Plasma levels of amino acids in elderly long term care residents with oropharyngeal dysphagia: comparison of hand-oral with tube-enteral-fed patients.
Dysphagia and eating difficulties are highly prevalent in long term care patients. Evaluation of their nutritional status is complicated by comorbidity, frailty and individual patterns of feeding. In previous studies we found vitamin deficiencies (folic acid B6 and B12) in orally fed elderly in early stages of oropharyngeal dysphagia despite satisfactory nutritional parameters (BMI, albumin and hemoglobin). The aim of this study is to evaluate the plasma amino acids levels in these hand-oral fed elderly patients with dysphagia. Plasma amino acids were measured in 15 orally fed elderly patients in early functional outcome swallowing scale (FOSS), stage 2, and compared with those of 15 matched nasogastric-tube-fed counterparts. The plasma levels of all measured amino acids, ratio of essential to nonessential, levels of conditionally essential and the immune-enhancing amino acids were similar in both groups and within the normal range of our laboratory. The traditional nutritional parameters were also similar in both groups and within the normal range. Plasma levels of amino acids in elderly patients in early stage of FOSS are satisfactory, supporting the view that their protein intake is adequate. Further studies should concentrate on patients in advanced stages of FOSS.


Cost of management of invasive growth hormone-secreting macroadenoma.
At the time of diagnosis, macroadenomas represent 60-80% of GH secreting adenomas, of which 25-30% are invasive macroadenomas. These aggressive tumors have the worst surgical success rates in terms of cure, and often need several therapeutic approaches in order to control disease status. Acromegalic patients are subject to increased mortality and important health resource consumption related to their associated co-morbidities, in addition to the costs that are related to diagnosis itself and initial treatment of the disease. Assessment of the cost of initial management and outcome of acromegalic patients with invasive pituitary adenomas. Retrospective and observational study of review of records. Two tertiary hospitals. 11 consecutive patients between 18 and 80 yr old diagnosed with acromegaly due to an invasive pituitary macroadenoma. Collection of data of biochemical and radiological tests, specialist visits, hospitalisation, surgery, pharmacological and radiotherapy treatment at diagnosis and over 4 yr of follow-up after initial treatment. Costs were evaluated using the data of the Centre for Health Economics and Social Policy Studies and the Official College of Pharmacists of Spain. Global and patient/yr follow-up costs of illness. The mean costs for acromegaly for the period of follow-up ranged from 7,072 to 9,874 euro/patient/yr, for biochemically non-controlled (no.=6) and controlled patients (no.=5) respectively. The most important cost in the perioperative period was for admission in the intensive care unit. After surgery, SS analogues were the principal contributors to the economic burden. In this paper we have for the first time presented a pharmacoeconomic study of GH secreting invasive macroadenoma. The poor prognosis of our cohort of patients and the higher rate of controlled patients and normal IGF-I levels warrant the employment of multiple therapeutic options. The cost associated with this treatment in this complex disease of low prevalence is not excessive and can be supported by healthcare services.


Orbital decompression in graves' ophthalmopathy by medial and lateral wall removal.
The objective of this study is to describe a technique for balanced orbital decompression and to analyze the results. We conducted a retrospective study of 140 patients (276 orbits). Orbital decompression was carried out by removal of the medial orbital wall by ethmoidectomy and complete removal of the lateral wall by bringing out the entire sphenoid wing together with part of the zygomatic bone down to the inferior orbital fissure. One hundred thirty-six patients underwent bilateral decompression, 4 patients underwent monolateral decompression. Proptosis was reduced on average by 5.3 mm; 28 (20%) patients showed onset or worsening of diplopia. Medial and lateral approach allows a balanced orbital decompression. As some patients may present different degrees of proptosis and visual impairment, we stress the importance of carefully weighing the preoperative conditions of the individual patient when choosing the surgical approach.


What Is the 30-Day Mortality Burden After Elective Total Hip Arthroplasty? An Analysis of 194,062 Patients.
This study aims to answer the following questions regarding elective total hip arthroplasty (THA): What is (1) the overall 30-day mortality rate; (2) the mortality rate when stratified by age, comorbidities, and preoperative diagnosis; and (3) the distribution of patient demographics, comorbidities, and preoperative diagnoses between the mortality and mortality-free cohorts? The American College of Surgeons National Surgical Quality Improvement Program database was reviewed for all patients undergoing elective primary THA (2011-2018). A total of 194,062 patients were categorized based on the incidence of 30-day mortality (mortality: n = 206 vs mortality-free: n = 193,856). Patient demographics, comorbidities, and preoperative diagnosis (osteoarthritis [OA] vs non-OA) were recorded. Age category, American Society of Anesthesiologists (ASA) score, and modified Charlson Comorbidity Index (CCI) scores were normalized per 1000 and stratified by preoperative diagnosis. The 30-day mortality rate was 0.11%. The percentage of deaths per age group (normalized per 1000) was 0% (18-29 years), 0% (30-39 years), 0.049% (40-49 years), 0.052%(50-59 years), 0.071% (60-69 years), 0.133% (70-79 years), and 0.352% (80-89 years). The percentage of deaths per ASA score was 0% (ASA I), 0.035% (ASA II), 0.174% (ASA III), and 1.008% (ASA IV). The percentage of deaths per CCI score was 0.09% (CCI = 0), 0.23% (CCI = 1), 0.74% (CCI = 2), 3.21% (CCI = 3), 4.76% (CCI = 4), and 0.57% (CCI ≥ 5). Non-OA diagnoses were significantly more frequent in the mortality cohort (16.0% vs 7.6%; P < .001). The risk of mortality was highest in patients aged 80-89, patients of ASA class IV, patients with a CCI score of 4, and patients with a non-OA diagnosis. The overall rate of death was higher in the non-OA cohort compared to the OA cohort. III.


Aspiration thrombectomy in ST-Elevation myocardial infarction: Further insights from a network meta-analysis of randomized trials.
The initial enthusiasm for thrombectomy during percutaneous coronary intervention (PCI) of ST-elevation myocardial infarction (STEMI) patients has given way to restraint. There has been some limited interest whether it is beneficial in a few selected subgroups. Hence, we performed a network meta-analysis to compare conventional PCI (cPCI), Aspiration or manual thrombectomy (AT) and Mechanical thrombectomy (McT) for clarification. Electronic databases were searched for randomized studies that compared AT, McT, or cPCI. A network meta-analysis was performed and odd's ratio (OR) with 95% confidence intervals was generated for major adverse cardiac events (MACE), mortality, myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST), stroke, left ventricular ejection fraction (LVEF), myocardial blush grade (MBG) and ST segment resolution (STR). A total of 43 randomized trials (n = 26,682) were included. The risk of MACE (OR 0.86 95% CI 0.73-1.00), Mortality (OR 0.85 95% CI 0.73-0.99), MI (OR 0.65, 95% CI: 0.44-0.95) and TVR (OR 0.86, 95% CI: 0.74-1.00) were lower with AT compared to cPCI. The risk of ST and stroke was no different with the use of adjunctive AT. MBG, STR, and LVEF improved with the use of AT while the infarct size was no different in the two groups. Our comprehensive network meta-analysis suggests conflicting outcomes with AT. While Mortality, MACE, MI seem better, there is a suggestion that, Stroke and ST might be worse. Whether AT can still be pursued in any select cases should be further scrutinized.


In vivo uptake of a fluorescent conjugate of melanin-concentrating hormone in the rat brain.
Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide synthesized by posterior hypothalamic and incerto-hypothalamic neurons that project throughout the central nervous system. The MCHergic system modulates several important functions such as feeding behavior, mood and sleep. MCH exerts its biological functions through interaction with the MCHR-1 receptor, the only functional receptor present in rodents. The internalization process of MCHR-1 triggered by MCH binding was described in vitro in non-neuronal heterologous systems with over-expression of MCHR-1. Reports of in vivo MCHR-1 internalization dynamics are scarce, however, this is an important process to explore based on the critical functions of the MCHergic system. We had previously determined that 60 min after intracerebroventricular (i.c.v.) microinjections of MCH conjugated with fluorophore rhodamine (R-MCH), the dorsal and median raphe nucleus presented R-MCH positive labeled neurons. In the present work, we further studied the in vivo uptake process focusing on the distribution and time-dependent pattern of R-MCH positive cells 10, 20 and 60 min (T10, T20 and T60, respectively) after i.c.v. microinjection of R-MCH. We also explored this uptake process to see whether it was receptor- and clathrin-dependent and examined the phenotype of R-MCH positive cells and their proximity to MCHergic fibers. We found a great number of R-MCH positive cells with high fluorescence intensity in the lateral septum, nucleus accumbens and hippocampus at T20 and T60 (but not at T10), while a lower number with low intensity was observed in the dorsal raphe nucleus. At T20, in rats pre-treated with a MCHR-1 antagonist (ATC-0175) or with phenylarsine oxide (PAO), a clathrin endocytosis inhibitor, a robust decrease (> 50 %) of R-MCH uptake occurred in these structures. The R-MCH positive cells were identified as neurons (NeuN positive, GFAP negative) and some MCHergic fibers run in the vicinities of them. We concluded that neurons localized at structures that were close to the ventricular surfaces could uptake R-MCH in vivo through a receptor-dependent and clathrin-mediated process. Our results support volume transmission of MCH through the cerebrospinal fluid to reach distant targets. Finally, we propose that R-MCH would be an effective tool to study MCH-uptake in vivo.


Luminescence sensitization of Tb3+-DNA complexes by Ag.
Terbium ions (Tb3+) with unique photophysical properties have been utilized to develop biosensors with low background and high sensitivity. In this study, the Ag+-sensitized luminescence of Tb3+-DNA complexes was uncovered. The luminescence of Tb3+-DNA complexes could be enhanced by more than 30 times in the presence of Ag+, when Tb3+ was bound with poly(G) and poly(T) whereas not with other homopolymers. This research confirmed that the sensitization resulted from the interaction of Ag+ with certain bases involved in DNA, not just with the reported certain G-quadruplex sequence. The coordination of Ag+ to guanine and thymine bases was expected to increase their rigidities, form Tb3+-DNA-Ag+ ternary structures, and thus enhance energy transfer from guanine and thymine to Tb3+. These findings benefit the development of sensitive luminescence probes for various nucleic acids-related targets.


Pharmacokinetics of voriconazole and its alteration by Candida albicans infection in silkworms.
Voriconazole (VRCZ) is a triazole antifungal agent used for the treatment and prophylaxis of invasive fungal infections. Therapeutic drug monitoring of VRCZ is widely applied clinically because of the large inter-individual variability that is generally observed in VRCZ exposure. The blood levels of VRCZ are increased during an underlying inflammatory reaction, which is associated with infections. Silkworms are useful experimental animals for evaluating the pharmacokinetics and toxicity of compounds. In this study, we investigated the pharmacokinetic parameters, such as elimination half-life, clearance, and distribution volume of VRCZ using silkworms. The pharmacokinetic parameters of VRCZ were determined based on the concentrations in silkworm hemolymph after injection of VRCZ. The elimination half-life of VRCZ in silkworms was found to be similar to that observed in humans. In addition, we assessed the impact of Candida albicans infection on VRCZ concentrations in a silkworm infection model. The VRCZ concentration at 12 h after injection in the Candida albicans-infected group was significantly higher than that in the non-infected group. In the silkworm infection model, we were able to reproduce the relationship between inflammation and VRCZ blood concentrations, as observed in humans. We demonstrate that silkworms can be an effective alternative model animal for studying the pharmacokinetics of VRCZ. We also show that silkworms can be used to indicate essential infection and inflammation-based pharmacokinetic variations in VRCZ, which is usually observed in the clinic.


Generation of induced pluripotent stem cells from a Bardet-Biedl syndrome patient carrying a homologous BBS2 c.534 + 1G > T mutation.
Bardet-Biedl syndrome is a autosomal recessive hereditary disorder characterized by polydactyly, multiple renal cysts, retinal cone-rod dystrophy, obesity, and variable neural development or cognitive impairment. We reported the generation and characterization of an iPS cell line, IBMS-iPSC-063-06, from a patient carrying the BBS2 homologous c534 + 1G > T mutation. The generated iPS cell line retains the mutation and exhibits pluripotency and differentiation ability both in vivo and in vitro condition.


CAP37-derived antimicrobial peptides have in vitro antiviral activity against adenovirus and herpes simplex virus type 1.
The antiviral activity of an established antibacterial CAP37 domain and its extracellular mechanism of action were investigated. CAP37-derived peptides modified to assess the importance of disulfide bonds were evaluated in cytotoxicity and antiviral assays (direct time kill, dose dependency, and TOTO-1) for adenovirus (Ad) and herpes simplex virus type 1 (HSV-1). Variable virus, adenovirus serotype-dependent, and dose-dependent inhibition were demonstrated without cytotoxicity. For peptide A (CAP37(20-44)), TOTO-1 dye uptake was demonstrated for Ad5 and HSV-1. Unlike the antibacterial activity of this CAP37 domain, its antiviral activity is not fully dependent upon disulfide bond formation. Viral inhibition appears to result, in part, from disruption of the envelope and/or capsid.


Prognosis and outcome determinants after heart failure diagnosis in patients who underwent aortic valvular intervention.
To study clinical phenotype, prognosis for all-cause and cardiovascular (CV) mortality and predictive factors in patients with incident heart failure (HF) after aortic valvular intervention (AVI) for aortic stenosis (AS). In this retrospective, observational study we included patients from the Swedish Heart Failure Registry (SwedeHF) recorded 2003-2016, with AS diagnosis and AVI before HF diagnosis. The AS diagnosis was established according to International Classification of Diseases 10th revision (ICD-10) codes, thus without information concerning clinical or echocardiographical data on the aortic valve disease. The patients were divided into two subgroups: left ventricular ejection fraction (LVEF) ≥ 50% (AS-HFpEF) and <50% (AS-HFrEF). We individually matched three controls with HF from the SwedeHF without AS (control group) for each patient. Baseline characteristics, co-morbidities, survival status and outcomes were obtained by linking the SwedeHF with two other Swedish registries. We used Kaplan-Meier curves to present time to all-cause mortality, cumulative incidence function for time to CV mortality and Cox proportional hazards model to evaluate the relative difference between AS-HFrEF and AS-HFpEF and AS-HF and controls. The crude all-cause mortality was 49.0%, CV mortality 27.9% in AS-HF patients, respectively 44.7% and 26.6% in matched controls. The adjusted risk for all-cause mortality and CV mortality was similar in HF, regardless of LVEF vs. controls. No significant difference in factors predicting higher all-cause mortality was observed in AS-HFrEF vs. AS-HFpEF, except for diabetes (only in AS-HFrEF), with statistically significant interaction predicting death between the two groups. In this nationwide SwedeHF study, we characterized incident HF population after AVI. We found no significant differences in all-cause and CV mortality compared with general HF population. They had virtually the same predictors for mortality, regardless of LVEF.


Effect of the probiotic Enterococcus faecium SF68 on presence of diarrhea in cats and dogs housed in an animal shelter.
Beneficial effects of probiotics have never been analyzed in an animal shelter. Dogs and cats housed in an animal shelter and administered a probiotic are less likely to have diarrhea of ≥2 days duration than untreated controls. Two hundred and seventeen cats and 182 dogs. Double blinded and placebo controlled. Shelter dogs and cats were housed in 2 separate rooms for each species. For 4 weeks, animals in 1 room for each species was fed Enterococcus faecium SF68 while animals in the other room were fed a placebo. After a 1-week washout period, the treatments by room were switched and the study continued an additional 4 weeks. A standardized fecal score system was applied to feces from each animal every day by a blinded individual. Feces of animals with and without diarrhea were evaluated for enteric parasites. Data were analyzed by a generalized linear mixed model using a binomial distribution with treatment being a fixed effect and the room being a random effect. The percentage of cats with diarrhea ≥2 days was significantly lower (P = .0297) in the probiotic group (7.4%) when compared with the placebo group (20.7%). Statistical differences between groups of dogs were not detected but diarrhea was uncommon in both groups of dogs during the study. Cats fed SF68 had fewer episodes of diarrhea of ≥2 days when compared with controls suggests the probiotic may have beneficial effects on the gastrointestinal tract.


Localized delivery of immunotherapeutics: A rising trend in the field.
Immunotherapy is becoming a new standard of care for multiple cancers, while several limitations are impending its further clinical success. Immunotherapeutic agents often have inappropriate pharmacokinetics on their own and/or exhibit limited specificity to tumor cells, leading to severe immuno-related adverse effects and limited efficacy. Suitable formulating strategies that confer prolonged contact with or efficient proliferation in tumors while reducing exposure to normal tissues are highly worthy to explore. With the assistance of biomaterial carriers, targeted therapy can be achieved artificially by implanting or injecting drug depots into desired sites, about which the wisdoms in literature have been rich. The relevant results have suggested a "local but systemic" effect, that is, local replenishment of immune modulators achieves a high treatment efficacy that also governs distant metastases, thereby building another rationale for localized delivery. Particularly, implantable scaffolds have been further engineered to recruit disseminated tumor cells with an efficiency high enough to reduce tumor burdens at typical metastatic organs, and simultaneously provide diagnostic signals. This review introduces recent advances in this emerging area along with a perspective on the opportunities and challenges in the way to clinical application.


Towards using convolutional neural network to locate, identify and size defects in phased array ultrasonic testing.
Machine learning algorithms are widely used in image recognition. In Phased Array Ultrasonic Testing (PAUT), images are typically formed through constructive and destructive superpositions of signals backscattered from flaws or geometric features. However, all PAUT data acquisition schemes require several emissions and the duration of the acquisition may be too slow in high-speed manufacturing. In this study, the Faster R-CNN was used to identify, locate and size flat bottom holes (FBH) and side-drilled holes (SDH) in an immersed test specimen using a single plane wave insonification. The training was performed on segmented and classified data generated using GPU-accelerated finite element simulations. SDH and FBH of different diameters, depths and lateral positions were included in the training set. The thickness of the test specimen was also variable. An ultrasonic phased array probe of 64 elements was simulated. All elements of the phased array probe were fired at the same time and the time traces from each element were recorded. The individual time traces were concatenated to form a matrix, which was then used in the training. This inspection scenario enables fast acquisition of data at the expense of poor lateral resolution in the resulting image. The trained neural network was initially tested using finite element simulations. Results were assessed in terms of the intersection of the union (IoU) between the ground truth geometry and the predicted geometry. With the simulated cases, the thickness of the test specimen was detected in all cases. When using a 40% IoU threshold, the detection rate of the FBH was 87% while only 20% for the SDH. The smallest detected FBH had a 0.56 wavelength depth and a lateral extent of 1.04 wavelength. Drawing a box using the -6dB drop method around the FBH always led to an IoU under 15%. On average, the lateral extent of the FBH using the -6dB method was three times larger than the diameter predicted by the proposed method. Then, the training was continued with a small augmented dataset of experiments (equivalent to 3% of the simulated dataset). In experiments, the results show that the test specimen was always correctly identified. When using a 40% IoU threshold the experimental detection rate of the FBH was 70%. The smallest detected defect in experiments had a depth of 2 wavelengths.


Risk factors for tuberculosis among health care workers in South India: a nested case-control study.
The epidemiology of tuberculosis (TB) among health care workers (HCWs) in India remains under-researched. This study is a nested case-control design assessing the risk factors for acquiring TB among HCWs in India. It is a nested case-control study conducted at a tertiary teaching hospital in India. Cases (n = 101) were HCWs with active TB. Controls (n = 101) were HCWs who did not have TB, randomly selected from the 6,003 subjects employed at the facility. Cases and controls were compared with respect to clinical and demographic variables. The cases and controls were of similar age. Logistic regression analysis showed that body mass index (BMI) <19 kg/m(2) (odds ratio [OR]: 2.96, 95% confidence interval [CI]: 1.49-5.87), having frequent contact with patients (OR: 2.83, 95% CI: 1.47-5.45) and being employed in medical wards (OR: 12.37, 95% CI: 1.38-110.17) or microbiology laboratories (OR: 5.65, 95% CI: 1.74-18.36) were independently associated with increased risk of acquiring TB. HCWs with frequent patient contact and those with BMI <19 kg/m(2) were at high risk of acquiring active TB. Nosocomial transmission of TB was pronounced in locations, such as medical wards and microbiology laboratories. Surveillance of high-risk HCWs and appropriate infrastructure modifications may be important to prevent interpersonal TB transmission in health care facilities.


Trade-Offs with rehabilitation Effectiveness (REs) and Efficiency (REy) in a sample of Italian disabled persons in a in post-acuity rehabilitation unit.
Intensive Rehabilitation Centres, known in Italy as "code 56", admit patients who need to recover from an acute episode. Different Rehabilitation Impact Indices have been proposed as composite rehabilitation outcomes measuring the rate of improvement due to a rehabilitation program. The most widely employed measure the performance of Activities of daily living in rehabilitation is the modified Barthel Index. The Barthel Index-based Rehabilitation Impact Indices are the Rehabilitation Effectiveness and the Rehabilitation Efficiency. The aim of our study was to evaluate the trade-off between Rehabilitation Effectiveness tayand Rehabilitation Efficiency with respect to the Barthel Index admission score and the Length Of Stay, and their ideal ranges that optimized both indices. We retrospectively evaluated data of all patients admitted to intensive rehabilitation unit of the Scientific Institute for Research and Healthcare San Raffaele Pisana of Rome, from January 2006 to March 2018. The primary outcome measures of our study were patient's Rehabilitation Effectiveness and Rehabilitation Efficiency during the hospital stay. A database of 3,466 patients was analysed and the Rehabilitation Effectiveness and Rehabilitation Efficiency indexes were calculated. We calculated the median rank ratio of the Rehabilitation Effectiveness to the Rehabilitation Efficiency against Barthel Index scores. We calculated the median rank ratio of the Rehabilitation Effectiveness to Rehabilitation Efficiency against Barthel Index scores and days of stay. The median rank ratio of the Rehabilitation Effectiveness to the Rehabilitation Efficiency value were 1 in the range of Barthel Index scores from 32 to 42. The median rank ratio of the Rehabilitation Effectiveness to Rehabilitation Efficiency value were 1 for a Length of Stay corresponding to 33 days. In our study we calculated the Trade-offs between Rehabilitation Effectiveness and Rehabilitation Efficiency with respect to admission Barthel Index Score and Length Of Stay in a population of 3,466 patients affected by orthopedic (1,707) and neurological (1,759) diseases. Every member of the healthcare team should be aware of such trade-offs when they make decisions about rehabilitation services.


Performance of pre-hospital evaluations in ruling out invasive chest stab wounds.
Some guidelines advocate for managing patients with penetrating thoracic wounds in trauma centres with cardiothoracic surgery. This systematic approach is questionable. Only 15% of these patients require surgery. It is known that clinical examination fails to detect hemopneumothorax in penetrating trauma. However, no studies have evaluated the combined diagnostic performance of vital signs and the clinical evaluation of wounds. The clinical characteristics of wounds have not been investigated. We aimed to evaluate the ability of combinations of pre-hospital signs to rule out invasive chest stab trauma. This was a prospective observational study. All consecutive adult patients hospitalized in the perioperative acute care unit of a tertiary university hospital were included. Injury diagnoses were provided by exploratory surgery and imaging tests. Patients with a final diagnosis of invasive wounds (IWs) and patients with only superficial wounds were compared. Data regarding management and outcome were analysed. A total of 153 patients were included. After imaging or surgery, 58 (38%) patients were diagnosed with only superficial wounds, and 95 (62%) were diagnosed with thoracic or abdominal IWs. The false-negative rate of pre-hospital evaluations in the diagnosis of IWs was 42% [31-51]IQR25-75. In stable patients, pre-hospital data could not rule out IWs, with a negative predictive value of 58% and a positive predictive value of 70%. Twenty-nine (19%) patients required early emergent cardiothoracic surgery. Among these patients, 8 (28%) had no evidence of IWs in the pre-hospital period. Among the 59 patients without pre-hospital signs of IWs, 19 (33%) underwent at least one emergent procedure. The combination of pre-hospital vital signs, visual evaluation of wounds, and physical examination failed to rule out IWs in patients with chest stab wounds. This implies that caution is needed in triage decision-making.


Contrasting effect of coniferous and broadleaf trees on soil carbon storage during reforestation of forest soils and afforestation of agricultural and post-mining soils.
Soils and forest soil in particular represent important pools of carbon (C). The amount of C stored in soil depends on the input of organic matter into the soil, but also on quality of the organic matter, which determines the proportion of organic matter that remains in the soil or that is released from the soil as CO2. Here, we present a quantitative review of common garden experiments in which various tree species were planted alongside each other. The main goals of the study were to determine whether: 1) the amount of sequestered C under broadleaf and coniferous trees could be affected by soil age and previous land use; 2) the C:N ratio of leaf litter is correlated with the amount of sequestered C; 3) the amount of sequestered C under broadleaf and coniferous trees could be affected by pH and clay content. We found that the effects of broadleaf and coniferous trees on soil organic carbon (SOC) sequestration differed with the stage of soil development. We used soils with different previous land uses as a representative of different stages of soil development. Forest soils and agricultural soils represent soils in later stages of soil development and post-mining soils represent soils in early stages of development. In forest soils, more SOC was stored under coniferous trees than under broadleaf trees. In post-mining soils the opposite trend was found, i.e., more SOC was stored under broadleaf than coniferous trees. In afforested agricultural soils, SOC sequestration did not differ between broadleaf and coniferous trees. SOC sequestration under broadleaf trees was highest in soils with high pH. SOC sequestration was negatively correlated with the litter C:N ratio in post-mining soils but not in other more mature soils. Similarly, SOC sequestration was negatively correlated with the litter C:N in alkaline soils and in soils with high clay content. These results suggest that dominant SOC sequestration mechanisms change with stage of soil development such that SOC storage is greater under broadleaf trees in immature soils but is greater under coniferous trees in mature soils.


Calibration for quantitative Fc-glycosylation analysis of therapeutic IgG1-type monoclonal antibodies by using glycopeptide standards.
Fc-glycosylation has crucial impact on the efficacy and safety of IgG-type therapeutic monoclonal antibodies (mAbs). In order to enhance the performance of MS-based bottom-up quantitation strategy, a library of glycopeptide standards containing 26 common IgG1-type Fc-glycoforms has been constructed via modified two-dimensional hydrophilic interaction liquid chromatography (HILIC) purification. Taking advantage of the acquired glycopeptide standards, calibrated quantitation strategy for Fc-glycosylation analysis of mAbs was established and evaluated on the basis of three LC-MS-based methods, including HILIC-MRM (multiple reaction monitoring), HILIC-SIM (selected ion monitor) and RPLC-SIM. Molar concentrations of eleven individual Fc-glycoforms (0.03 ± 0.001-13.77 ± 0.64 nmol mg-1) as well as degree of fucosylation (75.44-97.04%), galactosylation (3.39-49.47%) and mannosylation (1.12-21.22%) in six IgG1-type mAbs were achieved. In addition, Fc-glycosylation site occupancy was also determined from 98.05% to 99.83%. Compared with traditional MS-based quantitation via peak area normalization, the quantitation accuracy and precision of the calibrated strategy had been remarkably improved, especially when combining with HILIC separation. In addition, the transferability of calibrated quantitation as assessed by using MRM-based method had also been significantly enhanced on different instruments from different laboratories. This calibrated quantitation strategy using glycopeptide standards as calibrators will be useful for Fc-glycosylation analysis of IgG1-type mAbs with multiple glycosylation sites.


Deep learning early stopping for non-degenerate ghost imaging.
Quantum ghost imaging offers many advantages over classical imaging, including the ability to probe an object with one wavelength and record the image with another (non-degenerate ghost imaging), but suffers from slow image reconstruction due to sparsity and probabilistic arrival positions of photons. Here, we propose a two-step deep learning approach to establish an optimal early stopping point based on object recognition, even for sparsely filled images. In step one we enhance the reconstructed image after every measurement by a deep convolutional auto-encoder, followed by step two in which a classifier is used to recognise the image. We test this approach on a non-degenerate ghost imaging setup while varying physical parameters such as the mask type and resolution. We achieved a fivefold decrease in image acquisition time at a recognition confidence of [Formula: see text]. The significant reduction in experimental running time is an important step towards real-time ghost imaging, as well as object recognition with few photons, e.g., in the detection of light sensitive structures.


GABA enzymatic assay kit.
We developed an enzymatic assay system enabling easy quantification of 4-aminobutyric acid (GABA). The reaction of GABA aminotransferase obtained from Streptomyces decoyicus NBRC 13977 was combined to those of the previously developed glutamate assay system using glutamate oxidase and peroxidase. The three-enzyme system allowing GABA-dependent dye formation due to the oxidative coupling between 4-aminoantipyrine and Trinder's reagent enabled accurate quantification of 0.2 - 150 mg/L GABA. A pretreatment mixture consisting of glutamate oxidase, ascorbate oxidase and catalase eliminating glutamate, ascorbate, and hydrogen peroxide, respectively, was also prepared to remove those inhibitory substances from samples. Thus, constructed assay kit was used to measure the GABA content in tomato samples. The results were almost the same as that obtained by the conventional method using liquid chromatography-tandem mass spectrometry. The kit will become a promising tool especially for the on-site measurement of GABA content in agricultural products.


Handling climate change education at universities: an overview.
Climate change is a problem which is global in nature, and whose effects go across a wide range of disciplines. It is therefore important that this theme is taken into account as part of universities´ teaching and research programs. A three-tiered approach was used, consisting of a bibliometric analysis, an online survey and a set of case studies, which allow a profile to be built, as to how a sample of universities from 45 countries handle climate change as part of their teaching programs. This paper reports on a study which aimed at identifying the extent to which matters related to climate change are addressed within the teaching and research practices at universities, with a focus on the training needs of teaching staff. It consists of a bibliometric analysis, combined with an online worldwide survey aimed at ascertaining the degree of involvement from universities in reducing their own carbon footprint, and the ways they offer training provisions on the topic. This is complemented by a set of 12 case studies from universities round the world, illustrating current trends on how universities handle climate change. Apart from reporting on the outcomes of the study, the paper highlights what some universities are doing to handle climate issues, and discusses the implications of the research. The paper lists some items via which universities may better educate and train their students on how to handle the many challenges posed by climate change. The online version contains supplementary material available at 10.1186/s12302-021-00552-5.


Stationary distribution of a 2-island 2-allele Wright-Fisher diffusion model with slow mutation and migration rates.
The stationary distribution of the diffusion limit of the 2-island, 2-allele Wright-Fisher with small but otherwise arbitrary mutation and migration rates is investigated. Following a method developed by Burden and Tang (2016, 2017) for approximating the forward Kolmogorov equation, the stationary distribution is obtained to leading order as a set of line densities on the edges of the sample space, corresponding to states for which one island is bi-allelic and the other island is non-segregating, and a set of point masses at the corners of the sample space, corresponding to states for which both islands are simultaneously non-segregating. Analytic results for the corner probabilities and line densities are verified independently using the backward generator and for the corner probabilities using the coalescent.


Experiences of COVID-19-Related Racism and Impact on Depression Trajectories Among Racially/Ethnically Minoritized Adolescents.
In 2020, racially/ethnically minoritized (REMD) youth faced the "dual pandemics" of COVID-19 and racism, both significant stressors with potential for adverse mental health effects. The current study tested whether short- and long-term trajectories of depressive symptoms from before to during the COVID-19 pandemic differed between REMD adolescents who did and did not endorse exposure to COVID-19-era-related racism (i.e., racism stemming from conditions created or exacerbated by the COVID-19 pandemic). A community sample of 100 REMD adolescents enrolled in an ongoing longitudinal study of mental health was assessed before and during the COVID-19 pandemic. Participants were 51% girls, mean age = 16, standard deviation = 2.7, and identified as Latinx/Hispanic (48%), Multiethnic (34%), Asian American (12%), and Black (6%). REMD adolescents' depressive symptoms were elevated during the COVID-19 pandemic compared to pre-pandemic levels, and increases were more pronounced over time for those who endorsed exposure to COVID-19-era-related racism. In general, Asian American participants endorsed racism experiences at the highest rates compared to others, including being called names (42%), people acting suspicious around them (33%), and being verbally threatened (17%). Additionally, more than half of Black and Asian American participants reported worry about experiencing racism related to the COVID-19 pandemic, even if they had not experienced it to date. REMD adolescents are at increased risk for depressive symptoms related to converging stressors stemming from the COVID-19 pandemic and pandemic-related racism, which has the potential to widen racial/ethnic mental health disparities faced by the REMD youth.


A systematic review of non-drug interventions to prevent and treat anxiety in people with aphasia after stroke.
To investigate the effectiveness of non-drug interventions for people with aphasia in the prevention and/or treatment of anxiety post-stroke as either a primary or secondary outcome. A systematic search of Medline, CINAHL, PsycINFO and Cochrane Library up to March 2021 was carried out. Studies of stroke populations were included if people with aphasia represented 25% or more of the enrolled participants. Quality of the evidence was assessed. A narrative synthesis of results is presented. The PROSPERO record ID for this study is 106451. Ten studies were included: five randomised controlled trials (RCTs), a single case experimental design, and four pre-post studies. The quality of the RCT trials was at least adequate but none demonstrated a benefit to anxiety outcomes. Those studies that reported benefit were of lower-level evidence with respect to National Health and Medical Research Classifications. No studies were found that evaluated the prevention of anxiety after stroke for people with aphasia. Definitive conclusions about the effectiveness of non-drug interventions for the prevention and/or treatment of anxiety in people with aphasia post-stroke cannot be made. Interventions that may show promise for those with aphasia and symptoms of anxiety include mindfulness meditation, modified cognitive behaviour therapy, unilateral nostril breathing, and the "Enhance Psychological Coping after Stroke" programme. Further high-quality research with better reporting of the inclusion of participants with aphasia and their specific sub-group results are required.Implications for RehabilitationIt is important for rehabilitation professionals to consider prevention of anxiety post-stroke as well as treatment.Mindfulness meditation, modified cognitive behavioural therapy, unilateral nostril breathing, and the and the "Enhance Psychological Coping after Stroke" programme may be of benefit to people with aphasia post-stroke.Adapting intervention protocols to be more communicatively accessible and training health professionals in supported communication may help people with aphasia engage in psychological therapies.


Long-term protection in hamsters against human parainfluenza virus type 3 following mucosal or combinations of mucosal and systemic immunizations with chimeric alphavirus-based replicon particles.
No licensed vaccines are available to protect against parainfluenza virus type 3 (PIV3), a significant health risk for infants. In search of a safe vaccine, we used an alphavirus-based chimeric vector, consisting of Sindbis virus (SIN) structural proteins and Venezuelan equine encephalitis virus (VEE) replicon RNA, expressing the PIV3 hemagglutinin-neuraminidase (HN) glycoprotein (VEE/SIN-HN). We compared different routes of intramuscular (i.m.), intranasal (i.n.), or combined i.n. and i.m. immunizations with VEE/SIN-HN in hamsters. Six months after the final immunization, all hamsters were protected against live PIV3 i.n. challenge in nasal turbinates and lungs. This protection appeared to correlate with antibodies in serum, nasal turbinates and lungs. This is the first report demonstrating mucosal protection against PIV3 for an extended time following immunizations with an RNA replicon delivery system.


Intensive Care Unit Care of a Patient with Cirrhosis.
Patients with cirrhosis frequently require admission to the intensive care unit (ICU). Common indications for admission to ICU include one or more reasons of sepsis, shock due to any cause, acute gastrointestinal bleeding, and altered mentation either due to hepatic encephalopathy, alcohol withdrawal/intoxication, or metabolic encephalopathy. The appropriate critical care of an individual can determine the outcomes of these sick patients. The Airway, Breathing, Circulation, Disability (ABCD) approach to a patient admitted to ICU includes airway, breathing, circulation, and disability management. In this review, the authors discuss the common indications for ICU admission in a patient with cirrhosis and also their management.


Cloud shadows drive vertical migrations of deep-dwelling marine life.
Many zooplankton and fishes vertically migrate on a diel cycle to avoid predation, moving from their daytime residence in darker, deep waters to prey-rich surface waters to feed at dusk and returning to depth before dawn. Vertical migrations also occur in response to other processes that modify local light intensity, such as storms, eclipses, and full moons. We observed rapid, high-frequency migrations, spanning up to 60 m, of a diel vertically migrating acoustic scattering layer with a daytime depth of 300 m in the subpolar Northeastern Pacific Ocean. The depth of the layer was significantly correlated, with an ∼5-min lag, to cloud-driven variability in surface photosynthetically available radiation. A model of isolume-following swimming behavior reproduces the observed layer depth and suggests that the high-frequency migration is a phototactic response to absolute light level. Overall, the cumulative distance traveled per day in response to clouds was at least 36% of the round-trip diel migration distance. This previously undescribed phenomenon has implications for the metabolic requirements of migrating animals while at depth and highlights the powerful evolutionary adaptation for visual predator avoidance.


Transcriptome-wide characterization of the WRKY family genes in Lonicera macranthoides and the role of LmWRKY16 in plant senescence.
Lonicera macranthoides is an important woody plant with high medicinal values widely cultivated in southern China. WRKY, one of the largest transcription factor families, participates in plant development, senescence, and stress responses. However, a comprehensive study of the WRKY family in L. macranthoides hasn't been reported previously. To establish an extensive overview of the WRKY family in L. macranthoides and identify senescence-responsive members of LmWRKYs. RNA-Seq and phylogenetic analysis were employed to identify the LmWRKYs and their evolutionary relationships. Quantitative real-time (qRT-PCR) and transgenic technology was utilized to investigate the roles of LmWRKYs in response to developmental-, cold-, and ethylene-induced senescence. A total of 61 LmWRKY genes with a highly conserved motif WRKYGQK were identified. Phylogenetic analysis of LmWRKYs together with their orthologs from Arabidopsis classified them into three groups, with the number of 15, 39, and 7, respectively. 17 LmWRKYs were identified to be differentially expressed between young and aging leaves by RNA-Seq. Further qRT-PCR analysis showed 15 and 5 LmWRKY genes were significantly induced responding to tissue senescence in leaves and stems, respectively. What's more, five LmWRKYs, including LmWRKY4, LmWRKY5, LmWRKY6, LmWRKY11, and LmWRKY16 were dramatically upregulated under cold and ethylene treatment in both leaves and stems, indicating their involvements commonly in developmental- and stress-induced senescence. In addition, function analysis revealed LmWRKY16, a homolog of AtWRKY75, can accelerate plant senescence, as evidenced by leaf yellowing during reproductive growth in LmWRKY16-overexpressing tobaccos. The results lay the foundation for molecular characterization of LmWRKYs in plant senescence.


Design and implementation of a temporary emergency department-intensive care unit patient care model during the COVID-19 pandemic surge.
The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in rapid surges of critically ill patients infected with coronavirus disease 2019 (COVID-19) pneumonia presenting to the emergency department (ED) and requiring ICU admission nationwide. Despite adaptations in critical care personnel staffing, bed availability and supply provision, many inpatient ICUs have become acutely crowded, leading to boarding of critically ill patients with COVID-19 and other diseases in the ED. To address this scenario at our urban, safety net, tertiary care institution in the spring of 2020, we designed and implemented a temporary "emergency department-intensive care unit" (ED-ICU) patient care service. Critical care-trained emergency physicians took call and came into the hospital overnight/on weekends to provide bedside treatment to admitted ICU patients boarding for prolonged periods in our ED. In this manuscript, we describe the creation and execution of the ED-ICU service and the characteristics and management of the patients who received care under this model.


Induction of apoptosis in human lymphoblastoid cells by kaempferol 3-O-β-isorhamninoside and rhamnocitrin 3-O-β-isorhamninoside from Rhamnus alaternus L. (Rhamnaceae).
Kaempferol 3-O-β-isorhamninoside (K3O-ir) and rhamnocitrin 3-O-β-isorhamninoside (R3O-ir) from Rhamnus alaternus L leaves are investigated for their ability to induce apoptosis in human lymphoblastoid cells. We have attempted to characterize apoptotic pathway activated by these two flavonoids. Apoptosis of the human TK6 lymphoblastoid cell line was detected by DNA fragmentation, PARP cleavage and by evaluating caspase activity. Apoptosis was observed after 24- and 48-h incubation of the cells with the tested compounds. DNA fragmentation was observed after treatment with flavonoids; this was confirmed by demonstration of PARP cleavage. Caspase-3 and caspase-8 activities were induced by both K3O-ir and R3O-ir flavonoids showing highest activity with compound concentration of 400 μg/ml. We have demonstrated that K3O-ir and R3O-ir induce apoptosis in human lymphoblastoid cells by the extrinsic pathway of apoptosis.


The time it takes to reveal embarrassing information in a mobile phone survey.
To explore socially desirable responding in telephone surveys, this study examines response latencies in answers to 27 questions in 319 audio-recorded iPhone interviews from Schober et al. (2015). Response latencies were compared when respondents (a) answered questions on sensitive vs. nonsensitive topics (as classified by online raters); (b) produced more vs. less socially desirable answers; and (c) were interviewed by a professional interviewer or an automated system. Respondents answered questions on sensitive topics more quickly than on nonsensitive topics, though patterns varied by question format (categorical, numerical, ordinal). Independent of question sensitivity, respondents gave less socially desirable answers more quickly when answering categorical and ordinal questions but more slowly when answering numeric questions. Respondents were particularly quicker to answer sensitive questions when asked by interviewers than by the automated system. Findings demonstrate that response times can be (differently) revealing about question and response sensitivity in a telephone survey.


'I-shaped' sign in the upper mediastinum: a novel potential marker for antenatal diagnosis of d-transposition of the great arteries.
To investigate the 'I-shaped' sign as a novel echocardiographic marker for antenatal diagnosis of d-transposition of the great arteries (dTGA) in routine cardiac examination, and to compare its prevalence in fetuses with dTGA, those with other congenital heart diseases (CHDs) and those with normal structural hearts. This retrospective evaluation involved 1134 fetuses undergoing echocardiography to screen for CHD over a 4-year period. I-shaped sign was defined as the characteristic appearance of the aortic arch, resembling the letter 'I', from the most anterior to the most posterior point of the descending aorta visible in the three vessels and trachea view. The frequency of this sign was evaluated in cases with dTGA, those with other cardiac defects and those with normal cardiac structures. CHD was diagnosed in 671 (59.1%) cases, of which 31 (4.6%) had dTGA. I-shaped sign was observed in 30/31 (96.8%) cases of dTGA, compared with 31/640 (4.8%) cases with other cardiac anomalies, which included single ventricle with pulmonary atresia or severe pulmonary stenosis, hypoplastic left heart syndrome with aortic atresia, corrected transposition of the great arteries, and double outlet right ventricle with malposition of the great arteries. I-shaped sign was detected significantly more frequently in the dTGA group compared with the normal group and with the other CHDs group (both P < 0.001) and had 96.8% sensitivity and 97.1% specificity for diagnosis of dTGA. Importantly, I-shaped sign was never observed in fetuses with structurally normal hearts. Detection on echocardiography of an extremely long vessel with a marked I-shape should raise suspicion of cardiac anomaly, especially dTGA. This marker may therefore aid in the prenatal diagnosis of dTGA during routine ultrasound examination.


Time- and dose-dependent volume decreases in subcortical grey matter structures of glioma patients after radio(chemo)therapy.
Radiotherapy (RT) is an adjuvant treatment option for glioma patients. Side effects include tissue atrophy, which might be a contributing factor to neurocognitive decline after treatment. The goal of this study was to determine potential atrophy of the hippocampus, amygdala, thalamus, putamen, pallidum and caudate nucleus in glioma patients having undergone magnetic resonance imaging (MRI) before and after RT. Subcortical volumes were measured using T1-weighted MRI from patients before RT (N = 91) and from longitudinal follow-ups acquired in three-monthly intervals (N = 349). The volumes were normalized to the baseline values, while excluding structures touching the clinical target volume (CTV) or abnormal tissue seen on FLAIR imaging. A multivariate linear effects model was used to determine if time after RT and mean RT dose delivered to the corresponding structures were significant predictors of tissue atrophy. The hippocampus, amygdala, thalamus, putamen, and pallidum showed significant atrophy after RT as function of both time after RT and mean RT dose delivered to the corresponding structure. Only the caudate showed no dose or time dependant atrophy. Conversely, the hippocampus was the structure with the highest atrophy rate of 5.2 % after one year and assuming a mean dose of 30 Gy. The hippocampus showed the highest atrophy rates followed by the thalamus and the amygdala. The subcortical structures here found to decrease in volume indicative of radiosensitivity should be the focus of future studies investigating the relationship between neurocognitive decline and RT.


A quinoline-based fluorescent chemosensor for palladium ion (Pd2+)-selective detection in aqueous solution.
Quinoline-based fluorescent chemosensors have been extensively developed for various metal cations, but it was still rare for Pd2+-selective detection. In this work, a novel quinoline-benzimidazole conjugate containing one carboxylic acid group (QBM) was designed, and the QBM displayed highly selective fluorescence quenching response towards Pd2+ over other metal cations in aqueous solution. The fluorescence titration revealed a good linear relationship between the fluorescence intensity and the Pd2+ concentration in the range of 0.5-10 μmol L-1, with the detection limit of 0.26 μmol L-1 (S/N = 3). Fluorescence detection of Pd2+ in practical water sample was also successfully achieved.


Thickness Effect on the Solid-State Reaction of a Ni/GaAs System.
Ni thin films with different thicknesses were grown on a GaAs substrate using the magnetron sputtering technique followed by in situ X-ray diffraction (XRD) annealing in order to study the solid-state reaction between Ni and GaAs substrate. The thickness dependence on the formation of the intermetallic phases was investigated using in situ and ex situ XRD, pole figures, and atom probe tomography (APT). The results indicate that the 20 nm-thick Ni film exhibits an epitaxial relation with the GaAs substrate, which is (001) Ni//(001) GaAs and [111] Ni//[110] GaAs after deposition. Increasing the film's thickness results in a change of the Ni film's texture. This difference has an impact on the formation temperature of Ni3GaAs. This temperature decreases simultaneously with the thickness increase. This is due to the coherent/incoherent nature of the initial Ni/GaAs interface. The Ni3GaAs phase decomposes into the binary and ternary compounds xNiAs and Ni3-xGaAs1-x at about 400 °C. Similarly to Ni3GaAs, the decomposition temperature of the second phase also depends on the initial thickness of the Ni layer.


Deep learning nomogram based on Gd-EOB-DTPA MRI for predicting early recurrence in hepatocellular carcinoma after hepatectomy.
The accurate prediction of post-hepatectomy early recurrence in patients with hepatocellular carcinoma (HCC) is crucial for decision-making regarding postoperative adjuvant treatment and monitoring. We aimed to explore the feasibility of deep learning (DL) features derived from gadoxetate disodium (Gd-EOB-DTPA) MRI, qualitative features, and clinical variables for predicting early recurrence. In this bicentric study, 285 patients with HCC who underwent Gd-EOB-DTPA MRI before resection were divided into training (n = 195) and validation (n = 90) sets. DL features were extracted from contrast-enhanced MRI images using VGGNet-19. Three feature selection methods and five classification methods were combined for DL signature construction. Subsequently, an mp-MR DL signature fused with multiphase DL signatures of contrast-enhanced images was constructed. Univariate and multivariate logistic regression analyses were used to identify early recurrence risk factors including mp-MR DL signature, microvascular invasion (MVI), and tumor number. A DL nomogram was built by incorporating deep features and significant clinical variables to achieve early recurrence prediction. MVI (p = 0.039), tumor number (p = 0.001), and mp-MR DL signature (p < 0.001) were independent risk factors for early recurrence. The DL nomogram outperformed the clinical nomogram in the training set (AUC: 0.949 vs. 0.751; p < 0.001) and validation set (AUC: 0.909 vs. 0.715; p = 0.002). Excellent DL nomogram calibration was achieved in both training and validation sets. Decision curve analysis confirmed the clinical usefulness of DL nomogram. The proposed DL nomogram was superior to the clinical nomogram in predicting early recurrence for HCC patients after hepatectomy. • Deep learning signature based on Gd-EOB-DTPA MRI was the predominant independent predictor of early recurrence for hepatocellular carcinoma (HCC) after hepatectomy. • Deep learning nomogram based on clinical factors and Gd-EOB-DTPA MRI features is promising for predicting early recurrence of HCC. • Deep learning nomogram outperformed the conventional clinical nomogram in predicting early recurrence.


Assessment of dermal bioavailability: predicting the input function for topical glucocorticoids using stratum corneum sampling.
Predicting the dermal bioavailability of topically delivered drugs is challenging. In this work, minimally invasive stratum corneum (SC) sampling was used to quantify the delivery of betamethasone valerate (BMV) into the viable skin. Betnovate® cream (0.1% w/w BMV) was applied at three doses (2, 5, and 10 mg cm-2) to the ventral forearms of 12 healthy volunteers. The mass of drug in the SC was measured using a validated tape-stripping method (a) after a 4-h "uptake" period, and (b) following a 6-h "clearance" period subsequent to cream removal. Concomitantly, the skin blanching responses to the same doses were assessed with a chromameter over 22 h post-application. BMV uptake into the SC was significantly higher for the 5 mg cm-2 dose compared to those of 2 and 10 mg cm-2. In all cases, ~30% of the drug in the SC at the end of the uptake period was cleared in the subsequent 6 h. From the SC sampling data, the average drug flux into the viable epidermis and its first-order elimination rate constant from the SC were estimated as 4 ng cm-2 h-1 and 0.07 h-1, respectively. In contrast, skin blanching results were highly variable and insensitive to the dose of cream applied. The SC sampling method was able to detect a 50% difference between two applied doses with 80% power; detection of a 20% difference would require a larger sample size. SC sampling enabled quantitative metrics describing corticosteroid delivery to the viable epidermis to be determined.


Characterization of genetic diversity on tropical Trichoderma germplasm by sequencing of rRNA internal transcribed spacers.
Trichoderma species are found in soil and in association with plants. They can act directly or indirectly in the biological control of plant diseases and in the promotion of plant growth, being among the most used fungi in the formulation of bioproducts applied to agricultural systems. The main objective of this study was to characterize at a first-tier level a collection of 67 Trichoderma isolates from various tropical sources, based solely on sequencing of the internal transcribed spacer (ITS) region of the rRNA genes. Our goal was to provide a preliminary idea of the baseline diversity in this collection, to combine this information later with an array of other isolate-specific physiological data. This study provides a required knowledge at molecular level for assessment of this germplasm potential as a source of biotechnological products for beneficial effects in plants. Sequencing of the ITS region showed that the 67 Trichoderma isolates belonged in 11 species: T. asperellum, T. atroviride, T. brevicompactum, T. harzianum, T. koningiopsis, T. longibrachiatum, T. pleuroticola, T. reesei, T. spirale, T. stromaticum and T. virens. A total of 40.3% of the isolates were very closely related to each other and similar to T. harzianum. The baseline genetic diversity found indicates that the collection has different genotypes, which can be exploited further as a source of bioproducts, aiming at providing beneficial effects to plants of interest to cope with biotic and abiotic stresses.


Development and evaluation of a point-of-use UV appliance for fresh produce decontamination.
In-house treatment strategy for fresh produce decontamination has not been emphasized as much as industrial washing. The most common treatment for fresh produce decontamination and cleaning at home and other point-of-use places such as cafeteria is rinsing and/or soaking in a sink. In this study, an appliance utilizing UV and agitated water to decontaminate fresh produce was developed and its effectiveness was investigated in an aim to identify optimum processing parameters. Grape tomato and spinach representing two different surface smoothness were dip-inoculated in a four-strain Salmonella cocktail to reach a final population of 5-8 log CFU/g and air-dried. The produce samples were then washed in 1 gallon tap water under varying conditions, water agitation speed (0-190 RPM), sample size (50-400 g), UV intensity (0-30 mW/cm2) and treatment time (2, 5 and 10 min). In general, increasing the agitation speed and UV intensity enhanced Salmonella inactivation for both grape tomato and spinach. Sample size significantly affected the UV inactivation of Salmonella on grape tomato, but not on spinach. The effect of extending treatment time from 2 to 10 min was insignificant for almost all the UV treatments and the controls. The effect of UV intensity and treatment time on inactivation of Salmonella on spot-inoculated grape tomato and spinach was also determined. The most severe treatment used in this study, 30 mW/cm2 UV for 10 min, resulted in >4 log reductions of Salmonella dip- or spot-inoculated on grape tomato (200 g sample size and 190 RPM agitation speed) and 3.5 log reductions of Salmonella dip- or spot-inoculated on spinach (100 g sample size and 110 RPM agitation speed). We foresee that the UV appliance developed and evaluated in this study could be further fine-tuned and optimized to eventually construct a point-of-use UV appliance that can be used at home, cafeteria, restaurants, and hospitals for fresh produce decontamination and cleaning. The UV appliance could be an inexpensive and effective tool to improve fresh produce safety.


Quality of life and emotional burden after transnasal and transcranial anterior skull base surgery.
To analyze psychopathological outcome and health-related quality of life (QOL) for cohorts of patients undergoing transcranial or transnasal anterior skull base surgery. A prospective study of patients undergoing elective surgery for various entities of the anterior skull base was performed. Evaluation for depression (ADS-K score) and anxiety (PTSS, STAI-S, STAI-T, and ASI-3 scores) was done before surgery, at 3 and 12 months after surgery. The correlation between preoperative psychological burden and postoperative quality of life as measured by the SF-36 and EuroQol questionnaires was analyzed. Incidence and influence of these psychiatric comorbidities on clinical outcome were examined and compared between transnasal and transcranial subgroups. We included 54 patients scheduled for surgery of a pituitary adenoma or meningioma of the anterior skull base between January 2013 and July 2017. Of these, a cohort of 40 (74.1%) completed follow-up interviews after 3 and 12 months. There were 60.0% female patients, median age was 57 years. 57.5% of patients had a meningioma and were operated transcranially, while 42.5% of patients received transnasal surgery for pituitary adenoma. The proportion of pathological anxiety scores significantly decreased from 75.0 to 45.0% (p = 0.002), without difference between transnasal and transcranial subgroups. After 3 months, mean EuroQol VAS score non-significantly increased by 0.07 (p = 0.236) across the entire cohort without significant difference between transcranial and transnasal subgroups (p = 0.478). The transnasal cohort tended to score higher in anxiety scores, whereas the transcranial cohort demonstrated higher depression scores without significant difference, respectively. The individually declared emotional burden significantly decreased from 6.7 to 4.0 on the ten-point Likert scale (p < 0.001) equally for both subgroups (transnasal, - 2.3; transcranial, - 3.0; p = 0.174). On last examination, about half of the patients in each subgroup (41.2% vs. 52.2%; p = 0.491) expressed a considerable recovery of preoperative bodily complaints such as headaches, dizziness, and unrest defined as a score of at least 8 on the Likert scaled item. Both transnasal and transcranial approaches yield favorable postoperative QOL and psychopathological outcomes. The postoperative increase in QOL is partly influenced by preoperative expression of mental distress, which tends to resolve postoperatively.


Associations between early-life stress exposure and internalizing symptomatology during the COVID-19 pandemic: Assessing the role of neurobehavioral mediators.
The ongoing COVID-19 pandemic is a major stressor that has been associated with increased risk for psychiatric illness in the general population. Recent work has highlighted that experiences of early-life stress (ELS) may impact individuals' psychological functioning and vulnerability for developing internalizing psychopathology in response to pandemic-related stress. However, little is known about the neurobehavioral factors that may mediate the association between ELS exposure and COVID-related internalizing symptomatology. The current study sought to examine the mediating roles of pre-pandemic resting-state frontoamygdala connectivity and concurrent emotion regulation (ER) in the association between ELS and pandemic-related internalizing symptomatology. Retrospective life-stress histories, concurrent self-reported ER strategies (i.e., reappraisal and suppression), concurrent self-reported internalizing symptomatology (i.e., depression- and anxiety-related symptomatology), and resting-state functional connectivity data from a sample of adults (N = 64, M age = 22.12, female = 68.75%) were utilized. There were no significant direct associations between ELS and COVID-related internalizing symptomatology. Neither frontoamygdala functional connectivity nor ER strategy use mediated an association between ELS and COVID-related internalizing symptomatology (ps > 0.05). Exploratory analyses identified a significant moderating effect of reappraisal use on the association between ELS and internalizing symptomatology (β = -0.818, p = 0.047), such that increased reappraisal use buffered the impact of ELS on psychopathology. While frontoamygdala connectivity and ER do not appear to mediate the association between ELS and COVID-related internalizing symptomatology, our findings suggest that the use of reappraisal may buffer against the effect of ELS on mental health during the pandemic.


Dental students' treatment of anxious patients.
Patients' anxiousness over treatment is an important factor in the utilization, delivery, and outcome of health care. Patient anxiety over dental treatment is widespread and is a source of stress for both patients and dentists. This paper reports a study of how dental students cope with fearful patients they treat during training, and what tactics they believe are effective. Two classes of senior dental students at a state university (n = 127) completed a brief questionnaire that asked them to describe what they had done in a previous encounter with a nervous patient, and to assess the effect of their actions. Students estimated that almost a quarter of their patients were anxious; most believed that they themselves were made nervous by such patients. Virtually all were committed to using talk plus local anesthesia rather than more extensive, drug-oriented methods. The coping repertoire was extensive. Giving reassurance was the most prominent tactic, followed by providing information about the procedure; expressing empathy or identifying patient feelings and the source of fear; and presenting a calm manner. Most students believed their actions had at least some positive, if not a dramatic, effect. In rating the effectiveness of 10 actions a dentist can take to deal with patient anxiety, the large majority of students rated every behavior as being at least somewhat effective. The behaviors rated 'very effective' by half or more of the students included having a calm manner, demonstrating that what the patient says is taken seriously, being friendly, making the patient feel welcome, and giving moral support during the procedure.


Morbidity after neonatal inguinal herniotomy.
Neonatal inguinal herniotomy is recognised by paediatric surgeons to be a potentially difficult procedure. This study reviewed the clinical, operative, and outcome details of 74 infants undergoing herniotomy at less than 44 weeks' gestation with particular reference to the incidence of complications such as recurrent hernia and testicular atrophy. Follow-up information was obtained in 69 patients (93%, mean follow-up, 8.1 months). There were 8 recurrent hernias in 5 patients (2 bilateral recurrences, 1 second recurrence) giving an overall hernia recurrence rate of 8.6%. There was only 1 case of testicular atrophy (secondary to a wound infection and scrotal abscess). Despite the provision of a consultant-led service, the recurrence rate in neonates is much higher than that seen in the paediatric population as a whole. In light of commissioners' current demands for quality standards and managed healthcare, it is important that outcomes in this high-risk group are defined separately from those of other patients undergoing inguinal herniotomy.


Evolución de la cirugía urgente en un servicio de cirugía general durante la pandemia de COVID-19 y comparación con una cohorte histórica.
Acute care surgery decreased during the first wave of the COVID-19 pandemic. To study the evolution of acute care surgery and its relationship with the pandemic severity. Retrospective cohort study which compared patients who underwent acute care surgery during the pandemic to a control group. A total of 660 patients were included (253 in the control group, 67 in the first-wave, 193 in the valley, and 147 in the second wave). The median daily number of acute care surgery procedures was 2 during the control period. This activity decreased during the first wave (1/day), increased during the valley (2/day), and didn't change in the second wave (2/day). Serious complications were more common during the first wave (22.4%). A negative linear correlation was found between the daily number of acute care surgery procedures, number of patients being admitted to the hospital each day and daily number of patients dying because of COVID-19. Acute care surgery was reduced during the first wave of the COVID-19 pandemic, increased during the valley, and returned to the pre-pandemic level during the second wave. Thus, acute care surgery was related to pandemic severity, with fewer surgeries being performed when the pandemic was more severe.


Exploiting Electrode Nanoconfinement to Investigate the Catalytic Properties of Isocitrate Dehydrogenase (IDH1) and a Cancer-Associated Variant.
Human isocitrate dehydrogenase (IDH1) and its cancer-associated variant (IDH1 R132H) are rendered electroactive through coconfinement with a rapid NADP(H) recycling enzyme (ferredoxin-NADP+ reductase) in nanopores formed within an indium tin oxide electrode. Efficient coupling to localized NADP(H) enables IDH activity to be energized, controlled, and monitored in real time, leading directly to a thermodynamic redox landscape for accumulation of the oncometabolite, 2-hydroxyglutarate, that would occur in biological environments when the R132H variant is present. The technique enables time-resolved, in situ measurements of the kinetics of binding and dissociation of inhibitory drugs.


Casein kinase 1 and disordered clock proteins form functionally equivalent, phospho-based circadian modules in fungi and mammals.
Circadian clocks are timing systems that rhythmically adjust physiology and metabolism to the 24-h day-night cycle. Eukaryotic circadian clocks are based on transcriptional-translational feedback loops (TTFLs). Yet TTFL-core components such as Frequency (FRQ) in Neurospora and Periods (PERs) in animals are not conserved, leaving unclear how a 24-h period is measured on the molecular level. Here, we show that CK1 is sufficient to promote FRQ and mouse PER2 (mPER2) hyperphosphorylation on a circadian timescale by targeting a large number of low-affinity phosphorylation sites. Slow phosphorylation kinetics rely on site-specific recruitment of Casein Kinase 1 (CK1) and access of intrinsically disordered segments of FRQ or mPER2 to bound CK1 and on CK1 autoinhibition. Compromising CK1 activity and substrate binding affects the circadian clock in Neurospora and mammalian cells, respectively. We propose that CK1 and the clock proteins FRQ and PERs form functionally equivalent, phospho-based timing modules in the core of the circadian clocks of fungi and animals.


Influence of Co doping on phase, structure and electrochemical properties of hydrothermally obtained CoxZn1-xFe2O4 (x = 0.0-0.4) nanoparticles.
In this work, CoxZn1-xFe2O4 (x = 0.0-0.4) nanoparticles (NPs) were successfully synthesized by a hydrothermal method at 200 °C for 12 h. X-ray diffraction revealed a pure cubic spinel phase of all samples with space group Fd-3m. Fourier transform infrared spectrometry disclosed the vibrational modes of metal oxides in the spinel structure. Scanning electron microscopy and transmission electron microscopy disclosed a uniform distribution of cuboidal shape NPs with a decreased average NPs size from 22.72 ± 0.62 to 20.85 ± 0.47 nm as the Co content increased. X-ray absorption near edge spectroscopy results confirmed the presence of Zn2+, Co2+ and Fe2+/Fe3+ in Co-doped samples. The pore volume, pore size and specific surface area were determined using N2 gas adsorption/desorption isotherms by the Brunauer-Emmett-Teller (BET) and Barrett-Joyner-Halenda (BJH) techniques. Electrochemical properties of supercapacitors, having active CoxZn1-xFe2O4 (x = 0.0-0.4) NPs as working electrodes, indicated pseudo-capacitor performance related to the Faradaic redox reaction. Interestingly, the highest specific capacitance (Csc), 855.33 F/g at 1 A/g, with a capacity retention of 90.41% after 1000 GCD cycle testing was achieved in the Co0.3Zn0.7Fe2O4 electrode.


Plutonium in coral archives: A good primary marker for an Anthropocene type section.
While we officially live in the Holocene epoch, global warming and many other impacts of global change have led to the proposal and wide adoption of the Anthropocene to define the present geological epoch. The Anthropocene Working Group (AWG) established that it should be treated as a formal stratigraphic unit, demonstrated by a reference level commonly known as "golden spike", still under discussion. Here we show that the onset of bomb-derived plutonium recorded in two banded massive corals from the Caribbean Sea is consistent (1955-1956 CE), so sites far from nuclear testing grounds are potentially suitable to host a type section of the Anthropocene. Coastal coral demonstration sites are feasible, could foster economic development, and may serve as focal points for scientific dissemination and environmental education.


Early effects of COVID-19 on physical activity and screen time use among elementary school students in Columbus, New Mexico.
Adherence to national physical activity guidelines among youth ages 6-11 in the United States is low. The emergence of COVID-19 and the public health measures implemented in response may have decreased children's physical activity even further. We conducted an online survey among parents of students attending Columbus Elementary School in Columbus, New Mexico, a rural community on the US-Mexico border, to assess changes in children's physical activity and screen time use from summer 2019 to summer 2020. We also sought to identify important covariates. All parents (N = 55) and children (N = 87) identified as Hispanic; most parents were born in Mexico, while most children were born in the United States. Most parents (79.3%) reported a decrease in their children's physical activity from 2019 to 2020, and the vast majority of these parents reported that the changes were due to COVID-19 home confinement. The mean number of days children were physically active for >60 minutes significantly decreased, while daily screen time use increased. Having parents born in Mexico, infrequent family meals (<3/week), and not having community spaces for physical activity close by protected children from decreases in their level of physical activity from 2019 to 2020. Home-based exercise may serve as a suitable method of physical activity when public health responses to COVID-19 restrict community spaces. Future interventions should also be mindful of the role that parental nativity and related cultural factors may play in children's physical activity levels.


The value of cytoreductive nephrectomy for metastatic renal cell carcinoma in the era of targeted therapy.
We evaluated the value of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma in the targeted therapy era. We reviewed the records of 78 patients treated with targeted therapy for metastatic renal cell carcinoma between 2006 and 2009. A total of 45 patients underwent cytoreductive nephrectomy followed by targeted therapy (cytoreductive nephrectomy group) and 33 were treated with targeted therapy alone (noncytoreductive nephrectomy group). We estimated progression-free and overall survival using Kaplan-Meier curves. The prognostic significance of each variable was estimated with a Cox proportional hazards regression model. Clinicopathological variables did not differ in the 2 groups except for Karnofsky performance status and sarcomatoid feature. The treatment response rate did not differ in the 2 groups (23.1% vs 30.3%, p = 0.488). Median progression-free survival was 11.7 and 9.0 months in the cytoreductive and noncytoreductive nephrectomy groups (p = 0.270), and median overall survival was 21.6 and 13.9 months, respectively (p = 0.128). On multivariate analysis Karnofsky performance status (HR 2.9, 95% CI 1.4-5.7, p = 0.003) and sarcomatoid features (HR 2.9, 95% 1.3-6.7, p = 0.013) were independent predictors of progression-free survival. Karnofsky performance status (HR 3.3, 95% 1.7-6.5, p = 0.001), sarcomatoid features (HR 2.7, 95% 1.2-6.2, p = 0.021) and liver metastasis (HR 2.7, 95% 1.0-7.1, p = 0.045) were independent predictors of overall survival. We found no significant differences in tumor response or survival between the 2 groups. Prospective trials are needed to confirm our results.


Evaluation of the prognostic value of CBXs in gastric cancer patients.
Chromobox (CBX) proteins were suggested to exert epigenetic regulatory and transcriptionally repressing effects on target genes and might play key roles in the carcinogenesis of a variety of carcinomas. Nevertheless, the functions and prognostic significance of CBXs in gastric cancer (GC) remain unclear. The current study investigated the roles of CBXs in the prognosis of GC using the Oncomine, The Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, The Cancer Genome Atlas (TCGA), and cBioPortal databases. CBX1/2/3/4/5 were significantly upregulated in GC tissues compared with normal tissues, and CBX7 was downregulated. Multivariate analysis showed that high mRNA expression levels of CBX3/8 were independent prognostic factors for prolonged OS in GC patients. In addition, the genetic mutation rate of CBXs was 37% in GC patients, and genetic alterations in CBXs showed no association with OS or disease-free survival (DFS) in GC patients. These results indicated that CBX3/8 can be prognostic biomarkers for the survival of GC patients.


Factor product utilization and health outcomes in patients with haemophilia A and B on extended half-life concentrates: A Canadian observational study of real-world outcomes.
Recombinant factors VIII and IX Fc (rFVIIIFc/rFIXFc) became available in Canada in 2016 and were the only extended half-life (EHL) factor concentrates available in Canada until 2018. We aim to describe the change in product utilization in Canadians who switched to rFVIIIFc/rFIXFc. This prospective and retrospective cohort study enrolled males aged ≥6 years with moderate or severe haemophilia who switched to rFVIIIFc/rFIXFc and those who remained on standard half-life (SHL) between 2016 and 2018. Factor utilization and annualized bleeding rates (ABR) were collected at baseline, 1-year and 2-years. Due to low prospective enrolment (n = 25 switchers), prospective and retrospective data were pooled. 125 switchers (93 rFVIIIFc, 32 rFIXFc) and 33 non-switchers were included. The median age was 17 (rFVIIIFc) and 38 years (rFIXFc). Prior to switch, over 80% were on prophylaxis. There was a statistically significant reduction in the prescribed weekly prophylactic dose after the switch to rFVIIIFc/rFIXFc for all age groups, with a corresponding reduction (15-16%) in actual annualized FIX utilization in switchers (combined adults and children) to rFIXFc, and a smaller non-significant reduction in actual annualized FVIIII utilization (7%) in children who switched to rFVIIIFc. A significant reduction in the median ABR was only observed in children who switched to rFVIIIFc, but not in adults who switched to rFVIIIFc or rFIXFc. Switching from SHL to EHL products led to a small reduction in factor utilization, while preserving a low ABR in children and adults with haemophilia. Further patient-reported outcomes data will further elucidate the role of EHL in the haemophilia landscape.


Health Profiles of Military Women and the Impact of Combat-Related Injury.
The role of women in the United States military is expanding. Women are now authorized to serve in all military occupations, including special operations and frontline combat units, which places them at increased risk of combat exposure and injury. Little is known regarding the impact of these injuries on the health of military women. We conducted a retrospective matched cohort study of women service members who were injured during combat operations in Iraq and Afghanistan. Injured women were individually matched to non-injured controls at a 1:4 ratio. Medical diagnostic codes were abstracted from outpatient encounters in electronic health records, and hierarchical clustering was conducted to identify clusters of diagnostic codes, termed "health profiles." Conditional logistic regression was used to determine whether combat-related injury predicted membership in the profiles. The study sample included 590 injured women and 2360 non-injured controls. Cluster analysis identified six post-deployment health profiles: low morbidity, anxiety/headache, joint disorders, mixed musculoskeletal, pregnancy-related, and multimorbidity. Combat-related injury predicted membership in the anxiety/headache (odds ratio, 1.73; 95% confidence interval, 1.38-2.16) and multimorbidity (odds ratio, 3.43; 95% confidence interval, 2.65-4.43) profiles. Combat-related injury is associated with adverse post-deployment health profiles among military women, and women with these profiles may experience increased health care burden. As future conflicts will likely see a greater number of women with combat exposure and injury, health outcomes research among military women is paramount for the purposes of medical planning and resource allocation.


Nonviral liver disease is the leading indication for liver transplant in the United States in persons living with human immunodeficiency virus.
We evaluated whether indications for liver transplantation (LT) have changed among people with/without human immunodeficiency virus (HIV) infection and compared LT outcomes and trends by HIV serostatus. LT recipients (2008-2018) from the United Network for Organ Sharing and Organ Procurement and Transplantation Network (UNOS/OPTN) were identifed. Among 62 195 LT recipients, 352 (0.6%) were HIV-infected. The proportion of HIV-infected patients increased over time (P trend = .001), as did the number of transplant centers performing LT for HIV-infected recipients; average annual percentage change of 9.2% (p < .001). Nonviral causes became the leading indication in 2015 for HIV-uninfected and in 2018 for HIV-infected (P trend < .001). Three-year cumulative patient survival rates were 77.5%, for HIV-infected and 84.6%, for HIV-uninfected (p = .15). Over time, graft and patient survival rates improved for both HIV-infected and uninfected (p < .001). Among HCV-infected LT recipients, 3-year patient survival rates were 72.5% for HIV-infected and 81.8% for HIV-uninfected (p = .02). However, in a subanalysis restricted to 2014-2018, differences in graft and patient survival by HIV serostatus were no longer observed (3-year patient survival rates were 81.2% for HIV-infected and 86.4% for HIV-uninfected, p = .34). In conclusion, in the United States, nonviral liver disease is now the leading indication for LT in HIV-infected patients, and posttransplant outcomes have improved over time.


Cyathane diterpenes from Chinese mushroom Sarcodon scabrosus and their neurite outgrowth-promoting activity.
Two novel cyathane diterpenoids, designated scabronines K (1) and L (2), were isolated from the fruiting bodies of the basidiomycete Sarcodon scabrosus together with four known analogues, sarcodonins G (3), A (5), M (6), and scabronine H (4). Their structures were elucidated on the basis of extensive spectroscopic analysis including 2D-NMR (HMBC, HSQC, ROESY, (1)H,(1)H-COSY) and MS experiments. The isolated compounds were evaluated for nerve growth factor (NGF)-mediated neurite outgrowth using rat pheochromocytoma (PC12) cells as a model system of neuronal differentiation. Among these compounds, only sarcodonins G and A (3 and 5) at 25 μM showed significant neurite outgrowth (neuritegenesis)-promoting activity in the presence of 20 ng/mL NGF after 24h treatment. Their structure-neurite inducing activity relationship was also discussed.


Targeted Approaches to HER2-Low Breast Cancer: Current Practice and Future Directions.
HER2-low breast cancer (BC) has a poor prognosis, making the development of more suitable treatment an unmet clinical need. While chemotherapy is the main method of treatment for HER2-low BC, not all patients benefit from it. Antineoplastic therapy without chemotherapy has shown promise in clinical trials and is being explored further. As quantitative detection techniques become more advanced, they assist in better defining the expression level of HER2 and in guiding the development of targeted therapies, which include directly targeting HER2 receptors on the cell surface, targeting HER2-related intracellular signaling pathways and targeting the immune microenvironment. A new anti-HER2 antibody-drug conjugate called T-DM1 has been successfully tested and found to be highly effective in clinical trials. With this progress, it could eventually be transformed from a disease without a defined therapeutic target into a disease with a defined therapeutic molecular target. Furthermore, efforts are being made to compare the sequencing and combination of chemotherapy, endocrine therapy, and HER2-targeted therapy to improve prognosis to customize the subtype of HER2 low expression precision treatment regimens. In this review, we summarize the current and upcoming treatment strategies, to achieve accurate management of HER2-low BC.


Expression of ISL1 and its partners in prostate cancer progression and neuroendocrine differentiation.
ISL1 serves as a biomarker of metastasis and neuroendocrine neoplasia in multiple tumors. However, the expression and relation of ISL1 to other biomarkers in prostate cancer have not been fully elucidated. Here, we characterize the expression of ISL1 and its partners in PCa and document its association to disease progression and post castration resistance neuroendocrine differentiation. The expression of ISL1 was interrogated in > 6000 primary samples from the Decipher GRID registry and 250 mCRPC samples to assess its prognostic value and relation to neuroendocrine differentiation. ISL1 was highly correlated to MEIS genes and other genes related to cell motility. ISL1 down-regulation in PCa was associated with cancer progression, aggressive primary tumors, and metastatic outcome. We found that ISL1 is highly correlated to MEIS genes across multiple primary PCa and mCRPC cohorts. The expression of ISL1 and MEIS genes were significantly and inversely related to metastasis-free survival and lethal disease, and were downregulated in CRPC and hormone naïve metastatic tumors but showed upregulation in neuroendocrine tumors. Co-immunoprecipitation showed MEIS2 and ISL1 interacting with each supporting their role in modulating transcriptional regulation and nominating this complex for potential targeted therapy. ISL1 complex with MEIS2 serves a critical role in prostate tumor progression and its upregulation in mCRPC/NE provides a rationale for assessing the role of ISL1 and its associated protein in treatment resistance.


Revision risk after pediatric spinal deformity surgery: a nationwide study with 2-year follow-up.
Revision risk after pediatric spine surgery is not well established and varies between deformity etiologies. To report the 2-year revision risk following surgery for primary pediatric spinal deformity in a nationwide cohort and to evaluate potential risk factors and reasons for revision surgery. Retrospective nationwide cohort study. A national registry study of all pediatric spinal deformity patients undergoing surgery during 2006-2015 (n=1310). Two-year revision risk. All patients ≤21 years of age undergoing spinal deformity surgery in Denmark during 2006-2015 were identified by procedure and diagnosis codes in the Danish National Patient Registry (DNPR). Data on revision surgery were retrieved from the DNPR. Patients were categorized in six groups according to etiology. Medical records were reviewed for reason for revision in all patients. Potential risk factors for revision were assessed with multiple logistic regression analyses and included age, etiology, sex, Charlson comorbidity index (CCI), and growth-preserving treatment. Patients were categorized according to etiology: idiopathic deformity (53%), neuromuscular deformity (23%), congenital/structural deformity (9%), spondylolisthesis (7%), Scheuermann's kyphosis (5%), and syndromic deformity (3%). Of 1,310 included patients, 9.2% underwent revision surgery within 2 years and 1.5% was revised more than once. Median time to revision was 203 (interquartile range 35-485) days. The multivariable logistic regression found significantly higher odds ratio (OR) for revision in patients with growth-preserving treatment (OR=5.1, 95% confidence interval [CI] 2.6-10.1), congenital deformity (OR=2.7, 95% CI 1.3-5.3), spondylolisthesis (OR=3.5, 95% CI 1.9-6.7), Scheuermann kyphosis (OR=3.9, 95% CI 1.9-8.3), and CCI score ≥3 (OR=2.5 95% CI 1.1-5.6). The most common reason for revision was implant failure (32.5%) followed by residual deformity and/or curve progression (15.8%). In this nationwide study, the 2-year revision risk after primary pediatric spinal deformity surgery is 9.2%. Risk factors for revision are etiology of congenital deformity, spondylolisthesis, Scheuermann kyphosis as well as patients with growth-preserving treatment and higher CCI. The most common reason for revision is implant failure.


[A study on cytocompatibility of poly (lactic acid) membrane modified by polymer microspheres with different surface charges].
Poly(lactic acid) microspheres with different surface charges have been prepared by using cationic, anionic or nonionic surfactants as the microspheres' surface stabilizers. Embedded with these microspheres, the modified PLA membranes with different surface charges have been obtained. The test of stability by CLSM and the morphological test by SEM confirmed that we obtained the microspheres modified PLA membranes with different surface charges successfully. The chondrocyte compatibility test of these modified PLA membranes showed that the attachment, proliferation and activity of chondrocytes on the positive surface of the modified PLA were better than those of other modified PLA membranes. The positive charge on the surface of PLA membrane could improve the cell-compatibility of PLA well.


Effect of limited modification of amino groups on the reactivity of human factor Xa.
The basis of the specificity of human coagulation factor Xa has been probed with a reagent that reacts with nucleophiles, N-succinimidylpropionate. At pH 8.0 and 0.25 mM N-succinimidylpropionate, 0.4 microM factor Xa lost approx. 90% of its activity toward prothrombin in 4 min. The decay was first-order, k = 0.64 min-1, which increased to 0.98 min-1 in 1 mM Ca2+, and the dependence of k upon pH was consistent with primary amines being the target. The rate of modification was unaffected by the presence of a tetrapeptide substrate during modification; likewise, activity toward a tripeptide p-nitroanilide was unaltered during exposure of factor Xa to N-succinimidylpropionate with or without Ca2+. In addition, inhibition by antithrombin III was retained with a somewhat enhanced rate after modification; however, the acceleration of this by heparin was significantly less. Kinetic determination of the number of residues modified gave a reaction order of 2.0, while reaction with N-succinimidyl[3H]propionate yielded labeled factor Xa containing 1.0 mol N-succinimidylpropionate/mol factor Xa and 50% normal clotting activity, or 2.0 mol N-succinimidylpropionate/mol and 1% activity, respectively. Thus, one nucleophilic group is required for the reaction of factor Xa with prothrombin but not for the hydrolysis of peptides or recognition of antithrombin III. The decay of clotting activity of the factor X zymogen in N-succinimidylpropionate was much slower though still Ca2+-dependent. Conversely, the reaction of a related compound--N-succinimidyl(4-hydroxyphenyl)propionate or Bolton-Hunter reagent--with factor Xa broadly resembled that of N-succinimidylpropionate but the decay curves indicated more complex kinetics. Therefore, the target groups vary in their accessibility to modification according to the structural characteristics of both the protein and the reagent.


Distal embolization during primary angioplasty: histopathologic features and predictability.
Distal embolization during primary percutaneous coronary interventions (PCIs) may affect myocardial reperfusion. We evaluated the prevalence and features of embolization during primary PCI and its relationship with clinical and angiographic variables. Forty-six consecutive patients with acute myocardial infarction underwent primary PCI with a filter-based distal protection device. Histopathologic analysis was performed on retrieved embolic fragments, assessing the presence and relative amount of fibrin, necrosis, lipid droplets, collagen, mucopolysaccharides, and leukocytes, as well as the total debris volume. Such variables were related to baseline clinical and angiographic variables. Embolic material was recovered in 41 (89%) of 46 cases, with a mean total debris volume of 1.2 +/- 2.2 mm3. Prevalent histopathologic patterns were organized thrombus (47%), fresh thrombus (29%), and plaque fragments (24%). At multivariate analysis, none of the baseline clinical variables considered significantly predicted the total debris volume. Among angiographic variables, angiographic signs of high thrombus burden (cut-off coronary occlusion pattern or large intracoronary minus image) independently predicted the total debris volume at multivariate analysis (odds ratio 15.8, P < .005). Compared with its nonuse, abciximab did not affect the total number and the mean total volume of embolized material (15 +/- 16 vs 10 +/- 8 fragments, 1.5 +/- 2.5 vs 1.0 +/- 1.9 mm3, respectively, for both P > .20), or its qualitative composition. Distal embolization occurs in most patients during primary PCI and mainly consists of plaque fragments and partially organized thrombi, which are likely to be scarcely responsive to antiplatelet drugs. Baseline angiographic signs of a high thrombus burden are the only significant predictors of the extent of distal embolization.


Identification of potent inhibitors of DNA methyltransferase 1 (DNMT1) through a pharmacophore-based virtual screening approach.
DNA methylation is an epigenetic change that results in the addition of a methyl group at the carbon-5 position of cytosine residues. DNA methyltransferase (DNMT) inhibitors can suppress tumour growth and have significant therapeutic value. However, the established inhibitors are limited in their application due to their substantial cytotoxicity. Additionally, the standard drugs for DNMT inhibition are non-selective cytosine analogues with considerable cytotoxic side-effects. In the present study, we have designed a workflow by integrating various ligand-based and structure-based approaches to discover new agents active against DNMT1. We have derived a pharmacophore model with the help of available DNMT1 inhibitors. Utilising this model, we performed the virtual screening of Maybridge chemical library and the identified hits were then subsequently filtered based on the Naïve Bayesian classification model. The molecules that have returned from this classification model were subjected to ensemble based docking. We have selected 10 molecules for the biological assay by inspecting the interactions portrayed by these molecules. Three out of the ten tested compounds have shown DNMT1 inhibitory activity. These compounds were also found to demonstrate potential inhibition of cellular proliferation in human breast cancer MDA-MB-231 cells. In the present study, we have utilized a multi-step virtual screening protocol to identify inhibitors of DNMT1, which offers a starting point to develop more potent DNMT1 inhibitors as anti-cancer agents.