Continuous glucose monitoring in subjects undergoing bariatric surgery: Diurnal and nocturnal glycemic patterns.
Although the use of Continuous Glucose Monitoring (CGM) is rapidly extending, little evidence is currently available on daily glycemic excursions after different bariatric procedures. We assessed glycemic patterns after sleeve gastrectomy (SG) and roux-en-Y gastric bypass (RYGB) using CGM. Cross-sectional study in subjects who had undergone RYGB (n = 22) or SG (n = 29) since at least 1 year, without pre-surgery or in current diabetes (T2DM) remission. All subjects underwent 7 day-CGM (Dexcom G4 PLATINUM), which provides glucose variability (GV), number and time spent in hypoglycemia, hypoglycemia patterns (postprandial, nocturnal or mixed). All indexes of GV were higher after RYGB than after SG (p < 0.001). Twenty-eight (55%) subjects experienced hypoglycemia. The number of events was higher after RYGB than SG (p = 0.017) while it did not differ in subjects with or without pre-surgery T2DM (p = 0.129). Overall, 9 (32%) subjects presented hypoglycemia exclusively during the postprandial period, 8 (29%) an exclusively nocturnal pattern and 11 (39%) a mixed pattern. The nocturnal pattern was more frequent after SG than RYGB (53.8% vs 6.7%, p = 0.036) while no difference was observed in subjects with or without pre-surgery T2DM (p = 0.697). Hypoglycemia symptoms were more frequent in subjects with postprandial than in those with nocturnal pattern (77.8% vs 12.5%, p = 0.015). RYGB is characterized by a greater GV and a higher number of hypoglycemia events mostly post-prandial and symptomatic, while SG is associated with nocturnal and often asymptomatic hypoglycemia. These findings suggest that post-bariatric hypoglycemia is a more complex, not exclusively, postprandial phenomenon.


Reduction of pulmonary edema after SAH with a pulmonary artery catheter-guided hemodynamic management protocol.
The frequency of pulmonary edema, which occurs with high frequency following subarachnoid hemorrhage (SAH), can be worsened by hypervolemic, hypertensive, hemodilution therapy for vasospasm. This study compares the complication rates for patients with SAH before and after institution of a pulmonary artery catheter-guided hemodynamic management protocol. Complication and outcome data were prospectively collected on 453 patients with spontaneous SAH. The patients were divided into groups treated from July 1998 through January 2000 (n = 174) and from February 2002 through June 2002 (n = 279). In group I, treatment consisted of hypervolemia (central venous pressures: >8 mmHg) and hypertension (mean arterial pressure: 110-130 mmHg). In group II, normovolemia was the goal, defined using a pulmonary artery catheter (wedge pressure: 10-14 mmHg). Cardiac output was enhanced (index: >4.5 L/minute/m2), and blood pressure elevations were moderated (mean pressure: >100 mmHg). The average age, comorbidity, hemorrhage severity, and incidence of vasospasm were almost identical between the two groups. Statistically significant reductions were noted in patients in group II for two types of complications as well as for mortality. The rate of pulmonary edema (from 14 to 6%) and the rate of sepsis (from 14 to 6%) were both decreased (p <or= 0.03). Mortality decreased from 34 to 29% (p = 0.04). Other complications, such as myocardial infarction, were not affected. These data show that a significant reduction in the frequency of pulmonary edema after SAH can be attained using a pulmonary artery catheter-guided hemodynamic management protocol.


Integrated physical education and medicine in general physical education at universities in the age of educational technologies.
The integration of training sessions into modern education is of vital importance for such disciplines as Physical Education and First Aid for the non-core specialities. This research explored the opportunities to introduce a pilot programme for Sports Medicine based on the First Aid and Fitness Tests applications to develop critical thinking skills in students using an indirect learning method. This research used the Fitness Tests application developed by the ConnectedPE software company. The software contains more than 30 fitness tests and indicates the goal, equipment, procedure and standards so that students can easily and accurately complete all tasks and improve their fitness. The experimental group involved 60 first-year students (25 females and 35 males). The average age is 18.2 years. The control group involved 28 males and 32 females with an average age of 18.3 years. Students were assigned randomly to groups to ensure the experiment's validity. The analysis of the pre-test and post-test of Critical Thinking Skills Success showed significant improvements in critical thinking skills (Z = -6.755 at p = 0.00) based on the integrated sports medicine programme. A negative correlation was observed between the post-test scores of Critical Thinking Skills Success and the Integrated Sports Medicine Test (r = -0.280, p < 0.05). This article fills a gap in research on the possibility of integrating physical education and medicine into one ICT-based university course that would optimise study hours and develop critical thinking. The research's scientific value is to promote the discussion about the absence of a unified standard for the basic sports training of young individuals on a global scale. The practical significance lies in the enhanced development of critical thinking skills among students through integrated sports training sessions, as opposed to the conventional lecture format. The other important finding is the fact that the use of mobile applications and the development of a general programme in sports medicine have no positive impact or correlation with the academic outputs of students in these two disciplines. The research results can help educators to update curricula on physical education and extracurricular pre-medical training at universities. The perspective of this research is to integrate physical education with other academic disciplines, such as biology, mathematics, physics, and others, to determine the feasibility of this integration and investigate its effect on critical thinking.


STUDY OF TRAUMATIC CATARACT IN OCCUPATIONAL AND ENVIRONMENTAL TRAUMA AND ITS MANAGEMENT.
Sixty cases of traumatic cataract in 5 years due to occupational and environmental hazards were studied to highlight mode of trauma, structural damage; management profile and final visual outcome. Thirty six (60%) cases had mechanical trauma whereas 18 (30%) cases had injuries due to non metalic or organic substances. Industrial accidents were responsible in 25 (41.66%) cases. Forty four cases (73.3%) had associated anterior segment injuries. Reconstruction of anterior segment with Posterior Chamber Intraocular lens (PC IOL) implantation could be done in 42 (70%) cases as primary or secondary procedure. Adherent leucoma, iridal trauma, posterior capsular tear and dislocated lens were noted problems. Forty six (76.67%) cases had attained 6/12 or better corrected visual acuity. Defective visual gain was due to corneal opacities and post operative complications.


Lower temperature and orthophosphate control of alkaline phosphatase in a cold-requiring plant.
The elevated activity of alkaline phosphatase observed in roots and shoots of Verbascum rosettes grown in vitro at 15 degrees C may be the result of a reduced supply of orthophosphate. The rosette reveals greater activities of this enzyme under conditions of lower external phosphate or chilling temperature. Either of these treatments gives lower amounts of endogenous phosphate. The stimulation of phosphatase in tissues having lower levels of phosphate is thus a possible feature of other plant species which also display freezing tolerance.


Systematic synergy modeling: understanding drug synergy from a systems biology perspective.
Owing to drug synergy effects, drug combinations have become a new trend in combating complex diseases like cancer, HIV and cardiovascular diseases. However, conventional synergy quantification methods often depend on experimental dose-response data which are quite resource-demanding. In addition, these methods are unable to interpret the explicit synergy mechanism. In this review, we give representative examples of how systems biology modeling offers strategies toward better understanding of drug synergy, including the protein-protein interaction (PPI) network-based methods, pathway dynamic simulations, synergy network motif recognitions, integrative drug feature calculations, and "omic"-supported analyses. Although partially successful in drug synergy exploration and interpretation, more efforts should be put on a holistic understanding of drug-disease interactions, considering integrative pharmacology and toxicology factors. With a comprehensive and deep insight into the mechanism of drug synergy, systems biology opens a novel avenue for rational design of effective drug combinations.


Homeopathic Medicines Used as Prophylaxis in Kolkata during the COVID-19 Pandemic: A Community-Based, Cluster-Randomized Trial.
There is some evidence that homeopathic treatment has been used successfully in previous epidemics, and currently some countries are testing homeoprophylaxis for the coronavirus disease 2019 (COVID-19) pandemic. There is a strong tradition of homeopathic treatment in India: therefore, we decided to compare three different homeopathic medicines against placebo in prevention of COVID-19 infections. In this double-blind, cluster-randomized, placebo-controlled, four parallel arms, community-based, clinical trial, a 20,000-person sample of the population residing in Ward Number 57 of the Tangra area, Kolkata, was randomized in a 1:1:1:1 ratio of clusters to receive one of three homeopathic medicines (Bryonia alba 30cH, Gelsemium sempervirens 30cH, Phosphorus 30cH) or identical-looking placebo, for 3 (children) or 6 (adults) days. All the participants, who were aged 5 to 75 years, received ascorbic acid (vitamin C) tablets of 500 mg, once per day for 6 days. In addition, instructions on healthy diet and general hygienic measures, including hand washing, social distancing and proper use of mask and gloves, were given to all the participants. No new confirmed COVID-19 cases were diagnosed in the target population during the follow-up timeframe of 1 month-December 20, 2020 to January 19, 2021-thus making the trial inconclusive. The Phosphorus group had the least exposure to COVID-19 compared with the other groups. In comparison with placebo, the occurrence of unconfirmed COVID-19 cases was significantly less in the Phosphorus group (week 1: odds ratio [OR], 0.1; 95% confidence interval [CI], 0.06 to 0.16; week 2: OR, 0.004; 95% CI, 0.0002 to 0.06; week 3: OR, 0.007; 95% CI, 0.0004 to 0.11; week 4: OR, 0.009; 95% CI, 0.0006 to 0.14), but not in the Bryonia or Gelsemium groups. Overall, the trial was inconclusive. The possible effect exerted by Phosphorus necessitates further investigation. CTRI/2020/11/029265.


Association of acute hepatitis B and acute myopathy: a case report.
Hepatitis B virus infection is a global public health problem. Although hepatitis B virus primarily affects hepatocytes, it sometimes develops disease manifestations outside the liver, such as myopathy, which is commonly caused by chronic hepatitis B. This case report describes a 57-year-old Iranian woman admitted to the hospital with jaundice, fever, body itching, abdominal pain, progressive muscle weakness, icteric sclera, right upper quadrant pain, and decreased muscle force. Examination on the first day of admission revealed that the patient was negative for hepatitis D antibody, positive for hepatitis B core (IgM) antibody, positive for hepatitis B surface antigen, and negative for hepatitis B e antibody but positive for hepatitis B e antigen. Moreover, she showed high levels of hepatitis B virus DNA viral load, creatine kinase, lactate dehydrogenase, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, total bilirubin, direct bilirubin, and alkaline phosphatase, and electromyography/nerve conduction velocity showed acute myopathic process. Interestingly, myopathy symptoms improved after improving hepatitis symptoms and decreasing hepatitis B viral load, suggesting a close association between hepatitis B infection and myopathy.


B-cell function and blood glucose control in insulin dependent diabetics within the first month of insulin treatment.
Seventeen insulin dependent diabetics were studied after two to four weeks of insulin treatment in a situation approximating to their normal daily life. Some endogenous insulin secretion, assessed by plasma C-peptide determinations, was present in all. Plasma C-peptide concentration was positively correlated with the blood glucose concentration and increased after breakfast, lunch and dinner (p less than 0.01); both peak values and relative increases were lower than those observed in normal subjects (p less than 0.01). The highest insulin secretory capacity was found in subjects with the least unstable blood glucose concentration (r=0.57, p less than 0.03), and these patients required the smallest insulin doses (r=0.54, P less than 0.04). These findings demonstrate the metabolic importance of a preserved B-cell function.


Amino acid uptake and incorporation not cell-specific peptides and evidence for intracellular peptide pools in Aplysia neurons R3-R14.
1. Relationships between intracellular amino acid concentrations and uptake rates and their utilization in synthesis of cell-specific peptides in neurons R3-R14 in the Aplysia parietovisceral ganglion are explored. 2. The uptake rates and intracellular concentrations of most amino acids are positively correlated and inversely related to their degree of incorporation into the peptides. 3. The bulk cellular pool of arginine is probably utilized in the synthesis of R3-R14 peptides, but much of the glycine taken up appears not to be readily available for protein synthesis. 4. There are rapidly and slowly turning over pools of the peptides, and portions of the peptides stay in the cell bodies for days.


The effect of exercise therapy on balance in patients with diabetic peripheral neuropathy: a systematic review.
Peripheral sensory and motor nerves are often affected in people with diabetes mellitus (DM), and balance problems are widespread. Diabetic peripheral neuropathy is common. This study investigated the impact of exercise treatment on balance parameters in diabetic peripheral neuropathy patients. Electronic databases, such as PubMed, Web of Science, and Science Direct, were used to perform a search of accessible papers. The search strategy was (exercise therapy OR physical activity) AND (balance OR equilibrium OR postural control OR fall OR fall risk OR static balance OR dynamic balance OR functional balance) AND diabetic peripheral neuropathy. The Physiotherapy Evidence Database (PEDro) scale was used to rate the research in this review for its quality and reliability. Scores ranged from 5 to 9 on the PEDro scale. According to databases, about 9,103 articles were found in August 2021 from March 1984 to February 2020. From 9103 articles, 3872 were deleted for different reasons, including duplicate, non-randomized controlled trial (RCT) articles and after reviewing the title and abstract. About 5,231 articles were found in free full text. In the end, 12 submissions were approved. These studies investigated the effects of exercise treatment on static, dynamic, and functional balance parameters in diabetic peripheral neuropathy patients. This study showed the positive effects of balance and strengthening exercise on static balance indices in patients with diabetic peripheral neuropathy. The online version contains supplementary material available at 10.1007/s40200-022-01077-1.


Von Willebrand factor in aortic or mitral valve stenosis and bleeding after heart valve surgery.
Low von Willebrand factor (VWF) increases the risk of bleeding. The objective was to assess the influence of VWF on bleeding after valvular surgery. We studied 82 consecutive patients in median age of 65.5 years with severe isolated aortic stenosis (AS, n = 62) or mitral stenosis (MS, n = 20), undergoing heart valve surgery in extracorporeal circulation. Preoperatively, we assessed VWF antigen (VWF:Ag) and activity (VWF:RCo), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), and fibrinolysis inhibitors. Compared with AS, MS patients were more frequently female (80 vs. 55%, p = 0.045) with atrial fibrillation (AF) (80 vs. 8%, p < 0.0001), with no difference in age or comorbidities. Median postoperative drainage was 420 ml for AS, and 425 ml for MS (p = 0.37). Patients with AS had lower VWF:RCo (125.8 [88.5-160.8] vs. 188.0 [140.3-207.3] IU/dl, p = 0.003) and VWF:Ag (135.8 [112.0-171.2] vs. 191.7 [147.3-236.4] IU/dl, p = 0.01) than MS patients. Mean VWF:RCo/Ag ratio was 0.88 ± 0.17, with no intergroup differences. ADAMTS13 levels and activity were similar in both groups. In AS, both VWF:RCo and VWF:Ag correlated inversely with maximal (r = -0.39, p = 0.0003 and r = -0.39, p = 0.0004, respectively) and mean (r = -0.40, p = 0.0004 and r = -0.39, p = 0.0006, respectively) transvalvular pressure gradients. There was no difference in perioperative bleeding between patients following mitral and aortic valve surgery, and bleeding was not associated with VWF:Ag or VWF:RCo. In severe AS, VWF levels and activity correlate inversely with transvalvular pressure gradients, and are lower than in severe degenerative MS, but do not affect blood loss after valvular surgery in extracorporeal circulation.


Improved biomass saccharification by Trichoderma reesei through heterologous expression of lacA gene from Trametes sp. AH28-2.
The Trametes sp. AH28-2 laccase gene lacA fused to cellobiohydrolase I signal peptide coding sequence was heterologously expressed in T. reesei. The lacA cDNA was under the control of the Aspergillus nidulans glyceraldehyde-3-phosphate dehydrogenase promoter. Native PAGE analysis indicated that two transformants, L8 and L38, were able to secrete recombinant laccase A, and their laccase activities corresponding to ABTS oxidation reached 3.62 IUml(-1) and 1.50 IUml(-1) respectively. Most of the characteristics of the recombinant laccase were similar to those of the native enzyme. Reducing sugar yields of L8 and L38 obtained from saccharification of corn residue by crude enzyme increased by 31.3% and 71.6% respectively compared to the host strain. These results indicated that the engineering strains developed in this work could be potentially used for laccase production and tailoring cellulase properties with laccase proteins through genetic manipulation would be a feasible strategy to improve saccharification efficiency of biomass by cellulase preparation.


A rationale for surgical debulking to improve anti-PD1 therapy outcome in non small cell lung cancer.
Anti-PD1 immunotherapy has emerged as a gold-standard treatment for first- or second-line treatment of stage IV NSCLC, with response rates ranging from 10 to 60%. Strategies to improve the disease control rate are needed. Several reports suggested that debulking surgery enhances anti-tumor immunity. We aimed at examining tumor burden as a predictive factor of anti-PD1 tretment efficacy and to evaluate the role of cytoreductive surgery in anti-PD1 treated NSCLC. Immunocompetent DBA/2 mice engrafted with various amount of allogeneic lung squamous cancer KLN-205 cells were treated with anti-PD1 monoclonal antibody. Mice engrafted with two tumors also underwent a debulking surgery or a sham procedure. Tumor volume was monitored to assess treatment efficacy. Tumor infiltrating lymphocytes were assessed by flow cytometry. In a retrospective study of 48 stage IV NSCLC patients treated with Nivolumab who underwent a 18-FDG PETscan before treatment onset, the prognostic role of metabolic tumor volume was analysed. Anti-PD1 treatment effect was greater in mice bearing smaller tumors. Treatment with higher doses of anti-PD1 antibody did not improve the outcome, independently of the size of the tumor. In mice bearing 2 tumors, excision of 1 tumor improved the anti-PD1 treatment effect on the remaining tumor. In 48 NSCLC patients receiving anti-PD1 treatment, high metabolic tumor volume was associated with poor overall survival and the absence of clinical benefit. Treg infiltration, but not effector T cells, was positively correlated to tumor volume. Taken together, our results suggest that tumor volume is a predictive factor of anti-PD1 efficacy in NSCLC. Additionally, an experimental murine model suggests that tumor debulking may improve control of residual tumor.


Occupations with increased risk of pancreatic cancer in the Swedish population.
To identify occupations with increased risk of pancreatic cancer in the Swedish population gainfully employed in 1970 over the period 1971-89. The base population was made up of Swedish men (1 779 646) and Swedish women (1 101 669) gainfully employed at the time of the 1970 census and were still alive and over age 24 on 1 January 1971. Information was drawn from two data sets: the Swedish cancer environment register and a background population register. After 19 years of follow up, 4420 men and 2143 women were diagnosed with histologically confirmed incident pancreatic adenocarcinoma. Log linear Poisson models were fitted, allowing for geographical area and town size. Risk estimators were also calculated for workers reporting the same occupation in 1960 and 1970. Among women, a statistically significant risk excess of pancreatic cancer was observed for "educational methods advisors", "librarian, archivist, curator", "motor vehicle driver", "typographer, lithographer", "purser, steward, stewardess", "other housekeeping and related workers", and the groups of occupations of "electrical, electronic, and related" and "glass, pottery, and tile workers". Men showed a higher incidence of pancreatic cancer among "technical assistants", "travelling agents", "other metal processing workers", "baker and pastry cook", "docker and freight handler", and "waiters". This study does not indicate that occupational factors play an important role in the aetiology of pancreatic cancer in Sweden. Few occupations were at increased risk of pancreatic cancer in both men and women, and the associations observed are in accordance with some previous studies from Western countries.


Radioimmunoassay of anabolic steroids: an evaluation of three antisera for the detection of anabolic steroids in biological fluids.
Recently developed radioimmunoassays (RIA) for the analysis of anabolic steroids and their metabolites in biological fluids were tested for cross-reactivity with other types of steroids. Results show that the degree of desirable cross-reactivity within the two classes or orally active anabolic steroids vary widely and that the antiserum for 19-Nortestosterone (the active principle of intramuscular preparations) has a very high degree of undesirable cross-reactivity with components of oral contraceptives. Single and multiple dose studies in human volunteers demonstrate that the detection level and degree of retrospectivity are likewise variable but that the test easily detects most anabolic steroids during treatment. At the present time, the combination of the three antisera for the assay of a sample appears to be a relatively rapid and economic method for screening large numbers of samples in situations where doping control of anabolic steroids is required. The importance of utilizing physico-chemical means for identification of RIA potential positives is emphasized.


An introduction to programming in BBC BASIC.
The rudiments of programming in BASIC for the BBC microcomputer are outlined. The topics covered are input to and output from the computer, variable names, loops, arithmetic operations, data statements, arrays, branching, string variables and an introduction to structured programming. The topics are illustrated by simple programming exercises based on the calculation of stroke volume indices. In conclusion a brief review is given of some of the additional facilities which are available on the computer together with references for further reading.


Phospholipid, nature's own slide and cover slip for cryo-electron microscopy.
Thin films of surface-active compounds, with or without particulate material, can be obtained by immersing and withdrawing a bare specimen grid from a solution/suspension of the compound. Immediately after withdrawing the grid, thinning of the film starts. Thinning is initially powered by gravity and capillary forces and will proceed in thin films (less than 100 nm) driven by intermolecular forces until the London-van der Waals attractive forces come to an equilibrium with electrostatic repulsion of similarly charged surfaces of the film. With small unilamellar vesicles prepared from the phospholipid dimyristoyl phosphatidyl choline (DMPC) the draining behaviour of these films was studied by cryo-electron microscopy. Small unilamellar vesicles were observed within the film as well as the coalescence of these vesicles into sheets ('leaky' membrane fusion). Sheets dominate the images when films are allowed to drain for longer periods (greater than 3 min). Thin films were formed on grids from catalase crystals suspended in a DMPC suspension and vitrified by cooling. High-resolution information was obtained by electron diffraction at low temperature and under low-dose conditions from catalase crystals surrounded by small vesicles as well as from catalase crystals surrounded by sheets of DMPC. In the latter case the water content drops from 99% (DMPC in small vesicles) to less than 30% (DMPC in sheets) during draining. Ferritin was added to a DMPC suspension and thin films were prepared and vitrified. After prolonged draining ferritin molecules were deposited in layers with a stepwise increase in thickness. Draining of thin films has thus a dehydrating effect as well as a sorting and ordering effect. These effects must be considered when using surface-active compounds at air-water interfaces as a slide and cover slip for electron microscopy.


Role of mesenchymal stem cells in bone regeneration and fracture repair: a review.
Mesenchymal stem cells (MSCs) are non-haematopoietic stromal stem cells that have many sources, such as bone marrow, periosteum, vessel walls, adipose, muscle, tendon, peripheral circulation, umbilical cord blood, skin and dental tissues. They are capable of self-replication and of differentiating into, and contributing to the regeneration of, mesenchymal tissues, such as bone, cartilage, ligament, tendon, muscle and adipose tissue. The homing of MSCs may play an important role in the repair of bone fractures. As a composite material, the formation and growth of bone tissue is a complex process, including molecular, cell and biochemical metabolic changes. The recruitment of factors with an adequate number of MSCs and the micro-environment around the fracture are effective for fracture repair. Several studies have investigated the functional expression of various chemokine receptors, trophic factors and adhesion molecules in human MSCs. Many external factors affect MSC homing. MSCs have been used as seed cells in building tissue-engineered bone grafts. Scaffolds seeded with MSCs are most often used in tissue engineering and include biotic and abiotic materials. This knowledge provides a platform for the development of novel therapies for bone regeneration with endogenous MSCs.


Vitamin D and K status influences bone mineral density and bone accrual in children and adolescents with celiac disease.
Children with celiac disease (CD) are at risk for decreased bone mineral density (BMD) because of fat-soluble vitamin malabsorption, inflammation and/or under-nutrition. The study objective was to determine the interrelationships between vitamin K/D status and lifestyle variables on BMD in children and adolescents with CD at diagnosis and after 1 year on the gluten-free diet (GFD). Children and adolescents aged 3-17 years with biopsy proven CD at diagnosis and after 1 year on the GFD were studied. BMD was measured using dual-energy X-ray absorptiometry. Relevant variables included: anthropometrics, vitamin D/K status, diet, physical activity and sunlight exposure. Whole-body and lumbar-spine BMD-z scores were low (< or = -1) at diagnosis (10-20%) and after 1 year (30-32%) in the children, independent of symptoms. Whole-body BMD-z scores (-0.55±0.7 versus 0.72±1.5) and serum levels of 25(OH) vitamin D (90.3±24.8 versus 70.5±19.8 nmol/l) were significantly lower in older children (>10 years) when compared with younger children (< or =10 years) (P<0.001). Forty-three percent had suboptimal vitamin D status (25(OH)-vitamin D <75 nmol/l) at diagnosis; resolving in nearly half after 1 year on the GFD. Twenty-five percent had suboptimal vitamin K status at diagnosis; all resolved after 1 year. Children and adolescents with CD are at risk for suboptimal bone health at time of diagnosis and after 1 year on GFD; likely due in part to suboptimal vitamin D/K status. Therapeutic strategies aimed at optimizing vitamin K/D intake may contribute to improved BMD in children with CD.


NIR-dependent photothermal-photodynamic synergistic antibacterial mechanism for titanium carbide nanosheets intercalated and delaminated by tetramethylammonium hydroxide.
The infectious disease epidemics caused by pathogens are a serious and growing worldwide public health problem. More seriously, the multiple resistant bacteria extensively spread in hospitals or communities due to antibiotic abuse. In this paper, we fabricate two-dimensional Ti3C2 nanosheets with excellent biocompatibility and photothermal-photodynamic synergistic antibacterial activity against E. coli and S. aureus based on the strategy of tetramethylammonium hydroxide (TMAOH)-driven intercalation and delamination. Compared with the traditional Ti3C2 nanosheets exfoliated by HF or situ HF (HCl + LiF), the photothermal-photodynamic Ti3C2 nanosheets show higher synergistic antibacterial efficiency. In addition, the antibacterial mechanism demonstrates that biofilm disruption and leakage of bacterial contents contribute to reactive oxygen species reaction (ROS) and photothermal antibacterial activity irradiated by NIR after most Ti3C2 nanosheets adhering to target bacteria. In conclusion, the Ti3C2 nanosheets have great potential as an effective antibacterial material without causing drug resistance, relying on intercalating and delaminating by TMAOH.


Anti-Exceptionalism About Requirements of Epistemic Rationality.
I argue for the unexceptionality of evidence about what rationality requires. Specifically, I argue that, as for other topics, one's total evidence can sometimes support false beliefs about this. Despite being prima facie innocuous, a number of philosophers have recently denied this. Some have argued that the facts about what rationality requires are highly dependent on the agent's situation and change depending on what that situation is like (Bradley, Philosophers' Imprint, 19(3). 2019). Others have argued that a particular subset of normative truths, those concerning what epistemic rationality requires, have the special property of being 'fixed points'-it is impossible to have total evidence that supports false belief about them (Smithies, Philosophy and Phenomenological Research, 85(2). 2012; Titelbaum 2015). Each of these kinds of exceptionality permits a solution to downstream theoretical problems that arise from the possibility of evidence supporting false belief about requirements of rationality. However, as I argue here, they incur heavy explanatory burdens that we should avoid.


2-Methoxyestradiol inhibits carotid artery intimal hyperplasia induced by balloon injury via inhibiting JAK/STAT axis in rats.
Intimal hyperplasia (IH) is a common complication of vascular interventional procedures that leads to narrowing of the vessel lumen. 2-Methoxyestradiol (2ME), an estrogen metabolite, has numerous pharmacological actions, including vasoprotective and antiproliferative activities. The present study aimed to evaluate the potential of 2ME, prepared as a self-nanoemulsifying drug delivery system (SNEDDS), to inhibit IH induced by balloon injury (BI) in the rat carotid artery. The prepared 2ME SNEDDS had a particle size of 119 ± 2.3 nm and a zeta potential of -7.1 ± 1.4 mV. Animals were divided into 5 groups, namely control, sham, BI, BI + 2ME (100 μg/kg), and BI + 2ME (250 μg/kg). The obtained data indicated that 2ME significantly inhibited IH as indicated by the histological and morphometric assessment of the intima, media and lumen areas. This was associated with enhanced expression of Bax and inhibited expression of Bcl2 mRNA. Furthermore, 2ME exhibited significant antioxidant properties as evidenced by prevention of malondialdehyde accumulation as well as superoxide dismutase and catalase enzymatic exhaustion. In addition, 2ME showed significant anti-inflammatory actions as it significantly inhibited vascular content of interleukin-6, tumor necrosis factor-alpha, and nuclear factor-κB. The observed vasoprotective activities of 2ME were accompanied by inhibition of Janus kinase/signal transducers and activators of transcription (JAK/STAT) protein expression. In conclusion, this study revealed that 2ME ameliorates balloon injury-induced IH in rats via suppressing JAK/STAT axis. This may help to develop new strategies to combat IH.


[Clinical values of vascular endothelial growth factor expression and microvascular density analysis in liver cancer specimens].
To explore the roles of vascular endothelial growth factor (VEGF) in microvessel angiogenesis, development and metastasis of hepatocellular carcinoma (HCC). The cellular distributions of VEGF expression and microvascular density (MVD) in 36 HCCs were investigated, and the levels of total RNA and VEGF were detected in HCCs, Para cancerous, and distal cancerous tissues, respectively. The incidence of VEGF was 63.9% in 36 cases of HCCs, 78.3% in non-encapsulated HCCs, and 90.9% in HCCs with extrahepatic metastasis, respectively. The VEGF expression was tightly correlated with MVD (t=4.49, P<0.01). No significant difference was found between VEGF or MVD and tumor diameter or differentiation degree. The level of total RNA in HCCs was lower but the VEGF level significantly higher than those of Para cancerous or distal cancerous ones (q=6.10, P<0.01). The present data suggest that VEGF over expression and MVD abnormality are useful markers for vascular invasion and metastasis of liver tumors.


The relationship between functionality and erector spinae activity in patients with specific low back pain during dynamic and static movements.
Alterations in the activity of the lumbar erector spinae (LES) muscles on both sides of the spine have been inconsistently reported in patients with specific low back pain (sLBP) after measuring the muscular activity with surface electromyography (sEMG). It also remains unclear whether these alterations in LES activity can be related to the functional level of patients with sLBP. This study investigated the LES activity in patients with sLBP during activities of daily living (ADL) which included dynamic and static movement tasks. Moreover, the alterations in LES activity were correlated with the first seven questions of the Zurich Claudication Questionnaire (ZCQ-SS). Thirty patients with specific LBP and twenty healthy subjects were recruited to perform five ADLs including 'static waist flexion', 'sit to stand',' 30-seconds standing', '6-minutes walking' and 'climbing stairs'. sEMG sensors were mounted on the left and right LES muscles. The integrated EMG (IEMG) was calculated from the preprocessed sEMG data as statistical comparison criteria. LES activity was significantly higher in patients during 'sit to stand',' 30-seconds standing' and 'climbing stairs' and significantly lower during 'static waist flexion' compared to healthy controls. All tasks showed a significant correlation with the ZCQ-SS score except for '6-minutes walking', whereby LES activity and ZCQ-SS score correspondingly increased during 'sit to stand' and 'climbing stairs' and the LES activity decreased with an increasing ZCQ-SS score during 'static waist flexion' and' 30-seconds standing'. There was a high correlation between alterations in LES activity and the level of functionality in LBP patients. However, the LES activity showed an opposite behavior during static and dynamic movement tasks. The methodology presented can be a useful tool for quantifying improvements in functionality after rehabilitation processes.


Effect of Pre-Oxidation Treatment of Nano-SiC Particulates on Microstructure and Mechanical Properties of SiC/Mg-8Al-1Sn Composites Fabricated by Powder Metallurgy Combined with Hot Extrusion.
Nano-SiC particulates (n-SiCp) reinforced Mg-8Al-1Sn (AT81) composites with different pre-oxidation parameters were fabricated by powder metallurgy (P/M) process combined with hot extrusion. The effects of pre-oxidization treatment of n-SiCp on the microstructure and tensile properties of 0.5 vol % n-SiCp/AT81 composites were investigated accordingly. The distribution of n-SiCp with different pre-oxidation parameters was homogeneous in the composites. Moreover, it was found that a thin MgAl₂O₄ layer formed at the interface when the n-SiCp were pre-oxidized at 1073 K for 2 h, while the MgAl₂O₄ layer became much thicker with pre-oxidization temperature increasing to 1273 K for 2 h. After an appropriate pre-oxidization treatment of n-SiCp at 1073 K for 2 h, the as-extruded 0.5 vol % n-SiCp/AT81 composites exhibited an enhanced strength. It was found that the yield strength (YS) and ultimate tensile strength (UTS) increased from 168 MPa and 311 MPa to 255 MPa and 393 MPa compared with the as-extruded AT81 alloy, reflecting 51.8% and 26.4% increments, respectively. The improvement of mechanical properties should be mainly attributed to the grain refinement and homogeneous distribution of n-SiCp in the composites. Moreover, a well-bonded interface and the formation of an appropriate amount of interfacial product (MgAl₂O₄) benefited the material's mechanical properties.


"Understanding burns": research project BurnCase 3D--overcome the limits of existing methods in burns documentation.
Understanding burns means knowing what is necessary for the successful treatment of burns. Nobody in science, economics, or quality control can comprehend this issue's complexity without thorough documentation of the work involved. BurnCase 3D is a non-profit research project whose aim, achieved through software of the same name, is a thorough and accurate burn-treatment documentation schema, facilitated by three-dimensional digital models tracked over time. Adapting these models on the basis of gender, height, weight, and body shape avoids systemic errors. Superimposing photos of the burned areas on the model prevents individual error and can be combined with methods of burn-depth evaluation. The program includes automatic encoding of diagnostic and therapeutic procedures. Model resolution is 1cm(2) and finer, so that even small scars' locations and extents can be documented, thus enabling registration of long-term results. The program's status as a multilingual data-collection tool brings together multiple international efforts in data collection, and makes it suitable for e-medicine and disaster relief. In its basic form, it provides essential functions in burn documentation, photo documentation, and reporting. The four-dimensional database allows registration of interactions over time and can demonstrate the influence of location, timing, and intervention on outcome.


Comparison of lipid accumulation and metabolism in carrageenan-induced granulomas to aorta and blood monocytes of normal and cholesterol-fed rabbits.
New Zealand rabbits (six each) were either maintained on a standard chow diet (ND) or the chow diet supplemented with cholesterol/peanut oil (HD) for 2 weeks. After 2 weeks, each animal had 15 ml of a 1% carrageenan gel injected subcutaneously into the midabdominal area. Rabbits were maintained on the diets for an additional 4 weeks. At sacrifice, blood was collected both for serum and for monocyte isolation and granulomas and aorta were excised. Tissues were assayed for lipid composition and lipid metabolism. Electron and light microscopies were performed on granuloma tissue. Granulomas from ND animals did not stain with oil red O. Granulomas from HD animals had homogenous oil red O staining indicating lipid accumulation. Granulomas from both ND and HD animals consisted of macrophages. Macrophages from ND rabbits accumulated follicular carrageenan but not lipid, while HD macrophages had the appearance of foam cells. Granuloma lipid content and metabolism closely paralleled the aorta and blood monocytes. The HD tissue had increased acylCoA:cholesterol acetyltransferase (ACAT) activity and lipid composition changes reflective of the atherosclerotic process. ND granulomas had no elevation of lipid content or ACAT. The carrageenan-induced granulomas provide a useful model for studying the biochemical and morphologic changes characteristic of arteries undergoing atherogenic change.


Electrocorticographic evidence of a common neurocognitive sequence for mentalizing about the self and others.
Neuroimaging studies of mentalizing (i.e., theory of mind) consistently implicate the default mode network (DMN). Nevertheless, the social cognitive functions of individual DMN regions remain unclear, perhaps due to limited spatiotemporal resolution in neuroimaging. Here we use electrocorticography (ECoG) to directly record neuronal population activity while 16 human participants judge the psychological traits of themselves and others. Self- and other-mentalizing recruit near-identical cortical sites in a common spatiotemporal sequence. Activations begin in the visual cortex, followed by temporoparietal DMN regions, then finally in medial prefrontal regions. Moreover, regions with later activations exhibit stronger functional specificity for mentalizing, stronger associations with behavioral responses, and stronger self/other differentiation. Specifically, other-mentalizing evokes slower and longer activations than self-mentalizing across successive DMN regions, implying lengthier processing at higher levels of representation. Our results suggest a common neurocognitive pathway for self- and other-mentalizing that follows a complex spatiotemporal gradient of functional specialization across DMN and beyond.


Studies on immune responses to larval cestodes in mice: a simple mechanism of non-specific immunosuppression in Mesocestoides corti-infected mice.
After intraperitoneal (i.p.) injection of sheep erythrocytes (SRBC) or dinitrophenylated Ficoll (DNP-Ficoll), mice infected with the larval cestode, Mesocestoides corti, contain at least 20x fewer antibody-secreting cells (PFC) in their spleens (or spleens plus lymph nodes) than uninfected mice. By contrast, intravenous injection of antigen leads to normal PFC responses. Results of studies on the fate of labelled syngeneic erythrocytes and foreign proteins suggest that i.p. injected materials are retained in the inflamed peritoneal cavity. Sequestration of antigen, and its subsequent local destruction, presumably accounts for the markedly suppressed systemic immune responses induced by i.p. injected antigens in M. corti-infected mice.


Imaging of polarized components of Cerenkov light and luminescence of water during carbon-ion irradiation.
The luminescence image of water during the irradiation of carbon ions showed higher intensity at shallow depths than dose distribution due to the contamination of Cerenkov light from secondary electrons. Since Cerenkov light is coherent and polarized for the light produced during the irradiation of carbon ions to water, the reduction of Cerenkov light may be possible with a polarizer. In addition, there is no information on the polarization of the luminescence of water. To clarify these points, we measured the optical images of water during the irradiation of carbon ions with a polarizer by changing the directions of the transmission axis. Imaging was conducted using a cooled charge-coupled device (CCD) camera during the irradiation of 241.5 MeV/n energy carbon ions to a water phantom with a polarizer in front of the lens by changing the transmission axis parallel and perpendicular to the carbon-ion beam. With the polarizer parallel to the carbon-ion beam, the intensity at the shallow depth was ~26% higher than that measured with the polarizer perpendicular to the beam. We found no significant intensity difference between these two images at deeper depths where the Cerenkov light was not included. The difference image of the parallel and perpendicular directions showed almost the same image as the simulated Cerenkov light distribution. Using the measured difference image, correction of the Cerenkov component was possible from the measured luminescence image of water during the irradiation of carbon ions. We could measure the difference of the Cerenkov light component by changing the transmission axis of the polarizer. Also we clarified that there was no difference in the luminescence of water by changing the transmission axis of the polarizer.


Influence of Statins on the Survival Outcomes of Patients with Diffuse Large B Cell Lymphoma: A Systematic Review and Meta-Analysis.
Previous studies evaluating the influence of statins on the survival of patients with diffuse large B cell lymphoma (DLBCL) showed inconsistent results. This systematic review and meta-analysis was conducted to investigate whether statin use is correlated with the survival of DLBCL patients. Related cohort studies were obtained by searching PubMed, Embase, Cochrane's Library, and Web of Science databases. Study characteristics and outcome data were extracted independently by two authors. The random-effect model was used for meta-analysis, considering the possible influence of between-study heterogeneity. Eight studies involving 9927 patients with DLBCL were included. Results did not show significant associations of statins with overall survival (OS, hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.69∼1.11, p=0.27; I 2 = 60%) or progression-free survival (PFS, HR: 0.92, 95% CI: 0.72∼1.17, p=0.49; I 2 = 23%) in these patients. Subgroup analyses suggested that statin was be associated with survival of DLBCL patients from Asia (HR for OS: 1.19, 95% CI: 0.91∼1.56, p=0.19, I 2 = 2%; HR for PFS: 1.13, 95% CI: 0.89∼1.44, p=0.33, I 2 = 0%), but was associated with significantly improved survival of patients from Western countries (HR for OS: 0.73, 95% CI: 0.66∼0.81, p < 0.001, I 2 = 0%; for PFS, HR: 0.72, 95% CI: 0.53∼0.96, p=0.03, I 2 = 0%), which fully explained the heterogeneity (p for subgroup difference <0.05). Variables such as study design, patient age, and study quality were not shown to affect the findings. Overall, statins did not affect the survival of patients with DLBCL. However, statin use may be associated with an improved survival rate of DLBCL patients from Western countries.


Diagnostic value of SHOX2, RASSF1A gene methylation combined with CEA level detection in malignant pleural effusion.
To investigate the diagnostic value of combined detection of SHOX2 and RASSF1A gene methylation with carcinoembryonic antigen (CEA) level in diagnosing malignant pleural effusion. Between March 2020 and December 2021, we enrolled 68 patients with pleural effusion admitted to the Department of Respiratory and critical care medicine of Foshan Second People's Hospital. The study group included 35 cases of malignant pleural effusion and 33 cases of benign pleural effusion. Methylation of the short homeobox 2 genes (SHOX2) and RAS-related region family 1A gene (RASSF1A) in pleural effusion samples were detected by real-time fluorescence quantitative PCR, and the level of carcinoembryonic antigen (CEA) in pleural effusion samples was detected by immune flow cytometry fluorescence quantitative chemiluminescence. SHOX2 or RASSF1A gene methylation was detected in 5 cases in the benign pleural effusion group and 25 patients in the malignant pleural effusion group. The positive rate of SHOX2 or RASSF1A gene methylation in the malignant pleural effusion group was significantly higher than in the benign pleural effusion group (71.4% vs. 15.2%, P < 0.01). Positive CEA (CEA > 5 ng/m) was detected in 1 case in the benign pleural effusion group and 26 patients in the malignant pleural effusion group. The CEA-positive rate in the malignant pleural effusion group was significantly higher than in the benign pleural effusion group (74.3% vs. 3%, P < 0.01). When SHOX2 and RASSF1A gene methylation was combined with CEA detection, 6 cases were positive in the benign pleural effusion group, and 31 patients were positive in the malignant pleural effusion group. The positive rate of combined detection in the malignant pleural effusion group was significantly higher than in the benign pleural effusion group (88.6% vs. 18.2%, P < 0.01). The sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and Youden's index of SHOX2, RASSF1A gene methylation combined with CEA in diagnosing malignant pleural effusion were 88.6%, 81.8%, 85.3%, 83.8%, 87.1% and 0.7 respectively. The combined detection of SHOX2 and RASSF1A gene methylation with CEA level in pleural effusion has a high diagnostic value for malignant pleural effusion.


Transplacental transfer of propofol in pregnant ewes.
Propofol is an injectable anaesthetic that is currently used both in veterinary and human medicine for the induction and maintenance of anaesthesia. Although little is known about the pharmacokinetics of propofol in fetuses, it is widely used in obstetric procedures, particularly in caesarean section. This study determines the pharmacokinetics of propofol in pregnant ewes in the last third of pregnancy, and placental transfer and pharmacokinetics in fetuses after the administration of a 6 mg/kg intravenous (i.v.) bolus (phase 1) or a 6 mg/kg i.v. bolus followed by continued infusion of 0.4 mg/kg/min. In ewes, the area under the blood concentration-time curve (AUC) and C(max) (8.6 mgh/mL and 9.5mg/mL, respectively) was higher than those of the fetus (1.6 mgh/mL and 1.19 mg/mL, respectively). The mean half-life was 0.5h in the dam and 1.1h in the fetus.


Survival after aortic valve replacement for severe aortic stenosis with low transvalvular gradients and severe left ventricular dysfunction.
We sought to assess whether aortic valve replacement (AVR) among patients with severe aortic stenosis (AS), severe left ventricular (LV) dysfunction and a low transvalvular gradient (TVG) is associated with improved survival. The optimal management of patients with severe AS with severe LV dysfunction and a low TVG remains controversial. Between 1990 and 1998, we evaluated 68 patients who underwent AVR at our institution (AVR group) and 89 patients who did not undergo AVR (control group), with an aortic valve area < or = 0.75 cm(2), LV ejection fraction < or = 35% and mean gradient < or = 30 mm Hg. Using propensity analysis, survival was compared between a cohort of 39 patients in the AVR group and 56 patients in the control group. Despite well-matched baseline characteristics among propensity-matched patients, the one- and four-year survival rates were markedly improved in patients in the AVR group (82% and 78%), as compared with patients in the control group (41% and 15%; p < 0.0001). By multivariable analysis, the main predictor of improved survival was AVR (adjusted risk ratio 0.19, 95% confidence interval 0.09 to 0.39; p < 0.0001). The only other predictors of mortality were age and the serum creatinine level. Among select patients with severe AS, severe LV dysfunction and a low TVG, AVR was associated with significantly improved survival.


Successful treatment of acute myeloid leukaemia in a patient with ataxia telangiectasia.
Ataxia telangiectasia (AT) is a rare autosomal recessive multisystem disorder characterised by cerebellar degeneration, immunodeficiency and cancer predisposition. Around 10% of AT patients develop lymphoid malignancies, but the development of myeloid leukaemia with AT (AT-AML) is extremely rare, and there have been no previous publications regarding suitable therapies. Here, we first describe a successful therapeutic experience in a patient with AT-AML (FAB-M1) who attained remission after induction therapy and maintained stable disease for a year. To minimise therapy-induced toxicity, low-dose induction was applied first, though this was obviously insufficient and the patient subsequently responded well to dose-intensified short-term chemotherapy. In this report, we suggest a curative therapeutic approach for AT-AML, though the issue of how best to manage patients with cancer complicated by immunodeficiency remains undecided.


Citrus nobiletin suppresses inducible nitric oxide synthase gene expression in interleukin-1β-treated hepatocytes.
Nobiletin is a polymethoxylated flavone that is abundant in the peels of citrus fruits, such as Citrus unshiu (Satsuma mandarin) and Citrus sinensis. The dried peels of C. unshiu (chinpi) have been included in several formulae of Japanese Kampo medicines. Nobiletin may suppress the induction of inducible nitric oxide synthase (iNOS), which synthesizes the inflammatory mediator nitric oxide (NO) in hepatocytes. A C. unshiu peel (CUP) extract was prepared. Primary cultured rat hepatocytes were treated with the CUP extract or nobiletin in the presence of interleukin 1β (IL-1β), which induces iNOS expression. NO production and iNOS gene expression were analyzed. High-performance liquid chromatography analyses revealed that the nobiletin content in the CUP extract was 0.14%. Nobiletin dose-dependently reduced the NO levels and decreased iNOS expression at the protein, mRNA and antisense transcript levels. Flavone, which does not contain any methoxy groups, also suppressed iNOS induction. Nobiletin reduced the transcriptional activity of iNOS promoter-luciferase constructs and the DNA-binding activity of nuclear factor κB (NF-κB) in the nuclei. The suppression of iNOS induction by nobiletin suggests that nobiletin may be responsible for the anti-inflammatory effects of citrus peels and have a therapeutic potential for liver diseases.


Replacement Effects and Budget Impacts of Insurance Coverage for Sodium-Glucose Co-Transporter-2 Inhibitors on Oral Antidiabetic Drug Utilization.
A new oral antidiabetic drug class, sodium-glucose co-transporter-2 inhibitors (SGLT-2 inhibitors), has been covered by national health insurance in Taiwan since May 2016. This study estimated the impacts of insurance coverage for SGLT-2 inhibitors on the replacement effects of antidiabetic drug use and the overall budget for antidiabetic drugs in Taiwan. Antidiabetic drugs were divided into nine categories based on the American Diabetes Association guidelines. We retrieved claims data from 2015 to 2017 for all patients diagnosed with diabetes mellitus from the National Health Insurance Research Database. An interrupted time series design and segmented regression were used to estimate the budget impact of insurance coverage for SGLT-2 inhibitors. Three scenarios were designed for the prescribing pattern for SGLT-2 inhibitors: (1) monotherapy, (2) metformin-based (m-based) drug prescriptions, and (3) metformin and sulfonylurea-based (m-s-based) drug prescriptions. From May 2016 to April 2017, the prescription rate for m-based SGLT-2 inhibitors increased from 0.43 to 3.50%, and the expenditure rate increased from 0.82 to 6.58%. We found that the prescription rates of m-based and m-s-based dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) decreased by 6.23 and 11.51% following the initiation of insurance coverage for SGLT-2 inhibitors, respectively. Furthermore, there was a 5.95% increase in the overall budget impact of antidiabetic drugs 1 year following the initiation of insurance coverage for SGLT-2 inhibitors. Both the prescription rates and expenditure rates for SGLT-2 inhibitors have increased since they have been covered by national health insurance in Taiwan, which significantly reduced usage of DPP-4 inhibitors but caused the positive growth of overall antidiabetic drug expenditures.


BPIFB1 inhibits vasculogenic mimicry via downregulation of GLUT1-mediated H3K27 acetylation in nasopharyngeal carcinoma.
Nasopharyngeal carcinoma (NPC) demonstrates significant regional differences and a high incidence in Southeast Asia and Southern China. Bactericidal/permeability-increasing-fold- containing family B member 1 (BPIFB1) is a relatively specific and highly expressed protein in the nasopharyngeal epithelium. BPIFB1 expression is substantially downregulated in NPC and is significantly associated with poor prognosis in patients with NPC. However, the specific molecular mechanism by which BPIFB1 regulates NPC is not well understood. In this study, we found that BPIFB1 inhibits vasculogenic mimicry by regulating the metabolic reprogramming of NPC. BPIFB1 decreases GLUT1 transcription by downregulating the JNK/AP1 signaling pathway. Altered glycolysis reduces the acetylation level of histone and decreases the expression of vasculogenic mimicry-related genes, VEGFA, VE-cadherin, and MMP2, ultimately leading to the inhibition of vasculogenic mimicry. To our knowledge, this is the first report on the role and specific mechanism of BPIFB1 as a tumor suppressor gene involved in regulating glycolysis and vasculogenic mimicry in NPC. Overall, these results provide a new therapeutic target for NPC diagnosis and treatment.


High dose radiation with chemotherapy followed by salvage esophagectomy among patients with locally advanced esophageal squamous cell carcinoma.
Locoregional failure is a major problem associated with chemoradiation treatment for squamous cell esophageal carcinoma. The aim of this study was to assess the feasibility, efficacy, and toxicity of preoperative radiation (dose > 50 Gy) with platinum-based chemotherapy followed by esophagectomy in locally advanced squamous cell carcinoma. Data of patients with cT2-cT4 or node positive squamous cell carcinoma of the esophagus who received trimodality treatment between February 2006 and June 2015 were reviewed. Forty-four patients were treated with intensity-modulated radiation therapy, volumetric-modulated arc therapy or three-dimensional radiation therapy. The median radiation dose was 60 Gy. The average volume of the lungs receiving 10 Gy was 48.1%, 20 Gy was 24.5%, and the average mean lung dose was 14 Gy. After chemoradiation, R0 resection was achieved in 31 patients (71%). Patients who received >60 Gy had a higher pathologic complete remission rate than those in the lower dose group (59.1% vs. 36.4%). R0 resection and radiation dose >60 Gy were associated with better overall survival in Cox proportional hazards regression analysis. The median follow-up duration was 22.4 months and median survival was 25.6 months. Two-year overall, progression-free survival and locoregional control rates were 55.9%, 28.6%, and 56%, respectively. The most common grade 3-4 toxicities were esophagitis (63.6%) and neutropenia (25%). Grade 3-4 postoperative morbidities included surgical wound infection (2.3%), acute renal failure (2.3%), and anastomosis stricture (2.3%). Trimodality treatment with a high preoperative radiation dose and chemotherapy yielded a good pathologic complete response rate, and long-term survival with low toxicities.


Functional specialization of hippocampal somatostatin-expressing interneurons.
Hippocampal somatostatin-expressing (Sst) GABAergic interneurons (INs) exhibit considerable anatomical and functional heterogeneity. Recent single cell transcriptome analyses have provided a comprehensive Sst-IN subtype census, a plausible molecular ground truth of neuronal identity whose links to specific functionality remain incomplete. Here, we designed an approach to identify and access subpopulations of Sst-INs based on transcriptomic features. Four mouse models based on single or combinatorial Cre- and Flp- expression differentiated functionally distinct subpopulations of CA1 hippocampal Sst-INs that largely tiled the morpho-functional parameter space of the Sst-INs superfamily. Notably, the Sst;;Tac1 intersection revealed a population of bistratified INs that preferentially synapsed onto fast-spiking interneurons (FS-INs) and were both necessary and sufficient to interrupt their firing. In contrast, the Ndnf;;Nkx2-1 intersection identified a population of oriens lacunosum-moleculare (OLM) INs that predominantly targeted CA1 pyramidal neurons, avoiding FS-INs. Overall, our results provide a framework to translate neuronal transcriptomic identity into discrete functional subtypes that capture the diverse specializations of hippocampal Sst-INs.


Usability of encounter data for Medicaid comprehensive managed care vs traditional Medicaid fee-for-service claims among pregnant women.
The completeness of medical encounters capture among Medicaid enrollees in comprehensive managed care (CMC) has been shown to vary across states and years. CMC penetration has grown, and CMC encounter capture specific to pregnancy care is understudied. To compare the completeness of encounter data for pregnant beneficiaries in CMC versus traditional fee-for-service (FFS) in Texas and Florida between 2007 and 2010. Using Medicaid Analytic eXtract (MAX) data linked to Florida and Texas birth certificate records, for each state and study year, we compared proportions using seven themes: (a) delivery; (b) prenatal visits; (c) dispensed prescriptions during pregnancy; (d) gestational diabetes and blood glucose testing; (e) antidiabetics and diagnosis of diabetes mellitus; (f) antibiotics for urinary tract infection and outpatient encounter; and (g) bacterial vaginosis and dispensing for metronidazole or clindamycin. We considered CMC data to be acceptable if proportions were no less than 10% below the corresponding (2007 to 2010) FFS control values. Pregnancy-related characteristics of FFS vs CMC denominators were comparable. Proportions for the seven measures among FFS controls ranged from 26% to 98%. In Texas, CMC encounter data met the thresholds for all measures between 2007 and 2010. Florida had usable CMC encounter data starting from 2009 with incomplete medical and pharmacy records in 2007 and 2008. The quality of CMC encounter data in MAX files for pregnant women varied in Florida and Texas and improved over time. Use of pregnancy-specific measures can aid researchers in selecting states and years with acceptable encounter data quality.


Transitions between B-DNA and Z-DNA: a dilemma.
The intramolecular conformational change which occurs in double-stranded (dG-dC) oligonucleotides and polynucleotides in high salt solutions is currently assumed to be a transition between the presently accepted structures for B-DNA and Z-DNA. However, a serious dilemma results from the fact that these two structures are from topologically different families of helical duplexes. Mechanisms for interconversion between the two forms, under typical experimental conditions, are highly improbable from a physical-chemical viewpoint. The alternative possibility is that the structure of one of the forms in the transition is not as assumed. The resulting dilemma is addressed and alternative relationships between right- and left-handed DNA forms are discussed.


Booming trade in mammoth ivory may be bad news for elephants.
Paleontologists are urged to take a stand against a market that may provide cover for continued poaching.


Differential molecular connectivity in data-base fragment searching.
A general scheme is described in which molecular fragments are coded from molecular connectivity values. Specifically a fragment is described by the difference between a simple connectivity index of a certain order and the valence connectivity index of the same order. This numerical value is then used to search for that particular fragment among stored fragment values associated with a molecular connectivity calculation. Examples illustrate the method.


Release of cytokeratin-18 and -19 fragments (TPS and CYFRA 21-1) into the extracellular space during apoptosis.
Serum fragments of cytokeratins-18 and -19 (measured as TPS and CYFRA 21-1, respectively) have traditionally been considered as markers of tumor proliferation, although the evidence is scarce for a causative relationship between proliferation and levels of TPS and CYFRA 21-1. We examined whether apoptosis might produce TPS and CYFRA 21-1 fragments. MCF-7 breast cancer cells were treated with mitomycin C or agonistic anti-CD95 antibody, and levels of TPS and CYFRA 21-1 in tissue culture supernatants were compared with the frequency of cells exhibiting the following markers of cell death: intracellular cytokeratin-18 cleavage, surface staining with annexin-V, propidium iodide uptake, DNA fragmentation. Twenty-four hours after inducing apoptosis, levels of TPS and CYFRA 21-1 were elevated > or = 4-fold in culture supernatants. Elevations in TPS and CYFRA 21-1 coincided with apoptosis measured by the first three cell death markers but preceded DNA fragmentation. These mitomycin C- and CD95-mediated elevations were completely inhibited by co-incubation with the caspase inhibitors Z-VAD.fmk and Z-IETD.fmk, respectively. We conclude that TPS and CYFRA 21-1 can be abundantly released into the extracellular space during the intermediate stage of epithelial cell apoptosis.


Homocysteine is positively associated with cytokine IL-18 plasma levels in coronary artery bypass surgery patients.
Homocysteine, cytokines (IL-18, IL-6, IL-8) are involved in vascular inflammation and coronary artery disease. Homocysteine influences endothelial IL-6 and IL-8 cytokine expression and release, however, an association between homocysteine and IL-18 has not been previously investigated in endothelial/smooth muscle cells and or in coronary artery disease. We report in 9 coronary artery bypass surgery (CABG) patients a positive correlation r = 0.86 between homocysteine and IL-18 plasma levels (p < 0.05). Plasma IL-18 levels are significantly higher in those patients with elevated homocysteine compared to those with normal levels (p < 0.02; 153 +/- 19 pg/ml versus 116 +/- 14 pg/ml respectively). Our in vitro cell culture studies suggest that the source of IL-18 in CABG patients with elevated homocysteine is not from vascular smooth muscle or endothelial cells.


The activated mammary gland specific nuclear factor (MGF) enhances in vitro transcription of the beta-casein gene promoter.
The hormonal induction of the beta-casein gene in mammary epithelial cells is dependent on the action of peptide and steroid hormones. Epidermal growth factor, insulin, glucocorticoids and prolactin act in a sequential manner to regulate the transcription of the gene. We have studied the hormonal requirements as well as the nuclear proteins which are involved in the induction process. In vitro transcription in cell free nuclear extracts has been used to demonstrate the central role of the mammary gland specific nuclear factor, MGF, in the mediation of the hormonal signals to the transcription machinery. A gene construct comprising 344 nucleotides of wild type beta-casein promoter sequence and a G-free cassette of 220 nucleotides was used to test the activity of nuclear extracts in the in vitro transcription experiments. A construct in which the proximal MGF binding site in the beta-casein promoter region has been inactivated by mutation and a construct regulated by the adenovirus major late promoter served as controls. Nuclear extracts were prepared from Sf insect cells, HeLa cells and mammary epithelial cells of lactating rats. Strong transcription of the wild type beta-casein promoter construct was observed in the mammary cell extract, weak transcription in the extracts of Sf insect cells and the HeLa cells. The mutation of the MGF binding site drastically reduced the in vitro transcription in the mammary gland cell extract. Beta-casein promoter activity was also compared in nuclear extracts from uninduced and lactogenic hormone induced HC11 mammary epithelial cells. Extracts from induced cells are more efficient in the support of beta-casein gene transcription.


Structure of the lectin mannose 6-phosphate receptor homology (MRH) domain of glucosidase II, an enzyme that regulates glycoprotein folding quality control in the endoplasmic reticulum.
Here we report for the first time the three-dimensional structure of a mannose 6-phosphate receptor homology (MRH) domain present in a protein with enzymatic activity, glucosidase II (GII). GII is involved in glycoprotein folding in the endoplasmic reticulum. GII removes the two innermost glucose residues from the Glc3Man9GlcNAc2 transferred to nascent proteins and the glucose added by UDP-Glc:glycoprotein glucosyltransferase. GII is composed of a catalytic GIIα subunit and a regulatory GIIβ subunit. GIIβ participates in the endoplasmic reticulum localization of GIIα and mediates in vivo enhancement of N-glycan trimming by GII through its C-terminal MRH domain. We determined the structure of a functional GIIβ MRH domain by NMR spectroscopy. It adopts a β-barrel fold similar to that of other MRH domains, but its binding pocket is the most shallow known to date as it accommodates a single mannose residue. In addition, we identified a conserved residue outside the binding pocket (Trp-409) present in GIIβ but not in other MRHs that influences GII glucose trimming activity.


Simple, inexpensive, and ergonomic phantom for quality assurance control of MRI guided Focused Ultrasound systems.
The popularity of Magnetic Resonance guided Focused Ultrasound (MRgFUS) as a beneficial therapeutic solution for many diseases is increasing rapidly, thus raising the need for reliable quality assurance (QA) phantoms for routine testing of MRgFUS systems. In this study, we propose a thin acrylic film as the cheapest and most easily accessible phantom for assessing the functionality of MRgFUS hardware and software. Through the paper, specific QA tests are detailed in the framework of evaluating an MRgFUS preclinical robotic device comprising a single element spherically focused transducer with a nominal frequency of 2.75 MHz. These tests take advantage of the reflection of ultrasonic waves at a plastic-air interface, which results in almost immediate lesion formation on the film at a threshold of applied acoustic energy. The phantom offered qualitative information on the power field distribution of the FUS transducer and the ability to visualize different FUS protocols. It also enabled quick and reliable assessment of various navigation algorithms as they are used in real treatments, and also allowed for the assessment of the accuracy of robotic motion. Therefore, it could serve as a useful tool for detecting defects in system's performance over its lifetime after establishing a baseline while concurrently contributing to establish QA and calibration guidelines for clinical routine controls.


Immunosuppressive activities of 6(5H)-phenanthridinone, a new poly(ADP-ribose)polymerase inhibitor.
6(5H)-phenanthridinone, a recently identified poly(ADP-ribose)polymerase (PARP) inhibitor, is able, at micromolar concentrations, to inhibit concanavalin A-induced lymphocyte proliferation and to potentiate the effect of gamma radiation upon murine spleen cells. When added at the onset of a mixed lymphocyte culture, this compound strongly depresses the induction of primary allogeneic (anti-H2k) cytotoxic T-lymphocytes (CTLs). Lymphokine-activated killer (LAK) induction was also found to be impaired by the PARP inhibitor. Taken together, these results clearly indicate that PARP plays a key-role in immune reactions involving cytotoxicity and that 6(5H)-phenanthridinone could be considered as a potent immunomodulator.


Instruments used in graduating nursing students' exit exams: an integrative review.
This review provides a comprehensive analysis of undergraduate nursing students' exit examinations and indicates that more clinical evaluation methods should be developed to ensure adequate competence.


The outcome of community acquired pneumonia treated on the intensive care unit.
Eighteen patients with community acquired pneumonia required intensive care for severe or progressive hypoxaemia, rising arterial carbon dioxide tension or respiratory arrest, and 17 received intermittent positive pressure ventilation. Thirteen survived to leave hospital and 12 are long term survivors. Ventilation was started within 4 days of admission in all cases and was continued for up to 34 days; six patients required ventilation for over 3 weeks. The most common medical complication was renal failure. The most common iatrogenic complication was pneumothorax. We believe that all the hypoxic patients would have died from their hypoxia had it not been corrected. We estimated that up to 5% of patients admitted with community acquired pneumonia need intensive care. This study demonstrates the effectiveness of such care, which is multidisciplinary, demanding, and may need to be prolonged.


The influence of preoperative rotator cuff cross-sectional area and strength on postoperative outcomes in reverse shoulder arthroplasty.
Although preoperative function and range of motion (ROM) are determinants of postoperative outcome following reverse shoulder arthroplasty (RSA), there is limited data on the influence of preoperative rotator cuff status. The purpose of this study was to evaluate the relationship between preoperative rotator cuff physiologic cross-sectional area (PCSA) and strength on postoperative RSA outcome. A retrospective review was conducted on 53 primary RSAs from a multicenter database performed between 2015 and 2019 using a 135° humeral neck-shaft angle. Preoperative magnetic resonance imaging and computed tomographic scans were used to assess the PCSA of the subscapularis, supraspinatus, infraspinatus, and teres minor. American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores, ROM, and strength were measured preoperatively and at a minimum of 2 years postoperatively. Correlation coefficients were used to determine the relationship between variables. There were no significant correlations between preoperative PCSA of any rotator cuff muscles and postoperative ASES scores. Preoperative subscapularis PCSA positively correlated with change in belly press (BP) strength following RSA (⍴ = 0.37, P = .006). Preoperative abduction strength was significantly correlated with postoperative abduction strength (⍴ = 0.297, P = .006). Preoperative external rotation (ER) strength was significantly correlated with postoperative ER (⍴ = 0.378, P = .005) and abduction (⍴ = 0.304; P = .032) strength. Preoperative BP strength negatively correlated with postoperative ASES (⍴ = -0.283, P = .042) but positively correlated with postoperative BP (⍴ = 0.411, P = .001) and abduction (⍴ = 0.367, P = .009) strength. With the use of a 135° humeral implant, there is limited correlation between preoperative PCSA and postoperative outcomes 2 years following RSA; the only significant correlation was between preoperative subscapularis PCSA and postoperative BP strength. Preoperative strength is positively correlated with postoperative strength but not ROM or ASES scores.


Physicochemical properties and freeze-thaw stability of rice flour blends among rice cultivars with different amylose contents.
The effectiveness of the rice flour blends (RFB) for improving the processing suitability of Dodamssal rice flour (DD), a functional rice variety with a relatively high amylose and resistance starch content, was investigated. Physicochemical properties and freeze-thaw stability of RFB composed of DD and four rice flour (RF) samples with different amylose contents were measured at different DD ratios. DD, which has low swelling power and low pasting viscosity properties, has improved some quality in terms of physicochemical properties by blending with other RF. Especially, non-additive behavior was observed in the blend with Geonyang No.2 RF (GY), a medium waxy variety, due to water competition caused by the difference in pasting temperature. The syneresis of DD was reduced by blending with 75% Hanareum No. 4 RF, with a gradual reduction effect observed following a repeated freeze-thaw cycle. GY significantly improved the low freeze-thaw stability of DD with only a 25% blend. The online version contains supplementary material available at 10.1007/s10068-021-00989-7.


Long-term cost-effectiveness analysis of sacral neuromodulation in the treatment of severe faecal incontinence.
The aim of this study was to evaluate the long-term cost-effectiveness of sacral neuromodulation in the treatment of severe faecal incontinence as compared with symptomatic management. In the public health field, a micro-costing evaluation method was conducted from the perspectives of the health system and the society. The incremental cost-effectiveness ratio was used as a decision index, and we considered various scenarios to evaluate the impact of the cost of symptomatic management and percutaneous nerve evaluation success rate in its calculation. Clinical data were retrieved from a consecutive cohort of 93 patients with severe faecal incontinence undergoing sacral neuromodulation after a failure of conservative (pharmacological and biofeedback) and/or surgical (sphincteroplasty) first-line treatments were considered. The long-term incremental cost-effectiveness ratio comparing sacral neuromodulation versus symptomatic management was 14347€/QALY and 28523€/QALY from the societal and health service provider's perspectives, respectively. If the definitive pulse generator implant success rate was 100%, incremental cost-effectiveness would correspond to 6831€/QALY and 16761€/QALY, respectively. Sacral neuromodulation may be considered a cost-effective technique in the long-term treatment of severe faecal incontinence from the societal and health care sector perspectives. Improving patient selection and determining the predictive outcome factors for successful sacral neuromodulation in the treatment of faecal incontinence would improve cost-effectiveness.


Whole-transcriptome RNA sequencing reveals the global molecular responses and ceRNA regulatory network of mRNAs, lncRNAs, miRNAs and circRNAs in response to copper toxicity in Ziyang Xiangcheng (Citrus junos Sieb. Ex Tanaka).
Copper (Cu) toxicity has become a potential threat for citrus production, but little is known about related mechanisms. This study aims to uncover the global landscape of mRNAs, long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs) in response to Cu toxicity so as to construct a regulatory network of competing endogenous RNAs (ceRNAs) and to provide valuable knowledge pertinent to Cu response in citrus. Tolerance of four commonly used rootstocks to Cu toxicity was evaluated, and 'Ziyang Xiangcheng' (Citrus junos) was found to be the most tolerant genotype. Then the roots and leaves sampled from 'Ziyang Xiangcheng' with or without Cu treatment were used for whole-transcriptome sequencing. In total, 5734 and 222 mRNAs, 164 and 5 lncRNAs, 45 and 17 circRNAs, and 147 and 130 miRNAs were identified to be differentially expressed (DE) in Cu-treated roots and leaves, respectively, in comparison with the control. Gene ontology enrichment analysis showed that most of the DEmRNAs and targets of DElncRNAs and DEmiRNAs were annotated to the categories of 'oxidation-reduction', 'phosphorylation', 'membrane', and 'ion binding'. The ceRNA network was then constructed with the predicted pairs of DEmRNAs-DEmiRNAs and DElncRNAs-DEmiRNAs, which further revealed regulatory roles of these DERNAs in Cu toxicity. A large number of mRNAs, lncRNAs, circRNAs, and miRNAs in 'Ziyang Xiangcheng' were altered in response to Cu toxicity, which may play crucial roles in mitigation of Cu toxicity through the ceRNA regulatory network in this Cu-tolerant rootstock.


A modelling approach to disentangle the factors limiting muscle oxygenation in smokers.
Cigarette smoking is associated with a lower exercise capacity and lower muscle fatigue resistance. This is at least partly attributable to carboxyhaemoglobin (HbCO) in the blood that via reduction in the oxygen-carrying capacity, and the left-shift of the Hb-dissociation curve would reduce tissue oxygenation. On the other hand, a reduced oxygen uptake due to mitochondrial dysfunction would result in improved oxygenation. We used previously collected capillarisation, myoglobin and estimated cellular maximal muscle oxygen consumption data derived from succinate dehydrogenase-stained sections from the vastus lateralis muscle from six smokers and five non-smokers. These data were fed into an expanded Krogh tissue oxygenation model to assess whether an impaired muscle fatigue resistance in smokers is primarily due to HbCO or impaired mitochondrial respiration. The model showed that in smokers with 6% and 20% HbCO (causing a left-shift of the Hb-dissociation curve) average muscle oxygenation was reduced by 1.9% and 7.2%, respectively. Muscle oxygenation was increased by 13.3% when maximal mitochondrial respiration was reduced by 29%. A combination of a 29% reduction in maximal mitochondrial respiration and 20% HbCO led to no significant difference in muscle oxygenation from that in non-smokers. This indicates that while HbCO may explain the reduced exercise capacity after just one smoking session, in chronic smokers impaired mitochondrial respiration appears more important in reducing oxygen extraction and exercise capacity with only a small contribution of the left-shift of the Hb-dissociation curve.


Antifibrillatory actions of bepridil and butyl-MDI, two intracellular calcium antagonists.
The antifibrillatory and electrophysiologic actions of bepridil and butyl-methylenedioxyindene (BU-MDI), two intracellular calcium antagonists, were examined in anesthetized dogs. The administration of bepridil (1.0-10.0 mg/kg i.v.) significantly increased the electrical threshold for ventricular fibrillation determined during unobstructed coronary flow, and was associated with a significant decrease in ventricular excitability and a progressive depression in ventricular myocardial conduction. BU-MDI (3.0-30.0 mg/kg i.v.) did not significantly alter ventricular fibrillation thresholds during unobstructed coronary flow, nor did it significantly alter electrophysiologic properties such as ventricular excitability, conduction or refractoriness. The administration of either bepridil (10 mg/kg i.v.) or BU-MDI (30 mg/kg i.v.), however, resulted in significant increases in the ventricular fibrillation thresholds determined during transient myocardial ischemia, restoring the threshold values to corresponding non-ischemic levels. These results suggest that an inhibition of the action and/or availability of intracellular calcium may play a role in the antifibrillatory actions of BU-MDI and bepridil during transient ischemia.


Influencing medical student choice of primary care worldwide: international application of the four pillars for primary care physician workforce.
Primary care is a crucial part of a functional health care system, though in many parts of the world there are current or projected gaps in the primary care physician workforce. The academic family medicine organizations in the United States (US) developed the "Four Pillars for Primary Care Physician Workforce," a model built on decades of research, highlighting four main areas of emphasis for increasing primary care physician output: 1) pipeline; 2) process of medical education; 3) practice transformation; and 4) payment reform. This commentary proposes that this model, although developed in the US context, is applicable in other medical education settings, including Israel, based on the recently reported findings of Weissman and colleagues in this journal.


Corrigendum: Determinants of COVID-19 vaccine acceptance and access among people experiencing homelessness in Germany: a qualitative interview study.
[This corrects the article DOI: 10.3389/fpubh.2023.1148029.].


Pediatric Murmurs.
Many healthy children may be found to have a murmur on physical exam. Whether this murmur is discovered at a routine health maintenance visit or as a result of a focused exam on a child with illness, it is just one finding and must be considered in the context of the child's history and other physical exam findings. Murmurs associated with heart defect or dysfunction occur most often in infancy. Most murmurs discovered in children, especially after infancy, between ages 3 to 6 and in young-adulthood, are innocent or benign murmurs and less likely a symptom of cardiac dysfunction or defect.


Pediatric inflammatory bowel disease: imaging issues with targeted solutions.
To date, there have been many advances in inflammatory bowel disease (IBD) imaging in every cross-sectional imaging modality, particularly in children. The main emphasis in pediatric IBD imaging is on robust and reproducible measures of small bowel Crohn's disease inflammation, accurate diagnosis of IBD-related complications, and minimizing radiation burden to the patient, as repeat imaging is necessary over the course of their disease. In this article, we discuss the current state-of-the-art imaging techniques, in addition to routine fluoroscopy, including MR and CT enterography and bowel ultrasound. We also present the emerging use of new methods to characterize disease severity and distinguish active inflammation from fibrosis such as diffusion-weighted imaging, bowel elastography, and contrast-enhanced ultrasound. The diagnostic performance of particular examinations, their strengths and weaknesses, and role in IBD management will be discussed. Although these advanced imaging techniques applied to children are similar to those performed in adults, special considerations related to their application in pediatric patients will also be reviewed.


Rituximab for refractory digital infarcts and ulcers in systemic sclerosis.
Systemic sclerosis is an uncommon connective tissue disease characterised by excessive deposition of collagen and vasculopathy which affects the skin and multiple internal organs. It is associated with autoimmunity, inflammation, vasculopathy and fibrosis. Managing Raynaud's phenonemon, digital infarcts and ulcers in systemic sclerosis patients is often a challenge particularly among rheumatologists. We report a case of systemic sclerosis patient with refractory digital infarcts and ulcers responded successfully with rituximab.


Optic perineuritis: A Canadian case series and literature review.
Optic perineuritis (OPN) is a rare orbital inflammatory disorder that primarily involves the optic nerve sheath (ONS). This study aimed to describe the clinical features of idiopathic OPN as well as OPN secondary to other infectious and inflammatory conditions in a Canadian case series as current literature on secondary OPN in Western countries is mostly limited to case reports. Retrospective case series of all patients seen in a tertiary neuro-ophthalmology practice with a diagnosis of OPN from 2014 to 2020. A total of 21 patients (14 women, mean age 55.8) corresponding to 29 eyes with OPN were identified. Fifteen cases were associated with inflammatory or infectious conditions and only 6 were idiopathic. All idiopathic cases were unilateral. The most common secondary causes of OPN were anti-myelin oligodendrocyte glycoprotein (MOG) antibody disease (n = 4), syphilis (n = 3), sarcoidosis (n = 3), and giant cell arteritis (n = 3). At initial presentation, best-corrected visual acuity (BCVA) was 20/20 or better in 24% (n = 7) and visual field mean deviation (VF MD) was better than -5 dB in 34% of eyes (10/29). Treatment consisted of intravenous penicillin for syphilitic OPN and high-dose corticosteroids followed by oral taper with or without immunosuppressive therapy for non-syphilitic OPN. BCVA improved in 34% (10/29) and VF MD improved in 45% (13/29) eyes. OPN primarily occurred in association with systemic inflammatory conditions, especially in bilateral cases. Syphilis must be ruled out in all patients. Anti-MOG antibody disease is an important, newly recognized secondary cause of OPN, and serologic testing should be included in the investigation of all patients with OPN.


Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus: four-week stimulation trial.
This research examines the impact of 4 weeks of repetitive transcranial magnetic stimulation (rTMS) stimulation to the temporoparietal junction and compares the results of this longer duration of treatment with a similar stimulus protocol of only 2 weeks' duration. To examine the effectiveness and safety of 4 weeks of low-frequency rTMS to the left temporoparietal junction in a cohort of patients with bothersome tinnitus. Crossover, double-blind, randomized controlled trial. Outpatient academic medical center. The study population comprised 14 adults aged between 22 and 59 years with subjective, unilateral or bilateral, nonpulsatile tinnitus of 6 months' duration or greater and a score of 34 or greater on the Tinnitus Handicap Inventory (THI). Low-frequency (1 Hz) 110% motor threshold rTMS or sham to the left temporoparietal junction for 4 weeks. The difference of the change in the THI score between active rTMS and sham rTMS. Active treatment was associated with a median reduction in THI score of 10 (range, -20 to +4) points, and sham treatment was associated with a median reduction of 6 (range, -24 to +12) points. The median difference in THI score between the change associated with active and sham rTMS was 4 (95% CI, -9 to 10; and range, -32 to +14) points. Daily low-frequency active rTMS to the left temporoparietal junction area for 4 weeks was no more effective than sham for patients with chronic bothersome tinnitus. Possible explanations for this negative study include the failure of rTMS to stimulate deeper parts of auditory cortex within the sylvian fissure and more widespread cortical network changes not amenable to localized rTMS effects. clinicaltrials.gov Identifier: NCT00567892.


Hierarchical regression approach to quantify farm households' pro-environmental behavior.
The conflict which exists between a households' self-interest and pro-environmental behavior has led to emotional barriers in ecological conservation. We propose that self-construal affects preferences in this conflicting choice, and self-control plays the mediating role. This study provides conflicting decisions associated with the households' green pesticide adoption behavior in China. Individuals were inquired to select between environmental (pro-environmental) and cost-effective (self-interested) pesticide for food security. Hierarchical regression analysis was employed to progress standard regression estimates by adding a second-stage prior regression to an ordinary model and provides a practical method to evaluate multiple exposures. The results show that the hierarchical regression model may improve environmental protection behavioral studies by including socioeconomic, demographic, and psychological factors. Moreover, our study aims to examine the mediating effect of self-control on the relationship between "self-construal" (SC) and "conflict of self-interest and pro-environmental behavior" (CIPB). Results indicate that self-control (coefficient, - 0.0739; significant level, 5%) partially mediates the relationship between SC and CIPB. Our findings suggest that compared with independent self-construal (coefficient, - 0.05; significant level, 5%), the respondents with interdependent self-construal (coefficient, - 0.09; significant level, 1%) favor pro-environmental choices as they are better in applying self-control and perform pro-environmental behavior. The finding reveals that the hierarchical regression approach provides significant advantages in studying a rural households' pro-environmental decision-making. The current research has policy implications for the adoption of environment-friendly pesticide and organic fertilizer.


Neuroprotective potential of Bacopa monnieri and Bacoside A against dopamine receptor dysfunction in the cerebral cortex of neonatal hypoglycaemic rats.
Neonatal hypoglycaemia initiates a series of events leading to neuronal death, even if glucose and glycogen stores return to normal. Disturbances in the cortical dopaminergic function affect memory and cognition. We recommend Bacopa monnieri extract or Bacoside A to treat neonatal hypoglycaemia. We investigated the alterations in dopaminergic functions by studying the Dopamine D1 and D2 receptor subtypes. Receptor-binding studies revealed a significant decrease (p < 0.001) in dopamine D1 receptor number in the hypoglycaemic condition, suggesting cognitive dysfunction. cAMP content was significantly (p < 0.001) downregulated in hypoglycaemic neonatal rats indicating the reduction in cell signalling of the dopamine D1 receptors. It is attributed to the deficits in spatial learning and memory. Hypoglycaemic neonatal rats treated with Bacopa extract alone and Bacoside A ameliorated the dopaminergic and cAMP imbalance as effectively as the glucose therapy. The upregulated Bax expression in the present study indicates the high cell death in hypoglycaemic neonatal rats. Enzyme assay of SOD confirmed cortical cell death due to free radical accumulation. The gene expression of SOD in the cortex was significantly downregulated (p < 0.001). Bacopa treatment showed a significant reversal in the altered gene expression parameters (p < 0.001) of Bax and SOD. Our results suggest that in the rat experimental model of neonatal hypoglycaemia, Bacopa extract improved alterations in D1, D2 receptor expression, cAMP signalling and cell death resulting from oxidative stress. This is an important area of study given the significant motor and cognitive impairment that may arise from neonatal hypoglycaemia if proper treatment is not implemented.


Prediction of recurrent preterm delivery in asymptomatic women- an anxiety reducing measure?
The QUiPP application is used to predict the risk of recurrent preterm birth (PTB) in asymptomatic high risk women with a previous PTB. Our study aims to evaluate the impact of the use of the QUiPP app on maternal anxiety levels. A retrospective cohort study on asymptomatic pregnant women attending the Prevention of Preterm Birth Clinic in a busy tertiary unit. Women included in the study had a history of previous PTB. The study assessment occurred at approximately 4 weeks prior to the gestation of the earliest previous PTB and included measurement of cervical length and vaginal fetal fibronectin. Data was inputted into the QUiPP application, which in turn estimated risk of preterm delivery at specific intervals. Measured outcomes were gestation at delivery, time from risk assessment to delivery, infant birth weight, NICU admission and length of stay. In addition, maternal anxiety levels were retrospectively assessed using a questionnaire with a Likert scale. Seventy six women were included in the study. All women were asymptomatic for preterm labour at assessment. The mean gestation at the time of risk assessment was 27 weeks, the mean time from risk assessment to delivery was 72 days. Average gestation at time of delivery was 37 weeks (range 22-42 weeks). The preterm birth rate was 29% (n = 22).Seventy seven percent of women who delivered <37 weeks, and 80% who delivered <34 weeks were given QUiPP scores predicting a ≥5% chance of PTB within four weeks of their actual delivery date. Sixteen percent of infants were admitted to NICU (n = 12) with a mean length of stay of 21 days. All infants went home well with their parents.Eighty four percent of respondents to our questionnaire reported feeling anxious about their pregnancy prior to attending the clinic. After receiving a QUIPP score 90% said they felt reassured and 79% reported that the felt less anxious. In asymptomatic women, the use of the QUiPP app helps to predict, prevent, and optimise PTB. This surveillance has a beneficial role for maternal mental well-being in that it reduces anxiety at a key time during a pregnancy.


Transporter engineering in microbial cell factories: the ins, the outs, and the in-betweens.
Engineering the transport of small molecules is an effective approach to improve the performance of microbial cell factories. Transporter engineering can improve the utilization of low-cost alternative substrates, reduce the loss of pathway intermediates, and increase the titer and production rate of the target product. However, transporters are not commonly engineered in strain development programs because the functions of most of the transport proteins are not known. In the recent years, a variety of methods have been developed for identification of transporters for specific substrates and for characterizing transport mechanisms. This review presents recent examples of successful transport engineering for cell factories and discusses the methods for transporter identification and characterization.


Current Landscape and Future Direction of PD-1/PD-L1 Checkpoint Inhibitors in Cancer Treatment.
Immune checkpoints are involved in controlling the activation or inhibition of the immune response and are associated with receptors on the immune cell surface [...].