Iron supplementation maintains ventilatory threshold and improves energetic efficiency in iron-deficient nonanemic athletes.
To determine the effect of iron supplementation on iron status and endurance capacity. Randomized, double-blind iron supplementation. University of Missouri-Columbia and surrounding community. Twenty iron-deficient (serum ferritin, sFer<16 microg/l; serum transferrin receptor, sTfR>8.0 mg/l; or sTfR/log sFer index >4.5), nonanemic (hemoglobin, Hb>120 g/l, women; >130 g/l, men) men and women (18-41 years) were recruited via fliers and newspaper advertisements; 20 of 31 eligible subjects participated. A 30 mg measure of elemental iron as ferrous sulfate or placebo daily for 6 weeks. Dietary iron intake and physical activity did not differ between groups before or after supplementation. Iron supplementation significantly increased sFer compared to placebo (P=0.01), but did not affect Hb or hematocrit. Iron supplementation prevented the decline in ventilatory threshold (VT) observed in the placebo group from pre- to post-supplementation (P=0.01); this effect was greater in individuals with lower sFer before intervention (P<0.05). Changes in sFer from pre- to post-treatment were positively correlated with changes in VT (P=0.03), independent of supplementation. The iron group significantly increased gross energetic efficiency during the submaximal test (P=0.04). Changes in sFer were negatively correlated with changes in average respiratory exchange ratio during the submaximal test (P<0.05). Iron supplementation significantly improves iron status and endurance capacity in iron-deficient, nonanemic trained male and female subjects.


Impact of raising the upper extremity siding cardiac implantable electrical devices on postoperative safety.
The upper extremity siding cardiac implantable electrical device tends to have a limited range of motion during the perioperative period; however, the underlying reason lacks scientific evidence. This study aimed to investigate the safety of the two methods (stepwise or early) of postoperative early upper extremity rehabilitation. We retrospectively investigated 650 consecutive patients with a new implantable pacemaker (PM), implantable cardioverter-defibrillator (ICD), cardiac resynchronization therapy (CRT), or generator exchange between March 2017 and December 2020.The limitation program was conducted from March 2017 to March 2018. The intervention program started as a stepwise protocol in April 2018 and was switched to an early protocol in December 2019. This study analyzed 591 patients, excluding 59 who met the exclusion criteria. The mean age was 76.0 (69.0-82.0) years; 412 (69.7%) patients had a PM, 79 (13.4%) had an ICD, and 100 (16.9%) utilized CRT. There were 155 patients in the limitation protocol, 251 in the stepwise protocol, and 185 patients in the early protocol groups. Postoperative complications occurred in 53 (9.0%) patients. There was no significant difference in the incidence of all complications between the three groups (16 patients [10.3%] vs. 26 patients [10.4%] vs. 11 patients [5.9%]). Shoulder exercise-related complications were defined as hematoma (p = .94), lead dislodgement (p = .16), and increased pacing threshold (p = .23). General complications included wound infection (p = .51), pneumothorax (p = .27), tamponade (p = .07), and deep venous thrombosis (p = .26). Raising of the upper extremity siding cardiac implantable electrical devices above the head did not compromise postoperative safety.


Single-centre experience with allogeneic bone marrow transplantation for acute lymphoblastic leukaemia in childhood: similar survival after matched-related and matched-unrelated donor transplants.
Seventy percent of children with acute lymphoblastic leukaemia (ALL) who may benefit from bone marrow transplant (BMT) lack a human leucocyte antigen (HLA)-matched related donor (MRD). For these children, BMT from a matched unrelated donor (MUD) represents a therapeutic option. We reviewed the course of 62 children with ALL who received fully matched marrow allografts at our institution between 1990 and 1998: 36 with MRDs and 26 with MUDs. Clinical characteristics were similar in the two groups. The interval from attainment of pre-BMT complete remission to transplant was significantly longer in the MUD group. Conditioning (etoposide/total body irradiation) and graft-versus-host disease (GVHD) prophylaxis regimens were the same for all patients, and all received T cell-replete bone marrow. There was no significant difference in probability of engraftment, or time to engraftment, in the two groups. MUD BMT recipients had a significantly greater incidence of grade II-IV acute GVHD (58% versus 24% in the MRD group; P = 0.02), and demonstrated a trend towards more chronic GVHD (39% versus 15%; P = 0.06). Three years post BMT, the probabilities of transplant-related mortality were 33 +/- 11% and 20 +/- 8% in MUD and MRD groups respectively (P = 0.38); the probabilities of relapse were 28 +/- 12% and 41 +/- 9% respectively (P = 0.19). Lansky or Karnofsky performance scores in event-free survivors were 90-100 in 87% of the MUD group and 83% of the MRD group. With a median follow up of 38 months (range, 3-97), 3-year event-free survival was 49 +/- 11% and 47 +/- 9% in the MUD and MRD BMT groups respectively (P = 0.71). These results suggest that MUD BMT is a valuable therapy for children with ALL in whom BMT is indicated, and underscore the importance of efforts aimed at expediting unrelated donor searches for patients lacking a MRD.


Diffusion-weighted imaging of the spinal cord: interleaved echo-planar imaging is superior to fast spin-echo.
To compare and evaluate two novel diffusion-weighted sequences, based either on fast spin-echo (FSE) or interleaved echo-planar imaging (EPI) methods, as potential tools for investing spinal cord abnormalities. Following recent improvements, both interleaved EPI (IEPI) and FSE techniques could be alternative approaches for rapid diffusion-weighted imaging (DWI). Therefore, a navigated diffusion-weighted multishot FSE sequence and a fat-suppressed navigated diffusion-weighted IEPI sequence with local shimming capabilities were tested. Both methods were compared in a consecutive series of five healthy volunteers and five patients with suspected intramedullary lesions. The sequences were graded qualitatively as either superior, inferior, or equal in quality, and also quantitatively by measuring the amount of ghosting artifacts in the background. Quantitative measurements of the diffusion coefficients within the spine were included. The overall image quality of IEPI was superior to FSE. Two out of five FSE scans were rated with poor image quality, whereas all IEPI scans were of sufficient quality. The ghosting levels ranged from approximately 3.3% to 6.2% for IEPI and from approximately 7.5% to 18.9% for FSE. Diffusion coefficients measured in healthy volunteers were similar for both IEPI and FSE, but showed higher fluctuations with the FSE technique. Despite potential advantages of FSE, the IEPI technique is preferable for DWI applications in the spinal cord.


Pediatric firearm injury epidemiology at a level 1 trauma center from 2019 to 2021: including time of the COVID-19 pandemic.
Firearms are a leading cause of death in children. The demand for firearms increased following COVID-19 "stay-at home orders" in March 2020, resulting in record-breaking firearm sales and background checks. We aim to describe the changes in pediatric firearm-related injuries, demographics, and associated risk factors at a Level 1 trauma center in Houston before and during the COVID 19 pandemic. The total number of pediatric firearm-related injury cases increased during March 15th to December 31st, 2020 and 2021 compared to the same time period in 2019 (104 verses 89 verses 78). The demographic group most affected across years were males (87% in 2019 vs 82% in 2020 and 87% in 2021) between 14 and 17 years old (83% in 2019 vs 81% in 2020 and 76% in 2021). There was an increase in firearm injuries among black youth across all years (28% in 2019 vs 41% in 2020 vs 49% in 2021). Injuries in those with mental illness (10% in 2019 vs 24% in 2020 vs 17% in 2021), and injuries where the shooter was a known family member or friend (14% in 2019 vs 18% in 2020 vs. 15% in 2021), increased from 2019 to 2020. The total number of pediatric firearm-related injuries increased during the COVID-19 pandemic compared to the previous year despite a decline in overall pediatric emergency department visits. Increases in pediatric firearm-related injuries in already vulnerable populations should prompt further hospital initiatives including counseling on safe firearm storage, implementation of processes to identify children at risk for firearm injuries, and continued research to mitigate the risk of injury and death associated with firearms in our community.


Sequential bortezomib and temozolomide treatment promotes immunological responses in glioblastoma patients with positive clinical outcomes: A phase 1B study.
Glioblastoma (GBM) is an aggressive malignant brain tumor where median survival is approximately 15 months after best available multimodal treatment. Recurrence is inevitable, largely due to O6 methylguanine DNA methyltransferase (MGMT) that renders the tumors resistant to temozolomide (TMZ). We hypothesized that pretreatment with bortezomib (BTZ) 48 hours prior to TMZ to deplete MGMT levels would be safe and tolerated by patients with recurrent GBM harboring unmethylated MGMT promoter. The secondary objective was to investigate whether 26S proteasome blockade may enhance differentiation of cytotoxic immune subsets to impact treatment responses measured by radiological criteria and clinical outcomes. Ten patients received intravenous BTZ 1.3 mg/m2 on days 1, 4, and 7 during each 4th weekly TMZ-chemotherapy starting on day 3 and escalated from 150 mg/m2 per oral 5 days/wk via 175 to 200 mg/m2 in cycles 1, 2, and 3, respectively. Adverse events and quality of life were evaluated by CTCAE and EQ-5D-5L questionnaire, and immunological biomarkers evaluated by flow cytometry and Luminex enzyme-linked immunosorbent assay. Sequential BTZ + TMZ therapy was safe and well tolerated. Pain and performance of daily activities had greatest impact on patients' self-reported quality of life and were inversely correlated with Karnofsky performance status. Patients segregated a priori into three groups, where group 1 displayed stable clinical symptoms and/or slower magnetic resonance imaging radiological progression, expanded CD4+ effector T-cells that attenuated cytotoxic T-lymphocyte associated protein-4 and PD-1 expression and secreted interferon γ and tumor necrosis factor α in situ and ex vivo upon stimulation with PMA/ionomycin. In contrast, rapidly progressing group 2 patients exhibited tolerised T-cell phenotypes characterized by fourfold to sixfold higher interleukin 4 (IL-4) and IL-10 Th-2 cytokines after BTZ + TMZ treatment, where group 3 patients exhibited intermediate clinical/radiological responses. Sequential BTZ + TMZ treatment is safe and promotes Th1-driven immunological responses in selected patients with improved clinical outcomes (Clinicaltrial.gov (NCT03643549)).


Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594.
We conducted this analysis to determine whether survival of advanced NSCLC patients treated with platin-based chemotherapy doublets involving paclitaxel, docetaxel or gemcitabine was dependent on histological subtypes and treatment regimen. We retrospectively analyzed data from E1594, a front-line phase III study in which advanced NSCLC patients were randomized to receive one of four regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, and carboplatin-paclitaxel. Patients were classified into four histology groups: squamous cell (SCC), adeno- (AC), large cell (LCC) and others including not otherwise specified (O/NOS) carcinoma. Logrank test was performed to compare overall survival (OS) and progression free survival (PFS) distributions according to histology as well as treatment. Of 1139 patients including 716 men and 423 women, AC was the most common subtype (56.8%), followed by SCC (19.7%), O/NOS (17.0%) and LCC (6.5%). Men were more likely to have SCC and women were more likely to have AC (p = 0.002). Among the four histology groups, there was no imbalance in regard to race, performance status, weight loss, brain metastasis or treatment. In each histology group, we found no significant difference in OS and PFS between the four chemotherapy regimens. Conversely, in each treatment arm, the survival outcome was similar between the four histology subtypes. Our analysis suggests that histology does not predict survival benefit in advanced NSCLC patients treated with first-line platin-based doublets involving paclitaxel, docetaxel or gemcitabine.


The first linkage map for Australo-Papuan Treefrogs (family: Pelodryadidae) reveals the sex-determination system of the Green-eyed Treefrog (Litoria serrata).
Amphibians represent a useful taxon to study the evolution of sex determination because of their highly variable sex-determination systems. However, the sex-determination system for many amphibian families remains unknown, in part because of a lack of genomic resources. Here, using an F1 family of Green-eyed Treefrogs (Litoria serrata), we produce the first genetic linkage map for any Australo-Papuan Treefrogs (family: Pelodryadidae). The resulting linkage map contains 8662 SNPs across 13 linkage groups. Using an independent set of sexed adults, we identify a small region in linkage group 6 matching an XY sex-determination system. These results suggest Litoria serrata possesses a male heterogametic system, with a candidate sex-determination locus on linkage group 6. Furthermore, this linkage map represents the first genomic resource for Australo-Papuan Treefrogs, an ecologically diverse family of over 220 species.


Emodin induces apoptosis of human cervical cancer cells through poly(ADP-ribose) polymerase cleavage and activation of caspase-9.
Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is an active herbal component traditionally used in China for treating various ailments. Emodin exerts antiproliferative effects in many cancer cell lines and the actual molecular mechanism of which is still not clear. Since apoptosis could be a potential mechanism to explain these effects, we tested whether emodin induces cell death in human cervical cancer cells. Our results suggest that emodin exerts antiproliferative effects in human cervical cancer cells. Emodin inhibited DNA synthesis and induced apoptosis as demonstrated by increased nuclear condensation, annexin binding and DNA fragmentation in Bu 25TK cells in the presence of emodin. Moreover, we demonstrate for the first time in human cervical cancer cells that the apoptotic pathway involved in emodin-induced apoptosis is caspase-dependent and presumably through the mitochondrial pathway, as shown by the activation of caspases-3, -9 and cleavage of poly(ADP-ribose) polymerase.


The vitamin D3 metabolite-type activity of Solanum malacoxylon.
1. Administration of an aqueous extract of the dried leaves of Solanum malacoxylon (DLSM) to rats causes a rapid hyperphosphataemia and a decrease in plasma alkaline phosphatase activity; the two effects are typical of 1,25(OH)2D3, the hormonally active metabolite of vitamin D3. 2. DLSM, like both vitamin D3 and parathyroid hormone, increases plasma calcium and citrate levels in rats. The effect of DLSM in influencing plasma citrate, and the role of this important metabolite in mineral metabolism is discussed. 3. A decrease of plasma magnesium levels occurs in rats following treatment with DLSM. This decrease, which is associated with a renal loss of this cation, is remarkably similar to that produced by hypervitaminosis D3. 4. Prolonged administration of DLSM to vitamin D deficient rats causes a polyuria, hypercalciuria, hyperphosphaturia, hypermagnesuria, an increase in urinary total hydroxyproline, an increase in plasma total hexosamines, and a corresponding decrease in the bone total hexosamines. These effects, some of which can also be produced by hyperparathyroidism, or following the administration of parathyroid extract (PTE), large doses of vitamin D3, or 1,25(OH)2D3, suggest that DLSM, like the latter compounds, is capable of causing bone mineral mobilization, and the dissolution of bone organic matrix.


Is there clinical evidence to support autologous matrix-induced chondrogenesis (AMIC) for chondral defects in the talus? A systematic review and meta-analysis.
The aim of this study is to systematically review the literature on clinical outcomes of patients who have undergone autologous matrix-induced chondrogenesis (AMIC) for treatment of osteochondral lesions of the talus (OCL) and compare the studies' outcomes. Pubmed and Embase were searched in January 2020 for articles concerning OCL surgery. Studies were included if they had a minimum 1-year follow-up and the primary measures were functional outcomes. The meta-analysis compared the Visual Analogic Score (VAS), the American Orthopedic Foot and Ankle Score (AOFAS), and the Foot Function Index (FFI) between baseline and follow-up of 1-2years, and 3-5years. A random effects model was used to evaluate outcome changes. The search returned 15 studies, with a total of 492 patients. The VAS improved 4.45 and 4.6 points from baseline to the 1-2year and 3-5yearfollow-up, respectively (p<0.001). AOFAS improved 31.59 and 32.47 points from baseline to the 1-2year and 3-5yearfollow-up, respectively (p<0.001). The FFI showed a significant improvement of 30.93 points from baseline to year 3-5 (p<0.001). A total of 6 patients with revision surgeries have been reported within the follow up period. It was not possible to correlate clinical features like lesion size, surgical approach, and bone marrow stimulation technique to the reported outcome. Surgical treatment of OCL via the AMIC procedure provided significant improvement in the functional outcome and pain scores when compared to the pre-operative values. Improvements were observed up to 5years post-operatively.


An affinity chromatography-gel filtration device for preparing thyroid microsomal antigen.
On the basis of conventional differential centrifugation for preparing crude thyroid microsomal antigen (TMAg), we have employed Sepharose 4B gel filtration and affinity chromatography separately to study the elution pattern in terms of absorbance and antigenic activity. The result indicates that thyroglobulin (TG) exists in two forms in crude TMAg, i.e., 'free TG' and 'membrane-bound TG'. TMAg is present in two forms in the eluate: (1) the TM fragment or TMAg polymer, which is produced at a higher rate and has greater antigenic activity, but which is less pure; (2) soluble TMAg, which is produced at a lower rate and has less antigenic activity, but which is more pure. We have developed an affinity chromatography-gel filtration (AC-GF) device which is a combination of affinity chromatography and a Sepharose 4B column. Sephadex G-50 is placed between the rubber stopper and Sepharose 4B in the GF column to ensure intactness of the entire system. With such a device, the AC removes the contaminated TG from TM homogenate, and allows the latter to pass directly from AC to GF for rechromatography. This device extracts the full advantages of both methods and each compensates for any deficiency of the other. Using this one-step procedure, one has the greatest chance of removing TG and obtaining TM fragments of TMAg polymers of higher antigenic activity, as well as separating small amounts of more purified soluble TMAg. Thus, the newly developed method meets the need of large quantities of TMAg for practical application, and at the same time the more purified preparations can be used for analytical purposes.


NERVE: new enhanced reverse vaccinology environment.
Since a milestone work on Neisseria meningitidis B, Reverse Vaccinology has strongly enhanced the identification of vaccine candidates by replacing several experimental tasks using in silico prediction steps. These steps have allowed scientists to face the selection of antigens from the predicted proteome of pathogens, for which cell culture is difficult or impossible, saving time and money. However, this good example of bioinformatics-driven immunology can be further developed by improving in silico steps and implementing biologist-friendly tools. We introduce NERVE (New Enhanced Reverse Vaccinology Environment), an user-friendly software environment for the in silico identification of the best vaccine candidates from whole proteomes of bacterial pathogens. The software integrates multiple robust and well-known algorithms for protein analysis and comparison. Vaccine candidates are ranked and presented in a html table showing relevant information and links to corresponding primary data. Information concerning all proteins of the analyzed proteome is not deleted along selection steps but rather flows into an SQL database for further mining and analyses. After learning from recent years' works in this field and analysing a large dataset, NERVE has been implemented and tuned as the first available tool able to rank a restricted pool (approximately 8-9% of the whole proteome) of vaccine candidates and to show high recall (approximately 75-80%) of known protective antigens. These vaccine candidates are required to be "safe" (taking into account autoimmunity risk) and "easy" for further experimental, high-throughput screening (avoiding possibly not soluble antigens). NERVE is expected to help save time and money in vaccine design and is available as an additional file with this manuscript; updated versions will be available at http://www.bio.unipd.it/molbinfo.


Perioperative outcomes after open and endovascular repair of intact abdominal aortic aneurysms in the United States during 2001.
Small patient numbers, mixed data from clinical trials, and longitudinal series representing institutional learning curves have characterized previous studies of early outcomes after endovascular abdominal aortic aneurysm (AAA) repair. We compared the perioperative outcomes of endovascular and open surgical AAA repair in an unselected sample of patients in a single calendar year using a national administrative database. The 2001 National Inpatient Sample database was retrospectively reviewed. This database represents 20% of all-payer stratified sample of non-federal US hospitals. Patients older than 49 years were identified by primary diagnostic codes (International Classification of Disease, ninth revision [ICD-9], 441.4, intact, nonruptured AAA) and procedure codes (ICD-9 38.44 for open, 39.71 for endovascular repair). Patient demographic data (age, sex), comorbid conditions (ICD-9 coded), inpatient complications (ICD-9 coded), length of stay, final discharge disposition (home vs institution vs death), and hospital charges were examined with univariate and multivariate analyses. In calendar year 2001, 7172 patients underwent either open (64%) or endovascular (36%) repair of intact, nonruptured AAAs. Despite comparable rates of preoperative comorbid conditions and a greater proportion of octogenarians (23% vs 16%%; P =.0001), morbidity (18% vs 29%; P =.0001) and mortality (1.3% vs 3.8%; P =.0001) were significantly lower for endovascular repair than for open repair. The median length of stay (2 vs 7 days; P =.0001) and the rate of discharge to an institutional facility versus home (6% vs 14%; P =.0001) were also much lower in the endovascular group than in the open repair group. At multivariate analysis, open AAA repair and age older than 80 years were strong independent predictors (P =.0001 for all) for death (open repair: odds ratio [OR], 3.3; 95% confidence interval [CI], 2.3-4.9; age: OR, 14.2; 95% CI, 3.5-58.1), complications (open repair: OR, 1.9; 95% CI, 1.7-2.1; age: OR, 1.9; 95% CI, 1.5-2.5), and not being discharged to home (open repair: OR, 3.4; 95% CI, 2.9-4.1; age: OR, 12.0; 95% CI, 7.0-20.4). Mean hospital charges were significantly greater (difference, $3337; P =.0009) for endovascular repair than for open repair. Extrapolated to the total number of endovascular AAA repairs performed during the single 2001 calendar year, this resulted in a staggering $50.3 million in additional hospital charges. Endovascular repair of intact AAAs results in a significantly lower number of complications and deaths, shorter hospital stay, and improved likelihood of discharge to home, even in older patients, when compared with open surgical repair. These impressive gains in clinical outcome, however, are achieved at similarly impressive increases in health care costs.


Undescribed Vascular Signatures: A Contraindication to Ultrasound-guided Parasagittal Infraclavicular Block! A Retrospective Observational Study.
The ultrasound-infraclavicular block (US-ICB) is a popular and efficient block for below-elbow surgeries. However, the vascular anatomy of infraclavicular area close to the brachial plexus has remained unresearched. We aimed to explore the presence of aberrant vasculature in the infraclavicular area that could pose a contraindication to US-ICB. In this retrospective observational study, we reviewed the US images of patients undergoing below-elbow surgery under US-ICB. Before performing the block, a scout scan of parasagittal infraclavicular areas was performed and the scan images were saved. The primary objective was to find the prevalence of aberrant vasculature due to which the US-ICB was abandoned. The secondary objective was to understand the pattern and position of the aberrant vessels. Out of 912 patients, 793 patients underwent surgery under US-ICB and in 119 patients (13.05%), the USG-ICB was abandoned due to aberrant vasculature close to the brachial cords and intended position of the needle tip. The anomalous vessels were identified in the lower inner, lower outer, and upper outer quadrants around the axillary artery (AA). Some of these vascular structures also had classical patterns which we described as "satellites," "clamping," or "hugging" of the AA. Anomalous vascular structures in the infraclavicular area were seen in 13.05% of patients planned for US-ICB. We, therefore, recommend, that a thorough scout US scan should be mandatorily performed ICB and in the presence of aberrant vascular structures, an alternative approach to brachial plexus block may be adopted.


All in the family: using inherited cancer syndromes to understand de-regulated cell signaling in brain tumors.
The cell signaling pathways that are tightly regulated during development are often co-opted by cancer cells to allow them to escape from the constraints that normally limit cell growth and cell movement. In this regard, de-regulated signaling in cancer cells confers a number of key tumor-associated properties, including increased cell proliferation, decreased cell death, and increased cell motility. The identification of some of these critical signaling pathways in the nervous system has come from studies of inherited cancer syndromes in which affected individuals develop brain tumors. The study of brain tumors arising in patients with neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and tuberous sclerosis complex (TSC) has already uncovered several key intracellular signaling pathways important for modulating brain tumor growth. An in-depth analysis of these intracellular signaling pathways will not only lead to an improved understanding of the process of brain tumorigenesis, but may also provide important molecular targets for future therapeutic drug design.


Engineering the nanoarchitecture and texture of polymeric carbon nitride semiconductor for enhanced visible light photocatalytic activity.
In order to develop g-C3N4 for better visible light photocatalysis, g-C3N4 nanoarchitectures was synthesized by direct pyrolysis of cheap urea at 550°C and engineered through the variation of pyrolysis time. By prolonging the pyrolysis time, the crystallinity of the resulted sample was enhanced, the thickness and size of the layers were reduced, the surface area and pore volume were significantly enlarged, and the band structure was modified. Especially for urea treated for 4h, the obtained g-C3N4 nanosheets possessed high surface area (288 m(2)/g) due to the reduced layer thickness and the improved porous structure. A layer exfoliation and splitting mechanism was proposed to explain the gradual reduction of layer thickness and size of g-C3N4 nanoarchitectures with increased pyrolysis time. The as-synthesized g-C3N4 samples were applied for photocatalytic removal of gaseous NO and aqueous RhB under visible light irradiation. It was found that the activity of g-C3N4 was gradually improved as the pyrolysis time was prolonged from 0 min to 240 min. The enhanced crystallinity, reduced layer thickness, high surface area, large pore volume, enlarged band gap, and reduced number of defects were responsible for the activity enhancement of g-C3N4 sample treated for a longer time. As the precursor urea is very cheap and the synthesis method is facile template-free, the as-synthesized g-C3N4 nanoscale sheets could provide an efficient visible light driven photocatalyst for large-scale applications.


Association between body image perception with demographic characteristics of physically active individuals during COVID-19 lockdown in Saudi Arabia.
This study aimed to determine the relationship between body image perception and demographic factors among physically active (men and women) during the COVID-19 lockdown in Saudi Arabia. A descriptive cross-sectional survey was employed among physically active individuals in Saudi Arabia between June and July 2020. Eligible participants completed a 19-item self-administered questionnaire that covered three areas: demographic questions, reasons for physical activity, and role or perceptions of body image during the COVID-19 pandemic quarantine. A total of 323 physically active individuals participated in this study. The majority of the participants were female (N=217, 72.7%), were married (66.6%), and living in the Middle region of Saudi Arabia (N= 268, 83%). The analysis shows that majority of the participants were dissatisfied with their current body shape. The analysis also showed a significant association between participants' educational attainment and BMI and body dissatisfaction (p= 0.001). The strongest predictor was BMI level, recording an odds ratio (OR) of 5.99 (CI: 2.15 - 10.54, p=0.001) in obese and an OR of 4.55 (CI: 1.31 - 9.35, p=0.001) in overweight, indicating that compared with normal weight, obese and overweight participants were more likely to be dissatisfied by five and four times, respectively. This study indicates that physically active individuals are greatly influenced by the confinement period. Programs that promote physical activity in their house or during lockdown may help to encourage, lessen their anxiety, and maintain their health. This may also decrease the anxiety of individuals, particularly those active ones.


Blood-thirsty: S1PR5 and TRM.
In this elegant study, Evrard et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210116) find that sphingosine 1-phosphate receptor 5 (S1PR5) powerfully impairs tissue-resident memory T cell (TRM) formation, and that tissue-derived TGF-β limits S1pr5 expression by infiltrating T cells.


Approximate matching of regular expressions.
Given a sequence A and regular expression R, the approximate regular expression matching problem is to find a sequence matching R whose optimal alignment with A is the highest scoring of all such sequences. This paper develops an algorithm to solve the problem in time O(MN), where M and N are the lengths of A and R. Thus, the time requirement is asymptotically no worse than for the simpler problem of aligning two fixed sequences. Our method is superior to an earlier algorithm by Wagner and Seiferas in several ways. First, it treats real-valued costs, in addition to integer costs, with no loss of asymptotic efficiency. Second, it requires only O(N) space to deliver just the score of the best alignment. Finally, its structure permits implementation techniques that make it extremely fast in practice. We extend the method to accommodate gap penalties, as required for typical applications in molecular biology, and further refine it to search for sub-strings of A that strongly align with a sequence in R, as required for typical data base searches. We also show how to deliver an optimal alignment between A and R in only O(N + log M) space using O(MN log M) time. Finally, an O(MN(M + N) + N2log N) time algorithm is presented for alignment scoring schemes where the cost of a gap is an arbitrary increasing function of its length.


Tuberculosis infection in wildlife from the Ruaha ecosystem Tanzania: implications for wildlife, domestic animals, and human health.
Mycobacterium bovis, a pathogen of conservation, livestock, and public health concern, was detected in eight species of wildlife inhabiting protected areas bordering endemic livestock grazing lands. We tested tissues from 179 opportunistically sampled hunter-killed, depredation, road-killed, and live-captured wild animals, representing 30 species, in and adjacent to Ruaha National Park in south-central Tanzania. Tissue culture and PCR were used to detect 12 (8.1%) M. bovis-infected animals and 15 (10.1%) animals infected with non-tuberculosis complex mycobacteria. Kirk's dik-dik, vervet monkey, and yellow baboon were confirmed infected for the first time. The M. bovis spoligotype isolated from infected wildlife was identical to local livestock, providing evidence for livestock-wildlife pathogen transmission. Thus we advocate an ecosystem-based approach for bovine tuberculosis management that improves critical ecological functions in protected areas and grazing lands, reduces focal population density build-up along the edges of protected areas, and minimizes ecological stressors that increase animals' susceptibility to bovine tuberculosis.


The s-oph enzyme for efficient degradation of polyvinyl alcohol: soluble expression and catalytic properties.
Polyvinyl alcohol (PVA) is one of the most widely used water-soluble polymers with remarkable mechanical properties. However, water-soluble polymers are among the major organic pollutants of streams, river, and marine ecosystems. Once dispersed in aqueous systems, they can directly interfere with the life cycle of aquatic organisms via direct toxic effects. There is thus an urgent need for microorganisms or enzymes that can efficiently degrade them. Oxidized PVA hydrolase plays an important role in the pathway of PVA biodegradation. It is the key enzyme in the second step of the pathway for complete degradation of PVA. The s-oph gene was cloned from the laboratory-isolated strain Sphingopyxis sp. M19. This gene was expressed in the Escherichia coli system pET32a/s-oph expression vector, with the products forming an inclusion body. By binding with a molecular chaperone, pET32a/s-oph/BL21 (DE3)/pGro7 was successfully constructed, which enabled the s-oph gene to be solubly expressed in E. coli. The protein encoded by the s-oph gene was purified at a yield of 16.8 mg L-1, and its catalytic activity reached 852.71 U mg-1. In the s-oph enzyme reaction system, the efficiency of PVA degradation was increased to 233.5% compared with that of controls. The s-oph enzyme exhibited the characteristics of being able to degrade PVA with high efficiency, specificity, and stability. This enzyme has good potential for practical application in ameliorating plastic pollution and protecting the environment.


Proanthocyanidin B2 inhibits proliferation and induces apoptosis of osteosarcoma cells by suppressing the PI3K/AKT pathway.
Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. The long-term survival rate of OS patients is stubbornly low mainly due to the chemotherapy resistance. We therefore aimed to investigate the antitumoral effects and underlying mechanisms of proanthocyanidin B2 (PB2) on OS cells in the current study. The effect of PB2 on the proliferation and apoptosis of OS cell lines was assessed by CCK-8, colony formation, and flow cytometry assays. The target gene and protein expression levels were measured by qRT-PCR and Western blotting. A xenograft mouse model was established to assess the effects of PB2 on OS proliferation and apoptosis in vivo. Results from in vitro experiments showed that PB2 inhibited the proliferation and induced apoptosis of OS cells, and also increased the expression levels of apoptosis-related proteins. Moreover, PB2 induced OS cell apoptosis through suppressing the PI3K/AKT signalling pathway. The in vivo experiments further confirmed that PB2 could inhibit OS tumour growth and induce its apoptosis. Taken together, these results suggested that PB2 inhibited the proliferation and induced apoptosis of OS cells through the suppression of the PI3K/AKT signalling pathway.


Evidence for magnetic Weyl fermions in a correlated metal.
Weyl fermions have been observed as three-dimensional, gapless topological excitations in weakly correlated, inversion-symmetry-breaking semimetals. However, their realization in spontaneously time-reversal-symmetry-breaking phases of strongly correlated materials has so far remained hypothetical. Here, we report experimental evidence for magnetic Weyl fermions in Mn3Sn, a non-collinear antiferromagnet that exhibits a large anomalous Hall effect, even at room temperature. Detailed comparison between angle-resolved photoemission spectroscopy (ARPES) measurements and density functional theory (DFT) calculations reveals significant bandwidth renormalization and damping effects due to the strong correlation among Mn 3d electrons. Magnetotransport measurements provide strong evidence for the chiral anomaly of Weyl fermions-namely, the emergence of positive magnetoconductance only in the presence of parallel electric and magnetic fields. Since weak magnetic fields (approximately 10 mT) are adequate to control the distribution of Weyl points and the large fictitious fields (equivalent to approximately a few hundred T) produced by them in momentum space, our discovery lays the foundation for a new field of science and technology involving the magnetic Weyl excitations of strongly correlated electron systems such as Mn3Sn.


Ecology: The Patagonian Sun Dance.
Recent field experiments show how photodegradation and its legacy, increased microbial access to labile carbohydrates (photofacilitation), double rates of C loss to the atmosphere in a Mediterranean-type climate. The mechanisms demonstrated have implications for global C modeling beyond Mediterranean ecosystems.


[Place and role of safety pharmacology in drug development].
Safety pharmacology is a key regulatory step for drug development and approval. Prior to phase I, the effects of a drug candidate should be evaluated and characterized on vital functions (cardiovascular, respiratory and central nervous system) according to good laboratory practice standards. For cardiovascular evaluation, effects on blood pressure and electrocardiogram should be explored with a particular emphasis on ventricular repolarization prolongation, a major risk factor for life-threatening arrhythmias, like "torsades de pointe". Global behaviour, motor activity, reflexes and body temperature should be evaluated in animals. A dedicated study is necessary for respiratory function evaluation. All of these studies should be conducted after single administration of the compound administered by the anticipated clinical route. Dependence potential and abuse liability should be characterized for innovative drugs and/or drugs acting on the central nervous system. Evidence for adverse effects at discovery stage with high throughput systems is becoming a key step of decision-making process for pharmaceutical industry. Therefore, determination of the safety margin, risk/benefit ratio analysis and investigation of adverse effects are major decisional elements for providing safety reassurance to patients. Safety of patients will also be improved through modelling methodologies allowing a safer transposition of experimental pharmacology results to clinical pharmacology.


Cannabis users have higher premorbid IQ than other patients with first onset psychosis.
A number of studies have reported that patients with psychosis who use cannabis have better cognitive performance than those who do not. This is surprising as cannabis can impair cognition in healthy subjects. An obvious question is whether the better current performance of psychotic patients who have used cannabis is a reflection of their having a higher premorbid IQ than those psychotic patients who haven't used cannabis. In a sample of patients at their first episode of psychosis, we tested the hypothesis that patients who smoked cannabis would have a higher premorbid IQ than patients who did not. 279 participants (119 patients and 160 healthy controls) were assessed in order to obtain current and premorbid IQ measures and detailed information on cannabis use. We examined the association between cannabis use and both premorbid and current IQ in patients and controls. Patients who had ever smoked cannabis had significantly higher current (p<.001) and premorbid IQ (p=.004) compared to patients who had never used cannabis. This difference was not found among controls. These findings suggest that the better cognitive performance of patients with their first episode of psychosis who have used cannabis compared with those who haven't is due to the better premorbid IQ of the former.


Detection of Ia epitopes by monoclonal antibody blotting.
Monoclonal antibodies directed against human Ia alpha- and beta-subunit chains have been used as probes to detect polypeptides carrying recognized antigenic determinants or epitopes following two-dimensional PAGE separation. Approximately 4 sets of components differing in isoelectric point but not in molecular weight are recognized by each antibody. The anti-alpha-chain, McAb, reacts weakly with spots designated as epsilon but neither antibody recognizes Im, Ii or delta determinants under the conditions tested.


Systemic AL amyloidosis in a Beech Marten (Martes foina).
A wild Beech Marten (Martes foina), was referred for necropsy to the Department of Animal Pathology of the University of Turin (Italy). At gross examination, whitish and firm masses, 10-mm in diameter, were found on the heart and in the kidney. Spleen showed lighter color and greater consistency, and the cut surface of the liver appeared scattered with whitish-yellow coalescing foci homogeneously distributed. Amyloid deposits were present in the perivascular and intercellular spaces of the visceral organs, such as the heart, liver, and kidneys. Amyloid stained positively with Congo red with and without 5% potassium permanganate pretreatment and showed green birefringence observable under polarized light. A diagnosis of systemic AL amyloidosis was made. This is the first description of systemic AL amyloidosis in a wild Stone Marten.


Theoretical study of thieno-thiophene based low band gap copolymers and substituent effect on the optoelectronic properties of them.
This paper studies donor-acceptor systems which incorporate benzodithiophene (BDT), benzodifuran (BDF) and benzodipyrrole (BDP) units as the electron-rich monomer with TT unit representing the electron-deficient monomer. This research is based on employing density functional theory (DFT) and time-dependent DFT (TD-DFT). The highest occupied molecular orbitals (HOMO) and the lowest unoccupied molecular orbitals (LUMO), HOMO-LUMO gaps and dihedral-angles of these copolymers were calculated using oligomer extrapolation technique and periodic boundary condition (PBC) method. The optical band gaps and UV-vis absorption spectra of aforementioned copolymers were obtained by TD-DFT at the same level of theory. Based on the fair agreement between PBC-DFT calculated results and experimental data, the substituent effects of Cl, Br, CCH, COH, NO2, OH, SH and NH2 groups were investigated by PBC-DFT method. The difference between the ground and excited-states dipole moment (Δμge) of all derivatives were also calculated. Taking these results into account, a better understanding of the substituent effects on the photo-physical properties of the copolymers under study was achieved. Due to the shift of HOMO and LUMO energy levels, smaller band gaps and higher Δμge are observed in some derivatives. The calculation results demonstrate that the substitution of COH and NO2 by fluorine in BDF-TT and BDP-TT leads to higher maximum theoretical efficiencies (η).


In vivo evidence for reduced cortical glutamate-glutamine cycling in rats treated with the antidepressant/antipanic drug phenelzine.
Converging evidence has indicated that hyperglutamatergic activity and GABAergic dysfunction may play important roles in the neurobiology and treatment of depression and other mood disorders. In this study, in vivo 1H[13C] magnetic resonance spectroscopy was used to quantify the effects of acute phenelzine administration on cortical energetics, glutamate neurotransmission, and GABA synthesis flux. The time-resolved kinetics of cortical [4-13C]glutamate, [4-13C]glutamine, and [2-13C]GABA turnover from i.v.-infused [1,6-13C2]glucose was measured at 11.7 T in alpha-chloralose anesthetized rats four hours after phenelzine treatment (10 mg/kg, i.p.) and in non-treated controls. The rate of the tricarboxylic acid cycle flux was not affected by phenelzine treatment compared with the non-treated group (0.46+/-0.05 vs. 0.50+/-0.05 micromol/g/min, respectively). The rate of the glutamate-glutamine cycling flux between neurons and glia in the phenelzine-treated group was significantly reduced (from 0.16+/-0.04 to 0.10+/-0.03 micromol/g/min), providing in vivo evidence that phenelzine attenuates glutamate neurotransmission. Following phenelzine treatment, the cortical GABA concentration increased significantly (from 1.02+/-0.17 to 2.30+/-0.26 micromol/g), while the GABA synthesis flux was unchanged (from 0.07+/-0.02 to 0.06+/-0.02 micromol/g/min). The possible role of augmented GABAergic function resulting from elevated GABA levels in the observed modulatory effect of phenelzine on the glutamate-glutamine cycling flux was discussed. The reduced glutamate-glutamine cycling flux observed in this study suggests that, in addition to its effects on monoaminergic and GABAergic systems, the attenuation of glutamate neurotransmission resulting from phenelzine administration may also contribute to its efficacy in the treatment of depression. This study is the first demonstration that the glutamate-glutamine cycling flux, which can be measured non-invasively in the human brain in vivo, was altered due to the action of a psychotropic drug.


Ancient DNA of Metagonimus yokogawai Recovered from Joseon Period Human Remains Newly Discovered at Goryeong County in South Korea.
Metagonimiasis, commonly seen in East Asian countries, is a parasitic disorder caused by definitive hosts' ingestion of undercooked freshwater fishes. Recently, genetic analysis has proved 28S rRNA and cytochrome c oxidase subunit I (COI) mtDNA gene to be a successful marker differentiating species of the genus Metagonimus. In the present study, using specimens from the newly discovered Joseon Dynasty human remains of Goryeong, we obtained updated genetic data on genus Metagonimus, which was also prevalent during the Joseon period. The ancient DNA (aDNA) was retrieved from the coprolite sample of the seventeenth century, half-mummified individual discovered at Goryeong Country, South Korea. Cloning and sequencing were performed on PCR-amplified amplicons for M. yokogawai 28S rRNA and COI mtDNA gene. The consensus sequences were used for species identification and phylogenetic analysis using NCBI/BLAST and MEGA X software. Based on the COI mtDNA gene region, the Goryeong sequence was confirmed as belonging to M. yokogawai, as it was shown to form a separate cluster with other M. yokogawai taxa that are distinct also from M. takahashii and M. miyatai. In a series of our genetic analyses on genus Metagonimus using samples retrieved from Joseon-period cases, aDNA sequences of genus Metagonimus revealed in South Korea thus far are those of M. yokogawai, but not of M. miyatai or M. takahashii yet.


Red cell amino acid transport. Evidence for the presence of system Gly in guinea pig reticulocytes.
Guinea pig reticulocytes are shown to possess an Na+-dependent glycine transporter which also requires Cl- for activity. Glycine transport by this route is saturable (apparent Km 98 microM; Vmax 24 mumol/g Hb per h) and inhibited by sarcosine. The properties of this carrier closely resemble those of System Gly previously demonstrated in pigeon and human erythrocytes. In contrast, no System Gly activity was detected in mature guinea pig erythrocytes.


Nomogram for predicting the unfavourable outcomes of percutaneous endoscopic transforaminal discectomy for lumbar disc herniation: a retrospective study.
To investigate and integrate multiple independent risk factors to establish a nomogram for predicting the unfavourable outcomes of percutaneous endoscopic transforaminal discectomy (PETD) for lumbar disc herniation (LDH). From January 2018 to December 2019, a total of 425 patients with LDH undergoing PETD were included in this retrospective study. All patients were divided into the development and validation cohort at a ratio of 4:1. Univariate and multivariate logistic regression analyses were used to investigate the independent risk factors associated with the clinical outcomes of PETD for LDH in the development cohort, and a prediction model (nomogram) was established to predict the unfavourable outcomes of PETD for LDH. In the validation cohort, the nomogram was validated by the concordance index (C-index), calibration curve, and decision curve analysis (DCA). 29 of 340 patients showed unfavourable outcomes in the development cohort, and 7 of 85 patients showed unfavourable outcomes in the validation cohort. Body mass index (BMI), course of disease (COD), protrusion calcification (PC), and preoperative lumbar epidural steroid injection (LI) were independent risk factors associated with the unfavourable outcomes of PETD for LDH and were identified as predictors for the nomogram. The nomogram was validated by the validation cohort and showed high consistency (C-index = 0.674), good calibration and high clinical value. The nomogram based on patients' preoperative clinical characteristics, including BMI, COD, LI and PC, can be used to accurately predict the unfavourable outcomes of PETD for LDH.


Experiential input alters the phosphorylation of specific proteins in brain membranes.
The effects of a training experience that involves foot shock on the endogenous phosphorylation of membrane-bound proteins from brain were studied. Crude membrane fractions were prepared from the cerebral cortex and neostriatum of animals that had been sacrificed by quick freezing. In vitro incubation of the membranes with gamma-32P-ATP, follwed by SDS-gel electrophoresis of the phosphorylated substrates, revealed that the phosphorylation of two protein components (designated F and H-I) increased in preparations from animals that were subjected to a training experience 24 hr prior to sacrifice. These effects were greater in preparations from the neostriatum than from the cerebral cortex, and were observed in experiments using both rats and mice. Although all trained animals showed a high phosphorylation of bands F and H-I, control animals showed a greater variability in the phosphorylation of these bands. The results indicate that the phosphorylation of specific proteins may play a mediatory role in the processing of experiential information.


Item response theory analysis of the Clinical Dementia Rating.
The Clinical Dementia Rating (CDR) is widely used in Alzheimer's disease research studies and has well established reliability and validity. To facilitate the development of an online, electronic CDR (eCDR) for more efficient clinical applications, this study aims to produce a shortened version of the CDR, and to develop the statistical model for automatic scoring. Item response theory (IRT) was used for item evaluation and model development. An automatic scoring algorithm was validated using existing CDR global and domain box scores as the reference standard. Most CDR items discriminate well at mild and very mild levels of cognitive impairment. The bi-factor IRT model fits best and the shortened CDR still demonstrates very high classification accuracy (81%∼92%). The shortened version of the CDR and the automatic scoring algorithm has established a good foundation for developing an eCDR and will ultimately improve the efficiency of cognitive assessment.


Editorial: Combatting the Intergenerational Trauma of Structural Racism Through Practice, Policy, and Research.
Several recent studies have investigated the mental health consequences of structural racism. Structural racism has been defined as "macro-level societal conditions that limit opportunities, resources, and well-being of less privileged groups on the basis of race/ethnicity and/or other statuses, including but not limited to, gender identity, sexual orientation, disability status, social class or socioeconomic status (SES), religion, geographic residence, national origin, immigration status, limited English proficiency, physical characteristics, or health conditions."1 Researchers have hypothesized that the trauma of structural racism transmits across generations through pathways that are physiological (ie, compromised immune systems, activated hormonal stress responses), environmental (ie, limited access to housing, health care, employment, and income), social (ie, domestic violence, substance consumption, criminal justice involvement), and psychological (ie, family histories of depression, anxiety, and traumatic stress-disorders).2.


Promising Cerebral Blood Flow Enhancers in Acute Ischemic Stroke.
Ischemic stroke presents a major global economic and public health burden. Although recent advances in available endovascular therapies show improved functional outcome, a good number of stroke patients are either ineligible or do not have access to these treatments. Also, robust collateral flow during acute ischemic stroke independently predicts the success of endovascular therapies and the outcome of stroke. Hence, adjunctive therapies for cerebral blood flow (CBF) enhancement are urgently needed. A very clear overview of the pial collaterals and the role of genetics are presented in this review. We review available evidence and advancement for potential therapies aimed at improving CBF during acute ischemic stroke. We identified heme-free soluble guanylate cyclase activators; Sanguinate, remote ischemic perconditioning; Fasudil, S1P agonists; and stimulation of the sphenopalatine ganglion as promising potential CBF-enhancing therapeutics requiring further investigation. Additionally, we outline and discuss the critical steps required to advance research strategies for clinically translatable CBF-enhancing agents in the context of acute ischemic stroke models.


My Home is My Marae: Kaupapa Māori evaluation of an approach to injury prevention.
The objective of this study was to evaluate the New Zealand Accident Compensation Corporation's (ACC) 'My Home is My Marae' approach to injury prevention for whānau (families). Over an 18 month period from November 2013 to June 2014, 14 'My Home is My Marae' trials were conducted across the South Auckland and Far North regions of New Zealand. ACC engaged with local Māori providers of healthcare, education and social services to deliver the home safety intervention. Participants of this evaluation were a purposive sample of 14 staff from six provider organisations in South Auckland and the Far North regions of New Zealand. Kaupapa Māori theory-based evaluation and appreciative inquiry methodologies underpinned the evaluation. Interview participants led discussions about strengths and weaknesses of the approach, and partnerships with ACC and other organisations. The evaluation was also supported by pre-existing information available in project documentation, and quantitative data collected by Māori providers. Five key critical success factors of 'My Home is My Marae' were found from interviews: mana tangata (reputation, respect and credibility); manākitanga (showing care for people); kānohi-ki-te-kānohi (face-to-face approach); capacity building for kaimahi, whānau and providers and 'low or no cost' solutions to hazards in the home. Data collected for the Far North area showed that 76% of the hazards identified could be resolved through 'low or no cost' solutions. Unfortunately, similar data were not available for South Auckland. Injury prevention or health promotion approaches that seek to engage with whānau and/or Māori communities would benefit from applying critical success factors of 'My Home is My Marae'.


Influenza clinical testing and oseltamivir treatment in hospitalized children with acute respiratory illness, 2015-2016.
Antiviral treatment is recommended for all hospitalized children with suspected or confirmed influenza, regardless of their risk profile. Few data exist on adherence to these recommendations, so we sought to determine factors associated with influenza testing and antiviral treatment in children. Hospitalized children <18 years of age with acute respiratory illness (ARI) were enrolled through active surveillance at pediatric medical centers in seven cities between 11/1/2015 and 6/30/2016; clinical information was obtained from parent interview and chart review. We used generalized linear mixed-effects models to identify factors associated with influenza testing and antiviral treatment. Of the 2299 hospitalized children with ARI enrolled during one influenza season, 51% (n = 1183) were tested clinically for influenza. Clinicians provided antiviral treatment for 61 of 117 (52%) patients with a positive influenza test versus 66 of 1066 (6%) with a negative or unknown test result. In multivariable analyses, factors associated with testing included neuromuscular disease (aOR = 5.35, 95% CI [3.58-8.01]), immunocompromised status (aOR = 2.88, 95% CI [1.66-5.01]), age (aOR = 0.93, 95% CI [0.91-0.96]), private only versus public only insurance (aOR = 0.78, 95% CI [0.63-0.98]), and chronic lung disease (aOR = 0.64, 95% CI [0.51-0.81]). Factors associated with antiviral treatment included neuromuscular disease (aOR = 1.86, 95% CI [1.04, 3.31]), immunocompromised state (aOR = 2.63, 95% CI [1.38, 4.99]), duration of illness (aOR = 0.92, 95% CI [0.84, 0.99]), and chronic lung disease (aOR = 0.60, 95% CI [0.38, 0.95]). Approximately half of children hospitalized with influenza during the 2015-2016 influenza season were treated with antivirals. Because antiviral treatment for influenza is associated with better health outcomes, further studies of subsequent seasons would help evaluate current use of antivirals among children and better understand barriers for treatment.


Chemicals for evaluating the sensitivity and specificity of reduced/transgenic rodent cancer bioassay protocols.
The standard two-species/two-gender lifetime carcinogenicity bioassay protocol is not practical when assessing the possible carcinogenicity of a large number of chemicals. This has led to consideration of reduced cancer bioassay protocols (e.g., male rat/female mouse), or to the use of genetically altered rodents that succumb to chemically induced cancer in a fraction of their lifespans. Two uncertainties accompany these endeavours. First, that use of reduced protocols may lead to the non-detection of some weak or tissue-specific carcinogens. Second, that genetically altered rodents may be so sensitive to chemical disturbance of homoeostasis that their carcinogen specificity may be low. Such uncertainties lead to the requirement that the modified test protocols should be validated using appropriate carcinogens and non-carcinogens. Given that several such studies may take place over the coming years it seems appropriate that a common pool of chemicals should be agreed upon for this purpose. To this end a selection of human carcinogens, and rodent carcinogens/non-carcinogens defined by the US National Toxicology Program (NTP), have been collected together. Six categories of chemicals are listed: (1) representative human carcinogens; (2) representative trans-species genotoxic carcinogens; (3) all two-species non-carcinogens reported to be negative in the Salmonella mutation assay and lacking structural alerts to electrophilicity; (4) representative single-species/presumed non-genotoxic carcinogens; (5) all two-species non-carcinogens that are mutagens in the Salmonella mutation assay and which are structurally alerting; (6) all chemicals possessing equivocal evidence of carcinogenicity and which are both structurally alerting and mutagenic to Salmonella. Chemicals in the first four groups provide robust calibrants for determining the sensitivity and specificity of reduced/accelerated rodent carcinogenicity bioassay protocols. Chemicals in the last two groups may be of value when studying the interface between the sensitivity and the specificity of modified rodent carcinogenicity bioassay protocols.


A strategy for the generation of non-aggregating mutants of Anthozoa fluorescent proteins.
Recently, we cloned several fluorescent proteins of different colors homologous to Aequorea victoria green fluorescent protein, which have great biotechnological potential as in vivo markers of gene expression. However, later investigations revealed severe drawbacks in the use of novel fluorescent proteins (FPs), in particular, the formation of tetramers (tetramerization) and high molecular weight aggregates (aggregation). In this report, we employ a mutagenic approach to resolve the problem of aggregation. The elimination of basic residues located near the N-termini of FPs results in the generation of non-aggregating versions of several FPs, specifically, drFP583 (DsRed), DsRed-Timer, ds/drFP616, zFP506, zFP538, amFP486, and asFP595.


Subjective assessment of brexpiprazole in patients with schizophrenia: a prospective observational study.
To investigate the subjective assessments of an antipsychotic treatment with brexpiprazole. This was a 14-week prospective observational study. Nineteen patients participated in the study between February 2019 and January 2020. Patients had a mean age of 40.6±14.2 years and a Clinical Global Impressions-Severity of Illness scale (CGI-S) score of 4.6±1.2 at the initiation of brexpiprazole treatment. The Subjective Well-being under Neuroleptic drug treatment Short form, Japanese version (SWNS-J) total score significantly improved from 68.1±22.3 in week 2 to 79.5±21.0 in week 14 (p=0.0084). The SWNS-J subscales of self-control and social integration status also significantly improved from 14.0±4.7 and 13.9±6.0 in week 2 to 17.0±4.7 and 16.0±5.1 in week 14, respectively (p=0.0053 and 0.012, respectively). No significant improvements were observed in any other SWNS-J subscales or the Drug Attitude Inventory-10 (DAI-10) in the 14-week observation period. Moreover, the SWNS-J total score did not correlate with the DAI-10 (r=0.31, p=0.19), or CGI-S (r=-0.18, p=0.47) scores. The present results suggest that brexpiprazole might improve subjective well-being, although this may not necessarily reflect psychopathological improvements. To enhance medication adherence, it is important to perform subjective assessments on patients over time.


Photoaffinity labelling of a 150 kDa (Na + K + Cl)-cotransport protein from duck red cells with an analog of bumetanide.
We have used a radiolabelled, benzophenone analog of bumetanide, 4-[3H]benzoyl-5-sulfamoyl-3-(3-thenyloxy)benzoic acid ([3H]BSTBA) to photolabel plasma membranes from duck red blood cells. BSTBA, like bumetanide, is a loop diuretic and a potent inhibitor of (Na + K + Cl) cotransport, and [3H]BSTBA binds to intact duck red cells with a high affinity similar to that of [3H]bumetanide (K 1/2 congruent to 0.1 microM). We incubated duck red cells with [3H]BSTBA, then lysed the cells and exposed the ghosts to ultraviolet light. The ghosting and photolysis was done at 0 degree C to prevent dissociation of the [3H]BSTBA. The ghosts were then sonicated to remove the nuclei and run on SDS-polyacrylamide gels. Analysis of H2O2-digested gel slices revealed [3H]BSTBA to be incorporated into a protein of approx. 150 kDa. This is the same molecular weight we obtain for a protein from dog kidney membranes which is photolabelled by [3H]BSTBA in a manner highly consistent with labelling of the (Na + K + Cl) cotransporter (Haas and Forbush (1987) Am. J. Physiol. 253, C243-C252). Several lines of evidence strongly suggest that the 150 kDa protein from duck red cell membranes is an integral component of the (Na + K + Cl)-cotransport system in these cells: (1) Photolabelling of this protein by [3H]BSTBA is blocked when 10 microM unlabelled bumetanide is included in the initial incubation medium with [3H]BSTBA; (2) Photoincorporation of [3H]BSTBA into the 150 kDa protein is markedly increased when the initial incubation medium is hypertonic or contains norepinephrine, conditions which similarly stimulate both (Na + K + Cl) cotransport and saturable [3H]bumetanide binding in duck red cells; (3) The photolabelling of this protein shows a saturable dependence on [3H]BSTBA concentration, with a K1/2 (0.06 microM) similar to that for the reversible, saturable binding of [3H]BSTBA and [3H]bumetanide to duck red cells; and (4) [3H]BSTBA photoincorporation into the 150 kDa protein, like saturable [3H]bumetanide binding to intact cells, requires the simultaneous presence of Na+, K+, and Cl- in the medium containing the radiolabelled diuretic.


A pilot study to compare the detection of HPV-16 biomarkers in salivary oral rinses with tumour p16(INK4a) expression in head and neck squamous cell carcinoma patients.
Human papilloma virus-16 (HPV-16) infection is a major risk factor for a subset of head and neck squamous cell carcinoma (HNSCC), in particular oropharyngeal squamous cell carcinoma (OPSCC). Current techniques for assessing the HPV-16 status in HNSCC include the detection of HPV-16 DNA and p16(INK4a) expression in tumor tissues. When tumors originate from hidden anatomical sites, this method can be challenging. A non-invasive and cost-effective alternative to biopsy is therefore desirable for HPV-16 detection especially within a community setting to screen at-risk individuals. The present study compared detection of HPV-16 DNA and RNA in salivary oral rinses with tumor p16(INK4a) status, in 82 HNSCC patients using end-point and quantitative polymerase chain reaction (PCR). Of 42 patients with p16(INK4a)-positive tumours, 39 (sensitivity = 92.9 %, PPV = 100 % and NPV = 93 %) had oral rinse samples with detectable HPV-16 DNA, using end-point and quantitative PCR. No HPV-16 DNA was detected in oral rinse samples from 40 patients with p16(INK4a) negative tumours, yielding a test specificity of 100 %. For patients with p16(INK4a) positive tumours, HPV-16 mRNA was detected using end-point reverse transcription PCR (RT-PCR) in 24/40 (sensitivity = 60 %, PPV = 100 % and NPV = 71 %), and using quantitative RT-PCR in 22/40 (sensitivity = 55 %, PPV = 100 % and NPV = 69 %). No HPV-16 mRNA was detected in oral rinse samples from the p16(INK4a)-negative patients, yielding a specificity of 100 %. We demonstrate that the detection of HPV-16 DNA in salivary oral rinse is indicative of HPV status in HNSCC patients and can potentially be used as a diagnostic tool in addition to the current methods.


Do children with and without autism spectrum disorder use different visuospatial processing skills to perform the Rey-Osterrieth complex figure test?
Visuospatial organization abilities are closely related to other visuospatial processing skills, such as visuomotor coordination, perceptual abilities, mental rotation, and working memory (WM). One task that enables visuospatial organization abilities to be investigated is the Rey-Osterrieth complex figure test (ROCFT). When examining visuospatial functioning, individuals with autism spectrum disorder (ASD) have proved capable of operating both locally and globally, depending on the sub-domain embraced, with a preference for a locally-oriented processing of visuospatial information. The present research aimed to establish whether different underlying visuospatial skills might account for performance in the ROCFT in children and adolescents with ASD, compared with typically developing (TD), by considering the role of local/global visuospatial processing. The study involved 39 participants who have ASD without intellectual disability, and 57 TD aged 8-16 years. The participants were administered tasks assessing visuospatial organization abilities, manual dexterity, visual perception, mental rotation, spatial-sequential, spatial-simultaneous WM, and visuospatial processing. Our results suggest that manual dexterity and visuospatial processing similarly explain performance in both groups, while differences in visuospatial WM account for the two groups' visuospatial organization abilities. Spatial-simultaneous WM predicted performance in copy and recall conditions in the TD group but not in the ASD group, while spatial-sequential WM only did so in the latter group, reinforcing the tendency of children with ASD towards local bias in the visuospatial organization domain. The implications of these findings are discussed. LAY SUMMARY: The visuospatial organization abilities of children and adolescents with and without autism were compared, considering their underlying visuospatial skills. Visuospatial organization impairments emerged for children with autism, who differed from typically developing children in the underlying visuospatial skills involved. Given the crucial role of visuospatial organization abilities in everyday life, our results could inspire practitioners to develop training interventions that take into account the strengths and weaknesses of individuals with autism.


The preventive effect of diphenhydramine on bacterial growth in propofol: a laboratory study.
Diphenhydramine has local anaesthetic and antimicrobial activity and may be used to prevent intravenous propofol injection pain. We studied the effect of adding diphenhydramine to propofol emulsions for preventing bacterial growth. Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Candida albicans cultures were inoculated into the following solutions: 1% propofol, 0.05% diphenhydramine + 1% propofol, 0.1% diphenhydramine + 1% propofol, 0.2% diphenhydramine + 1% propofol, 0.3% diphenhydramine + 1% propofol, 1% diphenhydramine and 0.1% lidocaine + 1% propofol. A 100-microL of inoculum suspension adjusted for each of the micro-organisms was added separately to each tube and left at 20 degrees C. A 10-microL aliquot of each mixture was inoculated onto blood agar medium at 5 and 24 h. These plates were incubated at 35 degrees C for 24 h. Each plated medium was read, and the number of colony-forming units were counted and recorded (n = 2). Analysis of variance (ANOVA) with a post hoc Tukey HSD test and paired t-tests were used for data analysis. P < 0.05 was considered as significant. Diphenhydramine inhibited bacterial growth in propofol solutions in a dose-dependent manner. It was more effective than 0.1% lidocaine at similar concentrations in preventing bacterial growth for all organisms. Diphenhydramine had a significant inhibitory effect on bacterial growth in propofol.


Intestinal absorption and bioavailability of traditional Chinese medicines: a review of recent experimental progress and implication for quality control.
Experimental studies on the pharmacokinetics of traditional Chinese medicines (TCMs) have achieved great progress in recent years. This review aims to summarize the progress made on intestinal absorption and bioavailability of TCMs, and proposes the application of intestinal absorption assays as new tools for the quality and safety control of these medicines. Since only the absorbed constituents may produce possible therapeutic effect (except those that directly target the digestive tract), intestinal absorption is of utmost importance for the drug action of TCMs, which are usually taken orally. Meanwhile, complicated drug interactions may occur among the multiple ingredients in a herbal mixture. In this regard, the intestinal permeability assays not only provide useful pharmacokinetic data of TCMs, but have potential applications for quality and safety control. Moreover, knockout animals, 2/4/A1 in-vitro cell model and physiologically-based in-silico models based on the online TCM database can be quite useful for the prediction of absorption and bioavailability of TCMs. A variety of in-vivo, in-vitro, in-situ and in-silico models for predicting the intestinal absorption and bioavailability can be applied to study the herbal interactions and screen appropriate biomarkers for the quality and safety control of TCMs.


Analysis of temporal changes in thickness from conjunctiva to sclera after plication of the medial rectus muscle measured by anterior segment optical coherence tomography.
We evaluated long-term changes in conjunctival bulge after medial rectus muscle (MR) tightening using the plication method. Retrospective and observational. Patients who underwent MR plication for exotropia from December 2016-March 2020 at Okayama University Hospital were included. Thirty two eyes of 27 patients were enrolled. The thickness from the conjunctiva to sclera (TCS) at the limbus and insertion sites were measured using anterior segment optical coherence tomography preoperatively and 1 month, 4 months, and 12 months postoperatively. Correlations between the 1- and 12 month postoperative TCS and amount of MR tightening were analyzed. Preoperative and 4 month postoperative TCS at the limbus site were not significantly different (P=0.07). The 12 month postoperative TCS at the insertion site was significantly thinner than at 1 month postoperative (P<0.01), although significantly thicker than the preoperative TCS (P<0.01). No significant correlations were found between the amount of MR tightening (in mm) and 1- or 12 month postoperative TCS at the limbus (P=0.62 and P=0.98, respectively) and insertion (P=0.50 and P=0.24, respectively) sites. The TCS at the insertion site peaked at 1 month postoperatively, continued to decrease for longer than 4 months postoperatively, continuing until 12 months postoperatively. The TCS at the insertion site 12 months postoperatively is thicker than preoperatively. The TCS at both the limbus and insertion sites was not related to the amount of medial rectus muscle tightening.


Noninvasive diagnosis of left ventricular pseudoaneurysm: role of two dimensional echocardiography and radionuclide gated pool imaging.
This report describes a case of left ventricular pseudoaneurysm diagnosed with two dimensional real time echocardiography. The two dimensional echocardiogram identified not only the pseudoaneurysmal sac but also the site of left ventricular rupture. When supplemented with radioisotope gated cardiac blood pool scanning, the noninvasive studies demonstrated combined true and false left ventricular aneurysms. Left ventricular pseudoaneurysm can be diagnosed using two dimensional echocardiography and nuclear imaging, permitting early operative intervention before fatal rupture.


Lymphangiogenesis in myocardial remodelling after infarction.
The lymphatic system is involved in fluid homeostasis of the cardiac interstitium, but lymphangiogenesis in myocardial remodelling has not previously been examined histopathologically. The aim was to investigate by D2-40 immunohistochemistry the sequential changes in lymphatic distribution in the process of myocardial remodelling after myocardial infarction (MI). Myocardial tissues in various phases of healing after MI were obtained from 40 autopsied hearts. D2-40+ lymphatic vessel density (LD) and CD34+ blood vessel density (BD) in the lesion were determined. BD decreased with advance of myocardial necrosis, subsequently increased at the early stage of granulation and thereafter decreased with the progression of scar formation. In contrast, lymphatic vessels were not detected in lesions with coagulation necrosis, and newly formed lymphatics first appeared in the early stages of granulation. A subsequent increase in LD was demonstrated in the late stages of granulation, and lymphatics remained up to the scar phase. Vascular endothelial growth factor-C was consistently expressed in viable cardiomyocytes around the lesion in all of these stages. In myocardial remodelling after MI, lymphangiogenesis lags behind blood vessel angiogenesis; newly formed lymphatics may be involved mainly in the maturation of fibrosis and scar formation through the drainage of excessive proteins and fluid.


A new method of pancreatic juice collection in the conscious dog.
A simplified method for the collection of pancreatic juice in a conscious dog is described and the results of pancreatic secretions in response to both exogenous and endogenous stimulations are presented. This new method, simple to perform and providing easy collection of pancreatic juice, is also applicable to the intraduodenal infusion experiments.


The effect of temporary reductions in incubation temperature on growth characteristics and lipid utilisation in the chick embryo.
The effect(s) of finite exposure(s) to 22.0 degrees C on embryo weight gain, 3rd tarsus length, transfer of lipid from the yolk and uptake of specific lipid components by the liver, were measured in the chick embryo. Embryo growth was completely suspended over the period of temperature reduction, but resumed unimpaired when the optimum temperature of 37.5 degrees C was restored. Two successive periods of embryonic exposure to 22.0 degrees C (36 h at d 3 followed by 24 at d 10) were additive in their effect on growth retardation. Embryos subjected to temperature reductions on d 3 of incubation displayed significant changes in lipid concentrations and polyunsaturated fatty acid profiles within the liver when measured at d 18 of incubation. Yolk lipid uptake was significantly reduced but not suspended by embryonic exposure to 22.0 degrees C. It is suggested that the observed suspension of embryonic development was the result of a temperature dependent reduction in metabolism according to a Q10 approximately 2, which is typical of an ectothermic organism.


Short and long term outcomes of 200 patients supported by continuous-flow left ventricular assist devices.
To study the institutional experience over 8 years with 200 continuous-flow (CF) - left ventricular assist devices (LVAD). We evaluated our institution's LVAD database and analyzed all patients who received a CF LVAD as a bridge to transplant (BTT) or destination therapy from March 2006 until June 2014. We identified 200 patients, of which 179 were implanted with a HeartMate II device (Thoratec Corp., Pleasanton, CA) and 21 received a Heartware HVAD (HeartWare Inc., Framingham, MA). The mean age of our LVAD recipients was 59.3 years (range 17-81), 76% (152/200) were males, and 49% were implanted for the indication of BTT. The survival rate for our LVAD patients at 30 d, 6 mo, 12 mo, 2 years, 3 years, and 4 years was 94%, 86%, 78%, 71%, 62% and 45% respectively. The mean duration of LVAD support was 581 d (range 2-2595 d). Gastrointestinal bleeding (was the most common adverse event (43/200, 21%), followed by right ventricular failure (38/200, 19%), stroke (31/200, 15%), re exploration for bleeding (31/200, 15%), ventilator dependent respiratory failure (19/200, 9%) and pneumonia (15/200, 7%). Our driveline infection rate was 7%. Pump thrombosis occurred in 6% of patients. Device exchanged was needed in 6% of patients. On multivariate analysis, preoperative liver dysfunction, ventilator dependent respiratory failure, tracheostomy and right ventricular failure requiring right ventricular assist device support were significant predictors of post LVAD survival. Short and long term survival for patients on LVAD support are excellent, although outcomes still remain inferior compared to heart transplantation. The incidence of driveline infections, pump thrombosis and pump exchange have declined significantly in recent years.


Prevention and Management of Cardiac Implantable Electronic Device Infections: State-of-the-Art and Future Directions.
Cardiac implantable electronic device (CIED) infection is an increasingly common complication of device therapy. CIED infection confers significant patient morbidity and health care expenditure, hence it is essential that clinicians recognise the contemporary strategies for predicting, reducing and treating these events. Recent technological advances-in particular, the development of antimicrobial envelopes, leadless devices and validated risk scores-present decision-makers with novel strategies for managing this expanding patient population. This review summarises the key issues facing CIED patients and their physicians, and explores the supporting evidence for the latest therapeutic developments in this field.


Nanostructures from alkyl vitamin C derivatives (ASCn): properties and potential platform for drug delivery.
Alkyl vitamin C derivatives (ASC(n)) combine in their structure a lipophilic and a hydrophilic moiety and exhibit properties of typical surfactant molecules. Self-assembly properties of ASC(n) depend on the length of n-alkyl fatty chain. ASC(n) start to aggregate at temperatures (CMT, Krafft point) in which the solubility reaches the critical micellar concentration (CMC). Above this temperature, ASC(n) can aggregate in micelles or gel phase, depending of alkyl side chain. Upon cooling, for less soluble derivatives (ASC(12), ASC(14) and ASC(16)) liquid-crystal structures named coagels are obtained. They are able to solubilized insoluble and unstable drugs, protect them from any possible aggressive environment and promote their permeation through skin. Besides, the rheological properties of the coagels would be adequate for topical administration of pharmaceutical. These systems possess very interesting properties making ASC(n) coagels promising pharmaceutical platforms for drug delivery. Results from investigations about all these properties are described and analyzed. Also, the perspectives of these systems as drug delivery systems are discussed.


[Therapeutic education of children who are victims or at risk of a stroke].
Therapeutic patient education is one of the health improvement projects. It provides personalised support for a child who has suffered or is at risk of suffering a stroke, and their family. This approach requires the sharing and transfer of knowhow, behaviour and attitude on the part of specially trained health professionals.


The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress.
The nuclear receptor constitutive androstane receptor (CAR) (NR1I3) regulates hepatic genes involved in xenobiotic detoxification as well as genes involved in energy homeostasis. We provide data that extend the role of CAR to regulation of serum triglyceride levels under conditions of metabolic/nutritional stress. The typically high serum triglyceride levels of ob/ob mice were completely normalized when crossed onto a Car(-/-) (mice deficient for the Car gene) genetic background. Moreover, increases in serum triglycerides observed after a high-fat diet (HFD) regime were not observed in Car(-/-) animals. Conversely, pharmacological induction of CAR activity using the selective mouse CAR agonist TCPOBOP during HFD feeding resulted in a CAR-dependent increase in serum triglyceride levels. A major regulator of hepatic fatty oxidation is the nuclear receptor PPARalpha (NR1C1). The expression of peroxisome proliferator-activated receptor alpha (PPARalpha) target genes was inversely related to the activity of CAR. Consistent with these observations, Car(-/-) animals exhibited increased hepatic fatty acid oxidation. Treatment of mice with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) significantly decreased expression of PPARalpha mRNA as well as Cyp4a14, CPT1alpha, and cytosolic Acyl-CoA thioesterase (CTE) in the liver. These data have implications in disease therapy such as for diabetes and nonalcoholic steatohepatitis (NASH).


Inhibition of membrane fusion by suppression of lateral movement of membrane proteins.
Chicken erythrocytes were fused either by Sendai virus or by the combination of Ca2+ and ionophore A23187. Intramembrane particles and external anionic sites of cells undergoing fusion were found to acquire the ability to undergo a process of cold-induced clustering (thermotropic separation). Cationized ferritin (200 microgram/ml 5% (v/v) cell suspension) inhibited both the fusion process and the thermotropic separation of intramembrane particles and external anionic sites. The correlation between the mobility of membrane proteins and the fusion process is discussed. It is suggest that an increase in the lateral mobility of membrane proteins is a prerequisite for initiation of membrane fusion.


The promising interplay between sonodynamic therapy and nanomedicine.
Sonodynamic therapy (SDT) is a non-invasive approach for cancer treatment in which chemical compounds, named sonosensitizers, are activated by non-thermal ultrasound (US), able to deeply penetrate into the tissues. Despite increasing interest, the underlying mechanisms by which US triggers the sonosensitizer therapeutic activity are not yet clearly elucidate, slowing down SDT clinical application. In this review we will discuss the main mechanisms involved in SDT with particular attention to the sonosensitizers involved for each described mechanism, in order to highlight how much important are the physicochemical properties of the sonosensitizers and their cellular localization to predict their bioeffects. Moreover, we will also focus our attention on the pivotal role of nanomedicine providing the sonodynamic anticancer approach with the ability to shape US-responsive agents to enhance specific sonodynamic effects as the sonoluminescence-mediated anticancer effects. Indeed, SDT is one of the biomedical fields that has significantly improved in recent years due to the increased knowledge of nanosized materials. The shift of the nanosystem from a delivery system for a therapeutic agent to a therapeutic agent in itself represents a real breakthrough in the development of SDT. In doing so, we have also highlighted potential areas in this field, where substantial improvements may provide a valid SDT implementation as a cancer therapy.


Clinical pharmacodynamic index identification for micafungin in esophageal candidiasis: dosing strategy optimization.
Echinocandins exhibit concentration-dependent effects on Candida species, and preclinical studies support the administration of large, infrequent doses. The current report examines the pharmacokinetics/pharmacodynamics of two multicenter, randomized trials of micafungin dosing regimens that differed in both dose level and dosing interval. Analysis demonstrates the clinical relevance of the dose level and area under the concentration-time curve (AUC). Better, although not statistically significant (P = 0.056), outcomes were seen with higher maximum concentrations of drug in serum (Cmax) and large, infrequent doses. The results support further clinical investigation of novel micafungin dosing regimens with large doses but less than daily administration. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00666185 and NCT00665639.).


Color and shape discrimination in the stingless bee Scaptotrigona mexicana Guérin (Hymenoptera, Apidae).
To increase our understanding in bee vision ecology, we investigated the color and shape discrimination performance of the stingless bee Scaptotrigona mexicana Guérin. Our main goal was to describe the choice behavior of experienced foragers over time, trying to understand to what extent color and shape stimuli (separately tested) aid them to choose the rewarding option, in the presence of distracting, unrewarding stimuli. Single foragers were trained to collect sucrose solution from a target plate. Afterwards, one distracting, unrewarding plate was placed besides the target plate and eight choices were recorded. Our results showed that both color and shape stimuli assisted efficiently the trained foragers in locating the target plate. However, foragers chose significantly more often the target plate in the color experiments than in the shape experiments. In conclusion, in our experimental setup, color was of better assistance to the foragers of S. mexicana than shape to choose their rewards. This is the first study in which it is demonstrated that the choice performance over time in a stingless bee depends upon the characteristics of the resource, such as shape and color.


Occluding-like junctions at mesaxons of central myelin in Anolis carolinensis are not 'tight'. A freeze-fracture-protein tracer analysis.
The junctional complexes of the myelin sheath of central nervous system axons in the American chameleon, Anolis carolinensis, exhibit an intramembrane ridge and groove construction in freeze-fracture replicas that has usually been interpreted in other organisms as evidence for an occluding or tight intercellular junction. Close examination of PF fracture face ridges, however, shows them to be made up of discontinuous rows of particles of variable length separated by frequent gaps of non-uniform width. Introduction of horseradish peroxidase into the intercellular milieu of the lizard central nervous system is followed by appearance of this protein in interlamellar spaces of the myelin sheath and in the intercellular spaces containing focal membrane fusions that correspond precisely in position and center-to-center spacing to the ridges and grooves in platinum replicas of the same tissue. Since the junctional ridges on PF fracture faces in these mesaxonal junctional complexes are conspicuously discontinuous and since the areas within the myelin sheath where these junctional complexes are located inner and outer mesaxons) are readily permeated by exogenous protein tracer, it is concluded that the junctional complexes of central myelin mesaxons, heretofore incorrectly interpreted as functionally tight, are actually very leaky and probably contribute only to the structural stability of the myelin sheath architecture.


Risk of stillbirth in United States patients with diagnosed intrahepatic cholestasis of pregnancy.
Intrahepatic cholestasis of pregnancy is associated with a 4- to 10-fold increase in the risk of stillbirth in the absence of intervention, leading to recommendations for antenatal assessment, ursodiol use, and often preterm or early term delivery. This study aimed to determine whether current management strategies for intrahepatic cholestasis of pregnancy mitigate the elevated risk of stillbirth at a population level. This was a retrospective cohort study using the 2015-2020 National Readmissions Database, an administrative database developed by the United States Agency for Healthcare Research and Quality. Our study identified delivery hospitalizations, gestational age at delivery, occurrence of intrahepatic cholestasis of pregnancy and stillbirth, and comorbid conditions using the International Classification of Diseases diagnosis and procedure codes. Moreover, this study compared the timing of delivery and stillbirth rates of pregnant patients with intrahepatic cholestasis of pregnancy vs those without intrahepatic cholestasis of pregnancy at the time of delivery hospitalization. This study identified a cohort of 9,987,705 delivery hospitalizations in the National Readmissions Database, corresponding to a weighted national estimate of 18,609,207 births. Of these births, 152,040 (0.8%) were noted to have an intrahepatic cholestasis of pregnancy diagnosis. Patients with an intrahepatic cholestasis of pregnancy diagnosis were older, with small differences in comorbidities, such as a higher rate of gestational diabetes mellitus, than patients without an intrahepatic cholestasis of pregnancy diagnosis at delivery hospitalization. The overall rates of stillbirth were lower among those with intrahepatic cholestasis of pregnancy than among those without intrahepatic cholestasis of pregnancy (252 vs 386 per 100,000 deliveries; risk difference, 133 fewer per 100,000 deliveries; 95% confidence interval, 98-170), a finding that persisted after adjustment for insurance status, socioeconomic factors, and comorbid conditions (risk difference, 160 fewer stillbirths per 100,000 deliveries; 95% confidence interval, 127-194). Furthermore, although patients with intrahepatic cholestasis of pregnancy were more likely to deliver before term than those without intrahepatic cholestasis of pregnancy (30.1% vs 9.3%; P<.001), increased rates of stillbirth were not noted at any point after stratification of the cohort by gestational age at delivery. Patients with intrahepatic cholestasis of pregnancy diagnosis codes delivered earlier than those without intrahepatic cholestasis of pregnancy diagnosis codes, but the percentage of births affected by stillbirth was lower, even when stratifying for gestational age at birth. These results may provide reassurance to patients receiving an intrahepatic cholestasis of pregnancy diagnosis that current management does mitigate stillbirth risk in intrahepatic cholestasis of pregnancy.


Underwater endoscopic mucosal resection for superficial nonampullary duodenal adenomas.
Underwater endoscopic mucosal resection (UEMR) was recently developed in a Western country. A prospective cohort study to investigate the effectiveness of UEMR was conducted in patients with small superficial nonampullary duodenal adenomas. Patients with duodenal adenomas ≤ 20 mm were enrolled. After the duodenal lumen had been filled with physiological saline, UEMR was performed without submucosal injection. Endoclip closure was attempted for all mucosal defects after UEMR. Follow-up endoscopy with biopsy was performed 3 months later. The primary end point was the complete resection rate, defined as neither endoscopic nor histological residue of adenoma at the follow-up endoscopy. 30 patients with 31 lesions were enrolled. The mean (SD) tumor size was 12.0 mm (7.3). The complete resection rate was 97 % (90 % confidence interval, 87 % - 99 %). The en bloc resection rate was 87 %. All mucosal defects were successfully closed by endoclips. No adverse events occurred except for one case of mild aspiration pneumonia. UEMR is efficacious for the treatment of small duodenal adenomas, but further large-scale trials are warranted to confirm these results.


Posterolateral Disc Prolapse in Flexion Initiated by Lateral Inner Annular Failure: An Investigation of the Herniation Pathway.
Structural investigation of mechanically induced herniations in ovine lumbar motion segments. This new study addresses the question of whether there are regions other than the posterior and posterolateral aspects that are implicated in the initiation of disc disruption and herniation. Flexion in combination with compressive loading will induce disc herniations in healthy motion segments in vitro. Although it is widely accepted that the posterior and posterolateral regions of the disc are the primary sites of herniation much less is known as to whether other regions of the disc might be involved in the herniation process. Healthy ovine lumbar motion segments (n = 14) were flexed 10° and compressed at a rate of 40 mm/min up to point of failure. The discs were macroscopically analyzed using progressive transverse sectioning to obtain a more global picture of internal disc disruption and herniation. A high prevalence of disruption in the lateral annulus was found associated with circumferential tracking of nucleus between the annular layers toward the posterolateral and posterior regions. In all tests this lateral disruption did not cause any discernible external change in the lateral disc periphery after the removal of load. After imposing the predetermined flexion the applied compression also induced a forward anterior shear of the superior vertebra of approximately equal magnitude to the axial compressive displacement. The vulnerability of the lateral annulus to disruption is thought to arise from the overloading of its differentially recruited oblique/counteroblique fiber sets, this in turn generated by anterior shear developed in the flexed, compressed motion segment. This lateral annular disruption, followed by circumferential tracking of nuclear material and resulting in either contained or uncontained extrusions in the posterior or posterolateral annulus, highlights the complexity of the herniation process. N/A.