamin E on each of these two occasions. All does in estrus was intracervically inseminated at 12 and 24h after the onset of estrus. Blood samples were collected every 72h during the experimental period for evaluation of malondialdehyde (MDA) and vitamin E concentrations. Serum MDA level increased and vitamin E concentration decreased during the period of vaginal sponge application. Following the sponge removal, MDA level declined rapidly to below basal level in the treatment group but remained high in the control group. Conversely, vitamin E concentration increased in the treatment group after the sponge withdrawal and remained at a low level in the control group. No statistically significant differences (P>0.05) were observed between groups in terms of estrous response, conception rate, gestation length or kidding rate. However, the number of multiple births (70.0% versus 50.0%) and prolificacy rate (2.40+/-0.37 versus 1.63+/-0.26 kids per kidding) were significantly higher (P<0.05) for the treatment group than those of the control group. The results indicate that the use of intravaginal sponges for estrous synchronization of goats causes an increase in level of oxidative stress. However, the vitamin E treatment during preovulatory period can prevent the overproduction of reactive oxygen species (ROS), and it may improve the multiple birth rates and the number of kids born in estrous synchronized goats.


Secondary dengue virus infections during the 2009 outbreak in Buenos Aires.
To evaluate the occurrence of secondary dengue virus (DENV) infections during the 2009 outbreak in a non-endemic area. Viral loads were evaluated in serum from acute-phase patients, comparing primary and secondary infection. Serum samples from patients with clinical diagnosis of suspected dengue were referred to the Virology Laboratory at 'Ricardo Gutiérrez' Children's Hospital. Dengue-positive samples were classified as primary or secondary DENV infections through serological methods (anti-DENV IgM and IgG). Viral loads were measured by quantitative real-time PCR (qRT-PCR) in samples obtained in the first 5 days of infection. Statistical analyses were performed to evaluate factors that might correlate with differences in the viral load of primary or secondary infection. A total of 229 DENV cases were confirmed; among them, 22.7% were secondary infections. No significant differences were found between the viral load of primary and secondary infections. We detected a high percentage of secondary DENV infections in a non-endemic area; this finding might correspond to socio-demographic characteristics of the group under study or indicate a previous cryptic DENV circulation causing inapparent infections.


Zinc sulphadiazines: novel topical antimicrobial agents for burns.
Two new zinc sulphadiazine (Zn(SD)2)-amine complexes, zinc sulphadiazine-methylamine (Zn(SD)2(CH3NH2)2) and zinc sulphadiazine-ethylenediamine (Zn(SD)2(C2H8N2)3.H2O), were prepared and compared with silver sulphadiazine (AgSD). The compounds were readily obtained by reaction of zinc nitrate hexahydrate with sulphadiazine or its salt in methylamine and ethylenediamine, respectively. Structure was established by X-ray crystallography and ultraviolet-visible, infrared and nuclear magnetic resonance spectroscopy. The products were effective, in-vitro, against Gram-positive and Gram-negative bacteria as well as fungus. However, their activity is partially reversed by p-aminobenzoic acid. Further investigations in burned mice revealed that these compounds displayed a potential value in the prevention and treatment of wound healing, and diminution of mortality and weight loss. The toxicity of Zn(SD)2 derivatives was much lower than that of AgSD. The better aqueous solubility and skin permeability may explain the reason for their superiority over AgSD in the efficacy for topical therapy. Zn(SD)2(CH3NH2)2 was consistently more potent and was chosen for further development in clinical uses. The similarity in complexation between Zn(SD)2(CH3NH2)2 and AgSD may be significant to distinguish that from any other Zn(SD)2 derivative in bioactivity.


Effect of surgical delay on survival outcomes in patients undergoing curative resection for primary hepatocellular carcinoma: Inverse probability of treatment weighting using propensity scores and propensity score adjustment.
The evidence is conflicting regarding the effect of delays from the time of diagnosis to surgery on the survival in patients with hepatocellular carcinoma. We sought to investigate the impact of time to surgery on overall survival for patients who underwent curative resection for primary hepatocellular carcinoma. We performed a retrospective review of all patients who underwent liver resection for primary hepatocellular carcinoma between the years 2000 and 2015. Using 30-, 60-, and 90-day cutoffs, we investigated the effect of time to surgery on survival outcomes by dichotomizing the patients and using inverse probability of treatment weighting to ensure comparability. We also investigated time to surgery in prognostic subgroups by modeling the statistical interaction between time to surgery and the relevant prognostic variable in multivariable Cox models. A total of 863 patients underwent liver resection for primary hepatocellular carcinoma during the study period. Using 30-, 60-, and 90-day cutoffs, time to surgery did not have a significant bearing on overall survival. For elderly patients (>70 years), patients with Child-Pugh B liver disease, American Society of Anesthesiologists status 2/3, tumor size >5cm, tumor size ≥10cm and presence of extrahepatic invasion, hazard ratio decreased and overall survival improved as time to surgery increased. However, for patients with liver cirrhosis or portal hypertension, increasing time to surgery was found to portend higher risks of death. Time to surgery does not have a significant bearing on overall survival, and modest delays even appear to be associated with improved survival in specific subsets of patients. The importance of these findings is that patients with hepatocellular carcinoma should be fully optimized before and not rushed to surgery because of concerns of tumor progression and a diminished survival.


High-performance liquid chromatographic determination of ropivacaine, 3-hydroxy-ropivacaine, 4-hydroxy-ropivacaine and 2',6'-pipecoloxylidide in plasma.
A sensitive HPLC method has been developed for the determination of ropivacaine, 3-hydroxy-ropivacaine, 4-hydroxy-ropivacaine and 2',6'-pipecoloxylidide in plasma. The procedure involved extraction from plasma with a mixture of n-heptane-ethyl acetate and a back-extraction into an acidified aqueous solution. The chromatography was achieved using a LiChrospher RPB C8 column with a mobile phase consisting of a mixture of acetonitrile and pH 2.1, 0.01 M potassium dihydrogenphosphate, the latter phase containing 0.005 M 1-heptanesulfonic acid for ropivacaine metabolites analysis. The extraction yields of ropivacaine, 3-hydroxy-ropivacaine, 4-hydroxy-ropivacaine and 2',6'-pipecoloxylidide were 94.7%, 79.4%, 79.4% and 77.7%, respectively. The limits of detection of ropivacaine, 3-hydroxy-ropivacaine, 4-hydroxy-ropivacaine and 2',6'-pipecoloxylidide in plasma samples were 0.9 ng/ml, 3 ng/ml, 5 ng/ml and 1 ng/ml, respectively.


Growth discrepancy in twins in the first trimester of pregnancy.
The prevalence and significance of intertwin growth discrepancy in the first trimester of pregnancy are controversial. The aim of this study was to refine the incidence and outcome of this discrepancy in relation to dating of the pregnancy and other biometric parameters. This prospective study of twin pregnancies initially evaluated at 11-14 weeks' gestation was conducted between 2001 and 2004. Differences in crown-rump length (CRL) and estimated gestational age (GA) were calculated for each twin pair and their distribution was analyzed according to chorionicity and mode of conception (spontaneous or following assisted reproductive technologies). CRL-based GA and actual GA were compared. Other biometric parameters were also compared for each twin pair. The distribution of discrepancies was analyzed according to pregnancy outcome. A total of 182 twin pregnancies was included. The mean+/-SD discrepancy in CRL was 3.4+/-3.18 mm or 5.1+/-4.69% and the 95th centile was 9.8 mm or 14.3%. There was no influence of chorionicity (P=0.44), mode of conception (P=0.18) and no relation with outcome (P=0.54). In conceptions resulting from assisted technology, the measured CRL of the smaller twin was closer to the actual GA. Cephalic and abdominal biometric measurements were significantly greater in the twin with the smaller CRL (P<0.05). The two cases with a discrepancy>15 mm were affected by trisomy 18 and triploidy, respectively. CRL discrepancy in twin pregnancies in the first trimester is a frequent finding. Discrepancy>95th centile indicates major growth delay of one twin, which could indicate the presence of aneuploidy. For milder degrees of discordance the CRL of the smaller fetus is a more accurate estimate of the actual GA.


Computer graphics tools for radiation treatment planning.
The objective of radiation therapy treatment is to eradicate a cancerous tumor while keeping the damage to nearby healthy organs to a minimum. A variety of tools employing computer graphics exist to aid in the planning and verification of treatments. Three-dimensional (3D) image information available from sources such as computerized tomography (CT) scanners is used to define the sizes, shapes, and spatial locations of the tumor and normal structures in the form of transverse contours. These object definitions are displayed in 3D perspective to enable the determination of the best possible directions from which to aim radiation beams at the tumor. The beams may be shaped to match the outline of the tumor, and their intensities may be modified using compensating devices. The results of calculations done to predict the distribution of radiation dose throughout the body due to a given set-up of beams can be displayed to the user in many ways. Dose may be shown in the form of isodose contours overlaid on transverse CT images, or on reconstructed image planes of arbitrary orientation in space. There are also a number of methods of 3D display; dose can be shown on the surface of objects, or in the form of isodose surfaces relative to anatomical structures. Computer-generated beam film images may be used to verify patient set-up and tumor coverage.


EMBER: multi-label prediction of kinase-substrate phosphorylation events through deep learning.
Kinase-catalyzed phosphorylation of proteins forms the backbone of signal transduction within the cell, enabling the coordination of numerous processes such as the cell cycle, apoptosis, and differentiation. Although on the order of 105 phosphorylation events have been described, we know the specific kinase performing these functions for <5% of cases. The ability to predict which kinases initiate specific individual phosphorylation events has the potential to greatly enhance the design of downstream experimental studies, while simultaneously creating a preliminary map of the broader phosphorylation network that controls cellular signaling. We describe Embedding-based multi-label prediction of phosphorylation events (EMBER), a deep learning method that integrates kinase phylogenetic information and motif-dissimilarity information into a multi-label classification model for the prediction of kinase-motif phosphorylation events. Unlike previous deep learning methods that perform single-label classification, we restate the task of kinase-motif phosphorylation prediction as a multi-label problem, allowing us to train a single unified model rather than a separate model for each of the 134 kinase families. We utilize a Siamese neural network to generate novel vector representations, or an embedding, of peptide motif sequences, and we compare our novel embedding to a previously proposed peptide embedding. Our motif vector representations are used, along with one-hot encoded motif sequences, as input to a classification neural network while also leveraging kinase phylogenetic relationships into our model via a kinase phylogeny-weighted loss function. Results suggest that this approach holds significant promise for improving the known map of phosphorylation relationships that underlie kinome signaling. The data and code underlying this article are available in a GitHub repository at https://github.com/gomezlab/EMBER. Supplementary data are available at Bioinformatics online.


[Study on HPLC fingerprint of processed Radix Angelicae Dahuricae].
To establish HPLC fingerprint analysis for the quality control of processed Radix Angelicae Dahuricae. HPLC fingerprint analysis of processed Radix Angelicae Dahuricae was developed Agilent C18 column (250 mm x 4.6 mm, 5 microm) was used, with mixture of acetonitrile and 5% phosphorous acid mobile phase in a gradient mode. The flow rate was 1.0 mL/min. The wavelength of measurement was 254 nm. Fifteen batches of processed Radix Angelicae Dahuricae were determined. The methodological evaluation showed that the method had a good repeatability. The method can be used to identify and evaluate the quality of Radix Angelicae Dahuricae conveniently.


An ancestral molecular response to nanomaterial particulates.
The varied transcriptomic response to nanoparticles has hampered the understanding of the mechanism of action. Here, by performing a meta-analysis of a large collection of transcriptomics data from various engineered nanoparticle exposure studies, we identify common patterns of gene regulation that impact the transcriptomic response. Analysis identifies deregulation of immune functions as a prominent response across different exposure studies. Looking at the promoter regions of these genes, a set of binding sites for zinc finger transcription factors C2H2, involved in cell stress responses, protein misfolding and chromatin remodelling and immunomodulation, is identified. The model can be used to explain the outcomes of mechanism of action and is observed across a range of species indicating this is a conserved part of the innate immune system.


Repeat hepatic resections for colorectal metastases.
We identified 106 patients who had undergone complete resection of isolated colorectal hepatic metastases. Nine of these patients subsequently underwent repeat liver resections for isolated hepatic recurrences. The median follow-up for these patients was 21 months. One postoperative death was related to the second hepatectomy. At the time of last follow-up, five patients were alive and free of recurrent disease at 9, 19, 31, 50, and 67 months after their second hepatic resection. The remaining three patients were alive, but disease had recurred 11 months after resection in the first patient, 12 months after resection in the second, and 18 months after resection in the third. Among these three patients, two had solitary pulmonary nodules, which were resected, and one had unresectable liver disease. Our experience and a review of the literature suggest that repeat hepatic resection for isolated colorectal metastases can result in long-term survival in selected patients.


[Population genetic structure of northern Dolly Varden char Salvelinus malma malma in Asia and North America].
The level of genetic differentiation of northern Dolly Varden char Salvelinus malma malma from Asia and North America was evaluated using the data on mtDNA variation (regions ND1/ND2, ND5/ND6, and Cytb/D loop) obtained by means of PCR-RFLP analysis. For S. m. malma, the mean values of haplotype and nucleotide diversity were 0.5261 +/- 0.00388 and 0.001558, respectively. The mean estimate of the population nucleotide divergence constituted 0.055%. It was demonstrated that S. m. malma on the most part of the species range examined (drainages of the Beaufort Sea, Chukotka Sea, Bering Sea, and the Sea of Okhotsk) was characterized by the population genetic structure with the low level of genetic differentiation and divergence. At the same time, populations from the Pacific Ocean Gulf of Alaska demonstrated marked genetic differentiation, supported by the high pairwise phi(ST) values (from 0.4198 to 0.5211) and nucleotide divergence estimates (mean divergence, 0.129%), from Asian and North American populations. Nested analysis of molecular variance (AMOVA) showed that most of the mtDNA variation in S. m. malma fell in the intrapopulation component (72.5%). At the same time, the differences between the populations (21.1%) and between the regions (6.4%) made lower contribution to the total variation.


Contemporary radiotherapy in head and neck cancer: balancing chance for cure with risk for complication.
Radiotherapy plays an integral role in the management of most patients with cancers of the head and neck. Better understanding of radiobiology and radiation physics has allowed radiation oncologists to enhance the tumoricidal effects of radiation and reduce the severity of normal tissue toxicities. This article reviews the biologic foundation of head and neck radiotherapy, the physical principles and technological innovations that enable delivery of highly conformal radiation, the acute and late complications of radiation-based treatments, and the clinical evidence supporting contemporary practice.


Bochdaleck diaphragmatic hernia, complicated by an antenatal gastric perforation, presenting as a pneumothorax and a perforative peritonitis.
The presentation of congenital diaphragmatic hernia (CDH) at birth may fall outside the typical features (cyanosis, tachypnea and respiratory failure), manifesting, instead, also with others pictures that make the diagnosis difficult or even impossible. We report a case of CDH presenting as a pneumothorax and a perforative peritonitis due to an antenatal gastric perforation.


Getting groceries during the pandemic: How transit remained important despite the rise of e-delivery.
We model the use of public transit to reach grocery stores and the use of online delivery services to get groceries, before and during the COVID-19 pandemic among people who used transit regularly prior to the crisis. We draw upon a panel survey of pre-pandemic transit riders in Vancouver and Toronto. We conduct multivariable two-step tobit regression models that predict the likelihood of a respondent using transit as their primary mode for getting groceries before the pandemic (step 1) and then during the pandemic (step 2). Models are conducted for two survey waves, May 2020 and March 2021. We also conduct zero-inflated negative binomial regression models predicting the frequency respondents ordered groceries online. Transit riders over the age of 64 were more likely to use transit to reach groceries before the pandemic and more likely to continue to do so during the pandemic (wave 1, OR, 1.63; CI, 1.24-2.14; wave 2, OR, 1.35; CI, 1.03-1.76). Essential workers were more likely to continue using transit to reach groceries during the pandemic (wave 1, OR, 1.33; CI, 1.24-1.43; wave 2, OR, 1.18; CI, 1.06-1.32). Walking distance to the nearest grocery store was positively associated with using transit to get groceries pre-pandemic (wave 1, OR, 1.02; CI, 1.01-1.03; wave 2, OR, 1.02; CI, 1.01-1.03), and in May 2020 (wave 1, OR 1.01; (1.00-1.02). During the pandemic, people who stopped using transit to get groceries were less likely to have made zero online grocery purchases (wave 1, OR, 0.56; CI, 0.41-0.75; wave 2, OR, 0.62; CI, 0.41-0.94). People still physically commuting to work were more likely to still use transit to get groceries. Among transit riders, older adults and those living far walking distances from grocery stores are more likely to use transit to get groceries. Older transit riders and those with higher incomes were also more likely to use grocery delivery services, while female, Black, and immigrant riders were less likely to do so.


Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia-reperfusion injury.
Intestinal ischemia underlies several clinical conditions and can result in the loss of the intestinal mucosal barrier. Ischemia-induced damage to the intestinal epithelium is repaired by stimulation of intestinal stem cells (ISCs), and paracrine signaling from the vascular niche regulates intestinal regeneration. Here, we identify FOXC1 and FOXC2 as essential regulators of paracrine signaling in intestinal regeneration after ischemia-reperfusion (I/R) injury. Vascular endothelial cell (EC)- and lymphatic EC (LEC)-specific deletions of Foxc1, Foxc2, or both in mice worsen I/R-induced intestinal damage by causing defects in vascular regrowth, expression of chemokine CXCL12 and Wnt activator R-spondin 3 (RSPO3) in blood ECs (BECs) and LECs, respectively, and activation of Wnt signaling in ISCs. Both FOXC1 and FOXC2 directly bind to regulatory elements of the CXCL12 and RSPO3 loci in BECs and LECs, respectively. Treatment with CXCL12 and RSPO3 rescues the I/R-induced intestinal damage in EC- and LEC-Foxc mutant mice, respectively. This study provides evidence that FOXC1 and FOXC2 are required for intestinal regeneration by stimulating paracrine CXCL12 and Wnt signaling.


Enhancement of cellular and humoral immunity following embryonic exposure to melatonin in turkeys (Meleagris gallopavo).
Two experiments were performed to determine the effect of in ovo melatonin supplementation on the ontogeny of immunity in the Large White turkey poult. Different levels of melatonin were injected into the air cell of the egg 4 days prior to hatch. In Experiment 1, turkey embryos received 3 ml of solution containing 200, 100, 50, 25, 10, or 1 microg/ml of melatonin. The hatchability at each dose was determined and compared to vehicle-injected controls. In Experiment 2, only poults from melatonin treatments in Experiment 1 that resulted in normal hatchability (10 and 1 microg/ml) were used. Lymphoproliferative responses to phytohemagglutinin (PHA-P) and primary antibody responses to Chukar red blood cells (CRBC) were determine at five time intervals: 0, 1, 7, 14, and 21 days post-hatch. At each of these times, including 28 days post-hatch, treatment effects on body weights were determined. At 28 days post-hatch, bursal, thymic, and splenic weights were obtained. In ovo melatonin administration significantly accelerated (P0.05) the development of cell-mediated (PHA-P) and humoral (CRBC) immune responses, and these responses were significantly elevated above vehicle-injected controls through 21 days post-hatch. No effect was observed on bursal, thymic, splenic or body weights. These data suggest that embryonic exposure to melatonin enhances post-hatch immune development and responsiveness.


Effects of microbubbles on ultrasound-mediated gene transfer in human prostate cancer PC3 cells: comparison among Levovist, YM454, and MRX-815H.
We compared the enhancement effects of three different echo contrast agents (ECAs); Levovist, YM454, and MRX-815H as artificial microbubbles on ultrasound mediated gene transfection (USMGT) with 1MHz ultrasound at 0.2MPa using a luciferase expression vector in PC3 cells and elucidated the mechanisms of differences of USMGT facilitation by these ECAs. At a concentration of each ECA that induced iso-survival, ECAs with lipid shell (YM454 and MRX-815H) facilitated USMGT higher than those without shell (Levovist), and the order of the ECAs facilitating free radical formation by sonication was; YM454>MRX-815H>Levovist. These results suggested that the lipid shell type ECAs facilitated gene transfer higher than that by the non-shell type ECA.