[Studies on the absorption, excretion and distribution of aclacinomycin A: absorption, excretion and distribution of aclacinomycin A in mice, rabbits and dogs by photometric assay (author's transl)].
An anthracycline antitumor antibiotic, aclacinomycin A, was given to mice, rabbits or dogs intravenously to study the pharmacokinetics by photometric assay based on the absorption of anthracycline ring. The drug was rapidly eliminated from the blood in these animals. Drug levels were much higher in the blood cells than in the plasma. Tissue levels in dogs were 50 approximately 100 times higher than the blood levels, which showed the drug was rapidly transferred from the blood to tissues after administration. Higher levels were observed in the lungs, spleen and lymph nodes, where the drug was present as aclacinomycin A itself and the glycoside-type metabolites that were biologically active. The active form was also detected in the pancreas, heart, thymus, bone marrow and gastrointestinal tract. In the liver and kidneys, biologically inactive aglycone-type metabolites were observed. About 2 approximately 4% of the drug given to rabbits or dogs was recovered in the urine by 72 hours after administration, in which only 10% of the excreted drug was active form in rabbits but about 65% in dogs. The rest was inactive aglycone-type metabolites that were excreted almost in the conjugated form. Biliary excretion also contributed to the total clearance of the drug. Aclacinomycin A was absorbed even by oral administration in rabbits and dogs. Tissue distribution of the drug orally given to dogs was similar to that in intravenous administration, except that higher levels of active form were detected in the gastrointestinal tract and of inactive form in the liver.


Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma.
Advanced melanoma is a devastating disease that has propelled research in therapeutics beyond chemotherapy and radiotherapy. Being highly immunogenic, melanoma is a model tumor for immunotherapy and has highlighted the therapeutic potential of the immune checkpoint inhibitors. This review discusses the pharmacologic properties, clinical efficacy, and safety profile of pembrolizumab, an IgG4-kappa humanized monoclonal antibody against the programmed cell death protein 1 (PD-1) receptor, for the treatment of unresectable or metastatic melanoma. Pembrolizumab was the first PD-1 inhibitor to be approved by the U.S. Food and Drug Administration (FDA). Remarkably, this accelerated approval for the treatment of advanced, heavily pretreated melanoma was based on response rates alone from a phase I trial. As anticipated, pembrolizumab confirmed a survival advantage in phase II and III trials and has led the way for the study of other drugs that share its mechanism of action. Defining disease and patient characteristics associated with a response remains amongst the most pressing priorities.


TECPR2 Cooperates with LC3C to Regulate COPII-Dependent ER Export.
Hereditary spastic paraplegias (HSPs) are a diverse group of neurodegenerative diseases that are characterized by axonopathy of the corticospinal motor neurons. A mutation in the gene encoding for Tectonin β-propeller containing protein 2 (TECPR2) causes HSP that is complicated by neurological symptoms. While TECPR2 is a human ATG8 binding protein and positive regulator of autophagy, the exact function of TECPR2 is unknown. Here, we show that TECPR2 associates with several trafficking components, among them the COPII coat protein SEC24D. TECPR2 is required for stabilization of SEC24D protein levels, maintenance of functional ER exit sites (ERES), and efficient ER export in a manner dependent on binding to lipidated LC3C. TECPR2-deficient HSP patient cells display alterations in SEC24D abundance and ER export efficiency. Additionally, TECPR2 and LC3C are required for autophagosome formation, possibly through maintaining functional ERES. Collectively, these results reveal that TECPR2 functions as molecular scaffold linking early secretion pathway and autophagy.


Differential regulation of expression of RNA-editing enzymes, ADAR1 and ADAR2, by 5-aza-2'-deoxycytidine and trichostatin A in human neuronal SH-SY5Y cells.
Adenosine deaminase acting on RNA (ADAR) enzymes, ADAR1 and ADAR2, mediates adenosine-to-inosine RNA editing, and their mRNA expressions are altered during developmental, physiological, and pathophysiological processes in the nervous system. The present study attempted to investigate the involvement of epigenetic modifying enzymes, such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC), in the regulation of ADAR1 and ADAR2 mRNA expressions in neuronal cells. Using human neuronal SH-SY5Y cells, we found that the DNMT inhibitor 5-aza-2'-deoxycytidine led to an increase in ADAR2, but not ADAR1, mRNA expression in a concentration-dependent and time-dependent manner. However, treatment with HDAC inhibitor trichostatin A elicited an increase in ADAR2 mRNA expression and a decrease in ADAR1 mRNA expression, and these changes were blocked by actinomycin D, a transcription inhibitor. Taken together, these findings suggest that ADAR1 and ADAR2 expressions are subject to different regulations by DNMT and HDAC enzymes in neuronal SH-SY5Y cells.


Awake Plastic Surgery Procedures: The Use of a Sufentanil Sublingual Tablet to Improve Patient Experience.
Awake plastic surgery performed under minimal sedation has advantages including patient preference, affordability, and easier recovery compared to when performed under deeper sedation. Commonly used oral analgesics may not be adequate for awake procedures resulting in moderate to severe pain. Sufentanil sublingual tablet (SST) 30 mcg has been shown to provide timely analgesia with a safety profile appropriate for minimal-sedation settings. To examine perioperative outcomes in patients who underwent awake plastic surgery with local anesthesia and SST 30 mcg for pain control. This study was a prospective single-group cohort study conducted at a single plastic surgery center. SST 30 mcg was administered approximately 30 minutes prior to the procedure. Outcome measures included the number of patients with adverse events, the number of patients requiring medications in the post-anesthesia care unit (PACU), and recovery time. Among the 31 patients, the most common procedures were liposuction (71%), facelift (10%), and blepharoplasty (6%). The mean (± standard error [SE]) procedural duration was 81 ± 9 minutes. No vital sign instability or oxygen desaturation was observed. Three patients (10%) experienced nausea, only one of which required treatment with oral ondansetron 4 mg in the PACU. One patient (3%) experienced dizziness that did not require treatment. No patients required opioids or other analgesics in the PACU for pain. The mean (±SE) recovery time was 15 ± 4 minutes. Awake plastic surgery can be performed using SST 30 mcg with minimal side effects and a rapid recovery time.


Experimental evaluation of "The Images Within": an alcohol education and prevention program.
A program titled "The Images Within" was implemented and evaluated in three sites on the east coast of the United States. This school curriculum uses art work developed by children of alcoholics to stimulate classroom discussions of the problems of parental alcohol abuse. The evaluation with 278 experimental and 310 control students indicated increased knowledge about the effects of alcohol and improved skills in coping with alcohol problems and help seeking behavior. Process data indicated that related programs were initiated, students were stimulated by the program and teachers were positive in their perceptions of the program. Schools implementing this program need to have developed referral networks to handle the individual concerns that are expressed as a result of participation in "The Images Within."


[Surveillance of antimicrobial resistance of Streptococcus pneumoniae isolates from the Kinki Region of Japan during 2003/2004. The Surveillance Program of Bacterial Resistance in the Kinki Region of Japan; SBRK].
Three hundred seventy five isolates of Streptococcus pneumoniae were collected from 14 medical institutions in the Kinki region of Japan between November 2003 and February 2004. We determined the minimum inhibitory concentration (MIC) of penicillin G (PCG) and 25 of other antimicrobial agents against these isolates according to the National Committee for Clinical Laboratory Standards (NCCLS). Overall, 71.5% of all isolates were resistant to PCG (intermediate and resistant categories were 51.7% and 19.8%, respectively). For the carbapenems and penem, the rank order of activity was PAPM (MIC90, 0.12 microg/ml) > IPM (0.25 microg/ml) > MEPM (0.5 microg/ml) = FRPM (0.5 microg/ml). For the cephems, the overall rank order of activity was CPR (MIC90, 0.5 microg/ml) = CDTR (0.5 microg/ml) > CTRX (1 microg/ml) = CTX (1 microg/ml) = CZOP (1 microg/ml) = CFPN (1 microg/ml). Rank order activity for six of fluoroquinolones was TFLX = MFLX (MIC90, 0.25 microg/ml) > GFLX (0.5 microg/ ml) = SPFX (0.5 microg/ml) > LVFX (1 microg/ml) > PZFX (4 microg/ml). The rate of resistance to fluoroquinolones per the NCCLS criteria were very low, ranging from 0.7% to 2.6%. Rate of resistance to other antimicrobiotics were CAM, 77.0%; CLDM, 41.7%; TEL, 0%; VCM, 0%; ST, 32.7%, and CP, 21.4%.


[The process of integrating oncology nurse navigators into joint (hospital-community) local teams].
Implementing oncology nurse navigators or IPOs (which stands for "infirmière pivot en oncologie") is a key element of the Québec Cancer Control Program in order to improve the continuity of care. This qualitative study describes the process of implementing IPOs in teams working both in hospitals and in the community. Several groups of stakeholders (IPOs, physicians, nurses, various health workers, administrators, people with cancer and their families) described how they perceive the functions and effects related to this implementation. After putting results into perspective, we recommend developing measures promoting the dissemination of the role and integration of IPOs in formally defined health teams. We strongly advocate for the continuation of joint efforts in order to define and clarify this complex role.


Visual awareness, emotion, and gamma band synchronization.
What makes us become aware? A popular hypothesis is that if cortical neurons fire in synchrony at a certain frequency band (gamma), we become aware of what they are representing. We tested this hypothesis adopting brain-imaging techniques with good spatiotemporal resolution and frequency-specific information. Specifically, we examined the degree to which increases in event-related synchronization (ERS) in the gamma band were associated with awareness of a stimulus (its detectability) and/or the emotional content of the stimulus. We observed increases in gamma band ERS within prefrontal-anterior cingulate, visual, parietal, posterior cingulate, and superior temporal cortices to stimuli available to conscious awareness. However, we also observed increases in gamma band ERS within the amygdala, visual, prefrontal, parietal, and posterior cingulate cortices to emotional relative to neutral stimuli, irrespective of their availability to conscious access. This suggests that increased gamma band ERS is related to, but not sufficient for, consciousness.


Intersystem Crossings in Late-Row Elements: A Perspective.
Intersystem crossing (ISC), a vital component of the electronic and nuclear transitions that compose photophysics, has been successfully simulated in light elements and transition metal complexes. Derived from the Z-dependent spin-orbit coupling (SOC), ISC is expected to be of greater importance in heavier elements, but few attempts have been made at the simulation of ISC in lanthanides or actinides. In this work, we explore several of the challenges that will need to be overcome in order to treat ISC in late-row elements, including the loss of spin as a good quantum number, the need to include SOC variationally via two- or four-component electronic structure, and the high density of states present in late-row complexes. Density functional theory (DFT) calculations are used to illustrate several of these effects, while a model Hamiltonian is used to illustrate the importance of momentum rescaling in surface hopping simulations of strongly coupled states.


Acute effects of mindful interval exercise on cognitive performance in a higher education setting.
Interval exercise (IE) has been shown to have acute facilitating effects on cognition; however, the existing literature has been limited to laboratory settings and has focused on manipulating the parameters of exercise bouts during IE. This study included two classroom-based experiments to (1) investigate the effect of an acute bout of IE delivering mindfulness activity during its recovery intervals (mindful IE) on cognitive performance, and (2) compare cognitive performance following acute bouts of mindful IE with non-mindful IE. Experiment 1: Using a class-based within-subject crossover design, 59 participants completed the Stroop, d2, and trail-making tests to measure inhibitory control, attention, and cognitive flexibility, after a 30-min non-exercise or mindful IE session on separate counterbalanced days. Experiment 2: Using a similar design, 70 participants were assigned to two groups to receive a non-exercise and an IE session with (mindful) or without (non-mindful) mindfulness-based recovery intervals on separate counterbalanced days. Results from Experiment 1 showed superior d2 performance following the mindful IE than the non-exercise session. Although Experiment 2 found exercise-related decreases in commission error rate during the d2 test in both groups, the non-mindful group showed additional decreases in omission and total error rates. Further, higher scores on the nonreactivity facet of dispositional mindfulness were correlated with larger decreases in omission and total error rates during the d2 test for the mindful IE group. No exercise-related effect was found for outcomes of the Stroop and trail-making tests in both experiments. These findings in the selective improvements in d2 test performance are the first to suggest the feasibility of integrating mindfulness activity into the recovery intervals of IE for enhanced cognitive performance that may depend on individual differences in dispositional mindfulness.


Successful microsurgical replantation of an amputated penis.
Penile amputation is an uncommon injury for which immediate surgical replantation is warranted. Microsurgical replantation is the "standard" method for penile replantation. Early replantation yields a high success and low complication rate. We report a case of a 34-year-old male who presented with amputation at the proximal penile shaft which was successfully replanted using microsurgical techniques. Minor skin necrosis was noted post-operatively which was debrided and covered with skin graft. Follow-up at 6 months showed satisfactory cosmetic appearance, normal voiding, return of sensations and erectile function. The level of evidence was V.


Anatomy of Master Knot of Henry: A morphometric study on cadavers.
The objective of this study was to evaluate the features of flexor hallucis longus (FHL), flexor digitorum longus (FDL) and flexor digitorum accessorius (FDA) muscles with relevance to the tendon grafts and to reveal the location of Master Knot of Henry (MKH). Twenty feet from ten formalin fixed cadavers were dissected, which were in the inventory of Anatomy Department of Medicine Faculty, Mersin University. The location of MKH was identified. Interconnections of FHL and FDL were categorized. According to incision techniques, lengths of FHL and FDL tendon grafts were measured. Attachment sites of FDA were assessed. MKH was 12.61 ± 1.11 cm proximal to first interphalangeal joint, 1.75 ± 0.39 cm below to navicular tuberosity and 5.93 ± 0.74 cm distal to medial malleolus. The connections of FHL and FDL were classified in 7 types. Tendon graft lengths of FDL according to medial and plantar approaches were 6.14 ± 0.60 cm and 9.37 ± 0.77 cm, respectively. Tendon graft lengths of FHL according to single, double and minimal invasive incision techniques were 5.75 ± 0.63 cm, 7.03 ± 0.86 cm and 20.22 ± 1.32 cm, respectively. FDA was found to be inserting to FHL slips in all cases and it inserted to various surfaces of FDL. The exact location of MKH and slips was determined. Two new connections not recorded in literature were found. It was observed that the main attachment site of FDA was the FHL slips. The surgical awareness of connections between the FHL, FDL and FDA, which participated in the formation of long flexor tendons of toes, could be important for reducing possible loss of function after tendon transfers postoperatively.


Divide and Conquer: Strategies in Singapore to Manage a Nuclear Medicine Department During COVID-19.
The COVID-19 outbreak was declared a public health emergency of international concern by the World Health Organization on January 30, 2020. Since then, the virus has spread to affect more countries worldwide. During this period, our nuclear medicine department at Singapore General Hospital segregated our staff and patients by time, by space, or both, to minimize contact and prevent spread of the virus. Necessary changes to our clinical practices and stricter infection control measures were also enforced. We share our personal experience in managing a nuclear medicine department during this epidemic.


Oral rehabilitation for a patient with oligodontia and maxillary hypoplasia.
An 18 year old female with oligodontia and maxillary hypoplasia was treated using an interdisciplinary team approach involving orthodontists, maxillofacial surgeons and prosthodontists. Full mouth one-piece fixed partial dentures were the final restoration. The fixed partial dentures fabricated for the maxilla and mandible using the concept of a shortened dental arch resulted in improved esthetics and the masticatory function. This paper describes the treatment procedures for an oligodontia patient with alveolar bone hypoplasia.


SAIL--stereo-array isotope labeling.
Optimal stereospecific and regiospecific labeling of proteins with stable isotopes enhances the nuclear magnetic resonance (NMR) method for the determination of the three-dimensional protein structures in solution. Stereo-array isotope labeling (SAIL) offers sharpened lines, spectral simplification without loss of information and the ability to rapidly collect and automatically evaluate the structural restraints required to solve a high-quality solution structure for proteins up to twice as large as before. This review gives an overview of stable isotope labeling methods for NMR spectroscopy with proteins and provides an in-depth treatment of the SAIL technology.


Do cerebral motivational asymmetries mediate the relationship between handedness and personality?
Handedness has long been tied to personality, but detailed explanations for the association are lacking. Importantly for purposes of theory development, measures of approach and withdrawal associated with Big Five personality traits have also been traced back to activity in brain areas that relate to handedness. Specifically, increased right-hemisphere frontal activity appears to be linked to both withdrawal motivation and left/inconsistent-handedness, while increased left-hemisphere frontal activity is associated with approach motivation and right/consistent-handedness. Cerebral motivational asymmetries therefore present one plausible mechanism by which approach and withdrawal motivation could mediate the relationship between handedness and personality. We tested this possibility in a large online study (N = 499) in which participants completed multiple survey measures. Results indicated that approach/withdrawal motivation partially accounts for relationships between handedness and personality.


Compartment syndrome associated with bupivacaine and fentanyl epidural analgesia in pediatric orthopaedics.
Two patients had a compartment syndrome after surgery at a remote site performed under a continuous lumbar infusion of a mixture of narcotic (fentanyl) and local anesthetic (bupivacaine 0.1%). Each patient had inadvertent excessive pressure applied to the limb distally and had no perception of pain in the presence of this analgesic combination. After the relief of this pressure from a sling or traction apparatus, each child had signs of a compartment syndrome, and this sensation of pathologic pain was not masked by the epidural infusion. A discussion of the literature questions the benefits of bupivacaine local anesthetic as a routine addition to epidural analgesia for orthopaedic surgery.


Photon-counting three-dimensional integral imaging with compression of elemental images.
In this paper, we present lossless compression of elemental images in photon-counting integral imaging. In order to verify the performance of the compression method applied to low light level three-dimensional (3D) integral imaging, we compute the correlation coefficient and peak to mean square error (PSNR) as metrics for 3D scene reconstruction integrity. We show quantitatively via experiments that a considerable compression of the elemental images in photon-counting integral imaging may be achievable without significant loss in the performance in terms of correlation and PSNR metrics. To the best of our knowledge, this is the first report on applying lossless compression algorithms in photon-counting 3D computational integral imaging.


Prevalence of handheld laser device use, exposure and associated injury.
This study assessed the use of and exposure to handheld laser devices by Canadians and the potential associated health risks. The 2019 Canadian Community Health Survey collected data from 12,397 Canadians on the prevalence of handheld laser exposure or use, and associated eye or skin injuries. In 2019, an estimated 12.4% (95% CI: 11.4% to 13.4%) of Canadians reported using a handheld laser device or being exposed to its beam in the previous year, and those between the ages of 12 and 17 represented 30.5% (95% CI: 26.6% to 34.4%) of users. The highest laser device use or exposure was among those with a university education (13.8%; 95% CI: 11.8% to 15.8%), and a significant trend was found over income categories (p < 0.0001). The highest prevalence of exposure or use involved laser pointers (69.4%; 95% CI: 65.4% to 73.4%), followed by laser toys (38.5%; 95% CI: 34.6% to 42.5%), laser torches (8.2%; 95% CI: 6.1% to 10.4%) and-lastly-search-and-rescue lasers (0.8%E; 95% CI: 0.3% to 1.2%). Overall, 0.7%E (95% CI: 0.2% to 1.2%) of Canadians reported discomfort or injury in the past 12 months. One-quarter (27.9%; 95% CI: 23.8% to 31.9%) of users had a laser beam intentionally directed toward their eyes or skin. Most users did not buy the device (56.3%; 95% CI: 52.1% to 60.5%), while 40.5% (95% CI: 36.2% to 44.7%) purchased it at a Canadian retail store or online (3.8%E; 95% CI: 2.6% to 5.0%). The prevalence of handheld laser device use and beam exposure was 12.4% (95% CI: 11.4% to 13.4%), representing approximately 3.9 million Canadians. While the number of reported injuries was low, ongoing surveillance helps assess the effectiveness of current risk management approaches for laser products.


Hsp25 regulates the expression of p21(Waf1/Cip1/Sdi1) through multiple mechanisms.
Exposure of cells to external stresses leads to the induction or activation of certain proteins. Expression of heat shock proteins (Hsps) is induced in response to these stresses. Hsps are known to have molecular chaperone activities; but recent studies have shown that Hsps have a variety of functions such as the triggering of proliferation, differentiation, and apoptosis of cells. Previously, we found that overexpression of a 25 kDa Hsp (Hsp25) induced expression of cell cycle inhibitory protein p21 (Waf1/Cip1/Sdi1) in murine fibroblastoid L929 cells. However, the mechanisms underlying the induction of p21 by Hsp25 are unknown. In the present study, we investigated the mechanisms underlying the regulation of p21 expression by Hsp25 in these cells. The introduction of Hsp25 cDNA stimulated the accumulation of p21 transcripts through transcriptional but not posttranscriptional regulation in these cells. We also found that overexpression of Hsp25 markedly increased the translational rate of p21 and stabilized the protein. Studies involving proteasome inhibitors and Western blot analysis for ubiquitination of p21 demonstrated that the stabilization of p21 is regulated through a ubiquitin-independent pathway. However, no direct association of Hsp25 with p21 was observed. These findings suggest that Hsp25 induces p21 expression through multiple mechanisms, and that transcriptional, translational, and post-translational regulation are important in the regulation of p21.


Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection.
Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.


What do we really know about e-cigarettes?
Are e-cigarettes a "gateway" to the use of tobacco and other substances of abuse? Or do they represent an effective way to quit smoking?


Metal-decorated γ-graphyne as a drug transporting agent for the mercaptopurine chemotherapy drug: a DFT study.
In recent years, carbon-based two-dimensional (2D) materials have gained popularity as the carriers of various anticancer therapy drugs, which could reduce the crucial side effects by directly applying the drugs to the intended tumor cells. In this study, through first-principles density functional theory simulations, we have investigated the adsorption properties of a famous cancer chemotherapy drug called mercaptopurine (MC) on a 2D γ-graphyne (GYN) monolayer. Analyzing the geometric and electronic properties, we can summarize that the MC interaction with the pristine GYN is weak, with a small adsorption energy of -0.15 eV, which is too low for potential applications. Therefore, we have decorated the GYN monolayer with biocompatible metals such as Al, Ag, and Cu to trigger the adsorption capacity. The Al- and Cu-decorated GYN offered improved adsorption towards MC compared to the pristine case. The drug release from these metal-decorated systems was examined by creating an acidic environment. In addition, the desorption temperature of the drug from the system was also evaluated using ab initio molecular dynamics simulations. The calculations demonstrated that the Al-decorated GYN is a potential vehicle for MC drug delivery because of the favourable adsorption energy of -0.63 eV, charge transfer of 0.17e and desorption temperature above 270 K. The current research will stimulate the investigation of other low-dimensional carbon materials for drug-delivery applications.


Bioprinted hASC-laden cell constructs with mechanically stable and cell alignment cue for tenogenic differentiation.
3D bioprinting is a technology that enables the precise and controlled deposition of cells and an artificial extracellular matrix (ECM) to create functional tissue constructs. However, current 3D bioprinting methods still struggle to obtain mechanically stable and unique cell-morphological structures, such as fully aligned cells. In this study, we propose a new 3D bioprinting approach that utilizes a high concentration of bioink without cells to support mechanical properties and drag flow to fully align cells in a thin bath filled with cell-laden bioink, resulting in a hybrid cell-laden construct with a mechanical stable and fully aligned cell structure. To demonstrate the feasibility of this approach, we used it to fabricate a cell-laden construct using human adipose stem cells (hASCs) for tendon tissue engineering. To achieve appropriate processing conditions, various factors such as the bioink concentration, nozzle moving speed, and volume flow rate were considered. To enhance the biocompatibility of the cell-laden construct, we used porcine decellularized tendon ECM.In vitrocellular responses, including tenogenic differentiation of the fabricated hybrid cell structures with aligned or randomly distributed cells, were evaluated using hASCs. In addition, the mechanical properties of the hybrid cell-laden construct could be adjusted by controlling the concentration of the mechanically reinforcing strut using methacrylated tendon-decellularized extracellular matrix. Based on these results, the hybrid cell-laden structure has the potential to be a highly effective platform for the alignment of musculoskeletal tissues.


Cathepsin S, but not cathepsin L, participates in the MHC class II-associated invariant chain processing in large yellow croaker (Larimichthys crocea).
Two cysteine proteases, cathepsin S (CatS) and cathepsin L (CatL), have been identified as the key enzymes involved in the processing of invariant chain (Ii chain) in mammals. However, little is known about the roles of fish cathepsins in the Ii chain processing. In this study, large yellow croaker cathepsin S (LycCatS) and L (LycCatL) were identified and characterized. Based on the sequence comparison and phylogenetic analysis, both LycCatS and LycCatL are highly conserved to their counterparts in teleost. These two cathepsins were constitutively expressed in all tissues and immune-related cells tested, although at different levels. Both recombinant LycCatS (rLycCatS) and LycCatL (rLycCatL) possess the typical cysteine protease activity. Like other mammalian endopeptidase cathepsins, rLycCatS and rLycCatL could be autocatalytically activated to remove propeptides and release active mature peptides. On the other hand, the autocatalytic activation of rLycCatL could be inhibited by recombinant large yellow croaker Ii chain (rLyc-TR-Ii), but the autocatalytic activation of rLycCatS was not affected by rLyc-TR-Ii. Furthermore, the activated rLycCatS can efficiently process rLyc-TR-Ii in a stepwise manner in vitro, while the activated rLycCatL can not. These data indicate that cathepsin S may be the main cathepsin involved in the Ii chain processing in bony fish.


A reference-based approach for estimating leaf area and cover in the forest herbaceous layer.
Cover data are used to assess vegetative response to a variety of ecological factors. Estimating cover in the herbaceous layer of forests presents a problem because the communities are structurally complex and rich in species. The currently employed techniques for estimating cover are less than optimal for measuring such rich understories because they are inaccurate, slow, or impracticable. A reference-based approach to estimating cover is presented that compares the area of foliar surfaces to the area of an observer's hand. While this technique has been used to estimate cover in prior studies, its accuracy has not been tested. We tested this hand-area method at the individual plant, population, and community scales in a deciduous forest herbaceous layer, and in a separate farm experiment. The precision, accuracy, observer bias, and species bias of the method were tested by comparing the hand-estimated leaf area index values with actual leaf area index, measured using a leaf area meter. The hand-area method was very precise when regressed against actual leaf area index at the plant, population, and community scales (R(2) of 0.97, 0.93, and 0.87). Among the deciduous sites, the hand-area method overestimated leaf area index consistently by 39.1% at all scales. There was no observer bias detected at any scale, but plant overestimation bias was detected in one species at the population scale. The hand-area method is a rapid and reliable technique for estimating leaf area index or cover in the forest herbaceous layer and should be useful to field ecologists interested in answering questions at the plant, population, or community level.


Beauty.
Beauty is not race neutral. It is a racialized category/ perception which emerged through centuries of European colonization, Indigenous genocide, African/Black enslavement and indenture resulting in an aesthetic hierarchy with Blackness at the bottom. The coloniality of aesthetics means that still today hair perceived as Black in texture and styling and darker skin on African descent bodies are the repositories of anti-Blackness. However, Black women, children and men continue to fight back by (re)creating Black antiracist aesthetics focused on valorizing Black skin and hair.


Stability of affect associated with autobiographical memories.
Childhood family atmosphere is a frequent topic in psychotherapy. Our aim was to assess the stability of affect associated with autobiographical memories. In a 7-year follow-up study of depression, 414 primary care patients and psychiatric outpatients both at baseline and at follow-up completed the self-inquiry Depression Scale (DEPS) and answered simple questions about the mental atmosphere in their childhood families. The prevalence and the distribution of changes in affect were calculated by cross-tabulation. Logistic regression analyses were used to assess associations between depressiveness and changes in affect. Nearly 50% of the sample had at least one change in the responses. Young age and male gender were significant predictors for changes. Depressiveness was associated with changes in miserable affect of the childhood home. Affect associated with autobiographical memories seems to change over a longer period. The association between depressiveness and changes in recollections is convoluted. The large number of changes of affects concerning autobiographical memories should be taken into account both in psychotherapy and in studies of life-long experiences. Future long follow-up studies with more specific multi-item measures on family atmosphere are needed.


Pregnancy weight gain and its correlation to birth weight.
This study was done to determine whether a relationship existed between maternal weight gain during pregnancy and the birth weight and if such a relationship did exist, to establish the minimum weight gain required for a normal birth weight baby. This was a retrospective study involving an audit of all antenatal records at a rural hospital and health centre. The records reviewed belonged to a period between '86-'99. About 2000 antenatal records were scanned and cases with complications and multiple pregnancy were excluded. The records reviewed pertained only to mothers who had delivered at this rural hospital. The final sample size was 935 mothers. The study revealed that a greater weight gain in second trimester resulted in a better birth weight (P < 0.05). Other factors that influenced the birth weight were: age (P < 0.001), regular antenatal check up (P < 0.05) and parity (P < 0.05).


Eicosapentaenoic Acid supplementation changes Fatty Acid composition and corrects endothelial dysfunction in hyperlipidemic patients.
We investigated the effects of purified eicosapentaenoic acid (EPA) on vascular endothelial function and free fatty acid composition in Japanese hyperlipidemic subjects. In subjects with hyperlipidemia (total cholesterol ≥220 mg/dL and/or triglycerides ≥150 mg/dL), lipid profile and forearm blood flow (FBF) during reactive hyperemia were determined before and 3 months after supplementation with 1800 mg/day EPA. Peak FBF during reactive hyperemia was lower in the hyperlipidemic group than the normolipidemic group. EPA supplementation did not change serum levels of total, HDL, or LDL cholesterol, apolipoproteins, remnant-like particle (RLP) cholesterol, RLP triglycerides, or malondialdehyde-modified LDL cholesterol. EPA supplementation did not change total free fatty acid levels in serum, but changed the fatty acid composition, with increased EPA and decreased linoleic acid, γ-linolenic acid, and dihomo-γ-linolenic acid. EPA supplementation recovered peak FBF after 3 months. Peak FBF recovery was correlated positively with EPA and EPA/arachidonic acid levels and correlated inversely with dihomo-γ-linolenic acid. EPA supplementation restores endothelium-dependent vasodilatation in hyperlipidemic patients despite having no effect on serum cholesterol and triglyceride patterns. These results suggest that EPA supplementation may improve vascular function at least partly via changes in fatty acid composition.


Effectiveness of ceftazidime/avibactam as salvage therapy for treatment of infections due to OXA-48 carbapenemase-producing Enterobacteriaceae.
Experience in real clinical practice with ceftazidime/avibactam is limited, and there are even fewer data on infections due to OXA-48-producing Enterobacteriaceae. We designed an observational study of a prospectively collected cohort of adult patients receiving ceftazidime/avibactam in our centre. Only the first treatment course of each patient was analysed. Efficacy and safety were evaluated as 14 and 30 day mortality, recurrence rate at 90 days, resistance development and occurrence of adverse effects. Fifty-seven patients were treated with ceftazidime/avibactam. The median age was 64 years (range 26-86), 77% were male and the median Charlson index was 3. The most frequent sources of infection were intra-abdominal (28%), followed by respiratory (26%) and urinary (25%). Thirty-one (54%) patients had a severe infection (defined as presence of sepsis or septic shock). Most patients received ceftazidime/avibactam as monotherapy (81%) and the median duration of treatment was 13 days. Mortality at 14 days was 14%. In multivariate analysis, the only mortality risk factor was INCREMENT-CPE score >7 (HR 11.7, 95% CI 4.2-20.6). There was no association between mortality and monotherapy with ceftazidime/avibactam. The recurrence rate at 90 days was 10%. Ceftazidime/avibactam resistance was not detected in any case and only two patients developed adverse events related to treatment. Ceftazidime/avibactam shows promising results, even in monotherapy, for the treatment of patients with severe infections due to OXA-48-producing Enterobacteriaceae and limited therapeutic options. The emergence of resistance to ceftazidime/avibactam was not observed.


Chemical Variability of Essential Oils from Corsican Hops and Highlighting Their Influence on Hops' Aroma.
Essential oils from wild Corsican hops have never been described before. Following selective harvesting and extraction of plant material, chemical analysis was performed by GC-FID and GC-MS. Subsequent quantitative analysis demonstrated significant inter-stations variability due to pedoclimatic conditions. These singularities produce organoleptic differences, especially within Italian hops, which are the current benchmark for the Mediterranean hops' population. Corsican wild hops are no exception. Accordingly, three olfactive bouquets were identified by a panel of selected and trained sensory analysts: woody herbaceous ginger notes, herbaceous citrus notes, and common notes. These bouquets appeared to be correlated to pedoclimatic parameters mentioned earlier such as altitude and proximity to the sea. A very rare and appreciated bouquet was associated with high levels of zingiberene in hops growing at moderate altitude and relatively far from the coastline. This study shows the importance of growing sites and pedoclimatic conditions to produce hops with the desired organoleptic notes during the beer making process and provides detailed identification of essential oils from Corsican wild hops.


Vascular heterogeneity and targeting: the role of YKL-40 in glioblastoma vascularization.
Malignant glioblastomas (GBM) are highly malignant brain tumors that have extensive and aberrant tumor vasculature, including multiple types of vessels. This review focuses on recent discoveries that the angiogenic factor YKL-40 (CHI3L1) acts on glioblastoma-stem like cells (GSCs) to drive the formation of two major forms of tumor vascularization: angiogenesis and vasculogenic mimicry (VM). GSCs possess multipotent cells able to transdifferentiate into vascular pericytes or smooth muscle cells (PC/SMCs) that either coordinate with endothelial cells (ECs) to facilitate angiogenesis or assemble in the absence of ECs to form blood-perfused channels via VM. GBMs express high levels of YKL-40 that drives the divergent signaling cascades to mediate the formation of these distinct microvascular circulations. Although a variety of anti-tumor agents that target angiogenesis have demonstrated transient benefits for patients, they often fail to restrict tumor growth, which underscores the need for additional therapeutic tools. We propose that targeting YKL-40 may compliment conventional anti-angiogenic therapies to provide a substantial clinical benefit to patients with GBM and several other types of solid tumors.


Environmental and genetic variation in milk yield of native cattle and crosses with Brown Swiss in India.
Effects of year, season, parity, age, their two-way interactions, lactation length and calving interval on milk yield were investigated utilizing 9,086 lactation records collected from 1930 to 1975 from six breed groups kept in one herd at Karnal, India. The breed groups involved three native breeds (Sahiwal, Red Sindhi and Tharpakar) and three crossbreds with Brown Swiss (F1 crosses between Brown Swiss and three native breeds, inter se crosses, and 3/4 Brown Swiss). Breed, year, season, parity, age and all of the two-way interactions with the exception of breed X season and parity X season were important. Tharpakar produced more milk than Sahiwal and Red Sindhi by 232 and 204 kg. The milk production difference between Sahiwal and Red Sindhi was only 28 kg. The three crossbreds outproduced the purebreds by an average of 766 kg; however, differences in management could have favored crossbreds. Among the crossbreds, F1 crosses were superior. The linear and quadratic regressions on lactation length accounted for 28% of the variation in milk yield after year, season, parity, age and their interactions were absorbed. Calving interval and lactation length together accounted for 29%. Estimates of heritability, from paternal half-sib analyses, and repeatability of milk yield for Red Sindhi, Sahiwal and Tharpakar ranged from .10 to .30. Differences among heritability estimates from different parities were small when more than 500 records were involved.


A recipe for plastic: Expert insights on plastic additives in the marine environment.
The production and consumption of plastic products had been steadily increasing over the years, leading to more plastic waste entering the environment. Plastic pollution is ubiquitous and comes in many types and forms. To enhance or modify their properties, chemical additives are added to plastic items during manufacturing. The presence and leakage of these additives, from managed and mismanaged plastic waste, into the environment are of growing concern. In this study, we gauged, via an online questionnaire, expert knowledge on the use, characteristics, monitoring and risks of plastic additives to the marine environment. We analysed the survey results against actual data to identify and prioritise risks and gaps. Participants also highlighted key factors for future consideration, including gaining a deeper understanding of the use and types of plastic additives, how they leach throughout the entire lifecycle, their toxicity, and the safety of alternative options. More extensive chemical regulation and an evaluation of the essentiality of their use should also be considered.


Are declining populations of wild geese in China 'prisoners' of their natural habitats?
While wild goose populations wintering in North America and Europe are mostly flourishing by exploiting farmland, those in China (which seem confined to natural wetlands) are generally declining. Telemetry devices were attached to 67 wintering wild geese of five different species at three important wetlands in the Yangtze River Floodplain (YRF), China to determine habitat use. 50 individuals of three declining species were almost entirely diurnally confined to natural wetlands; 17 individuals from two species showing stable trends used wetlands 83% and 90% of the time, otherwise resorting to farmland. These results confirm earlier studies linking declines among Chinese wintering geese to natural habitat loss and degradation affecting food supply. These results also contribute to explaining the poor conservation status of Chinese wintering geese compared to the same and other goose species wintering in adjacent Korea and Japan, western Europe and North America, which feed almost entirely on agricultural land, liberating them from winter population limitation.


The changing face of chemotherapy.
The historical development of antibiotics has been summarized. Three distinct phases are discernible. The first (from historical times to about 1900) involved mostly folk remedies. The second (1900-c. 1940) was ushered in by Paul Ehrlich's development of the concept of 'selective toxicity' and saw the establishment of arsenicals and sulphonamides. The third, lasting to the present day, started with the exploitation of the pioneering studies of Fleming, Dubos and Waksman on antibiotic production by soil fungi. This latest phase has continued with the improvement of natural products by the skills of the medicinal chemist. The properties and evolution of three major groups of antibiotics, penicillins, cephalosporins and aminoglycosides are fully described. Finally, pathways of possible future evolution of antibiotics are outlined.


Nonlinear Characterization of Tissue Viscoelasticity With Acoustoelastic Attenuation of Shear Waves.
Shear-wave elastography (SWE) measures shear-wave speed (SWS), which is related to the underlying shear modulus of soft tissue. SWS in soft tissue changes depending on the amount of external strain that soft tissue is subjected to due to the acoustoelastic (AE) phenomenon. In the literature, variations of SWS as a function of applied uniaxial strain were used for nonlinear characterization, assuming soft tissues to be elastic, although soft tissues are indeed viscoelastic in nature. Hence, nonlinear characterization using SWS alone is insufficient. In this work, we use SWS together with shear-wave attenuation (SWA) during incremental quasi-static compressions in order to derive biomechanical characterization based on the AE theory in terms of well-defined storage and loss moduli. As part of this study, we also quantify the effect of applied strain on measurements of SWS and SWA since such confounding effects need to be taken into account when using SWS and/or SWA, e.g., for staging a disease state, while such effects can also serve as an additional imaging biomarker. Our results from tissue-mimicking phantoms with varying oil percentages and ex vivo porcine liver experiments demonstrate the feasibility of our proposed methods. In both experiments, SWA was observed to decrease with applied strain. For 10% compression in ex vivo livers, shear-wave attenuation decreased, on average, by 28% (93 Np/m), while SWS increased, on average, by 20% (0.26 m/s).


Synthesis of Enantiopure α'-Amino α,β-Epoxy Ketones from α'-Amino Bromomethyl Ketones.
Preparation of enantiomerically pure α'-amino α,β-epoxy ketones 2 in an efficient synthesis starting from α'-amino bromomethyl ketones 5 and the obtention of amino diepoxido 10a as synthetic application of 2 are described. We also report the generalization of the synthesis of 1-aminoalkyl halomethyl ketones to their bromo derivatives.


Novel Inhalable Ciprofloxacin Dry Powders for Bronchiectasis Therapy: Mannitol-Silk Fibroin Binary Microparticles with High-Payload and Improved Aerosolized Properties.
Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease associated with the high morbidity and mortality. Long-term intermittent therapy by inhalable antibiotics has recently emerged as an effective approach for NCFB treatment. However, the effective delivery of antibiotics to the lung requires administering a high dose to the site of infection. Herein, we investigated the novel inhalable silk-based microparticles as a promising approach to deliver high-payload ciprofloxacin (CIP) for NCFB therapy. Silk fibroin (SF) was applied to improve drug-payload and deposit efficiency of the dry powder particles. Mannitol was added as a mucokinetic agent. The dry powder inhaler (DPI) formulations of CIP microparticles were evaluated in vitro in terms of the aerodynamic performance, particle size distribution, drug loading, morphology, and their solid state. The optimal formulation (highest drug loading, 80%) exhibited superior aerosolization performance in terms of fine particle fraction (45.04 ± 0.84%), emitted dose (98.10 ± 1.27%), mass median aerodynamic diameter (3.75 ± 0.03 μm), and geometric standard deviation (1.66 ± 0.10). The improved drug loading was due to the electrostatic interactions between the SF and CIP by adsorption, and the superior aerosolization efficiency would be largely attributed to the fluffy and porous cotton-like property and low-density structure of SF. The presented results indicated the novel inhalable silk-based DPI microparticles of CIP could provide a promising strategy for the treatment of NCFB.


Impact of hepatobiliary service centralization on treatment and outcomes in patients with colorectal cancer and liver metastases.
Centralization of specialist surgical services can improve patient outcomes. The aim of this cohort study was to compare liver resection rates and survival in patients with primary colorectal cancer and synchronous metastases limited to the liver diagnosed at hepatobiliary surgical units (hubs) with those diagnosed at hospital Trusts without hepatobiliary services (spokes). The study included patients from the National Bowel Cancer Audit diagnosed with primary colorectal cancer between 1 April 2010 and 31 March 2014 who underwent colorectal cancer resection in the English National Health Service. Patients were linked to Hospital Episode Statistics data to identify those with liver metastases and those who underwent liver resection. Multivariable random-effects logistic regression was used to estimate the odds ratio of liver resection by presence of specialist hepatobiliary services on site. Survival curves were estimated using the Kaplan-Meier method. Of 4547 patients, 1956 (43·0 per cent) underwent liver resection. The 1081 patients diagnosed at hubs were more likely to undergo liver resection (adjusted odds ratio 1·52, 95 per cent c.i. 1·20 to 1·91). Patients diagnosed at hubs had better median survival (30·6 months compared with 25·3 months for spokes; adjusted hazard ratio 0·83, 0·75 to 0·91). There was no difference in survival between hubs and spokes when the analysis was restricted to patients who had liver resection (P = 0·620) or those who did not undergo liver resection (P = 0·749). Patients with colorectal cancer and synchronous metastases limited to the liver who are diagnosed at hospital Trusts with a hepatobiliary team on site are more likely to undergo liver resection and have better survival.


Protein-losing enteropathy in systemic lupus erythematosus.
Two patients with systemic lupus erythematosus (SLE) presented with anasarca, pleural effusions and severe hypoalbuminema. Both were demonstrated to have protein-losing enteropathy, a rare complication of SLE. Other causes of gastrointestinal protein loss were excluded. There were marked similarities in both cases including circulating ANF with speckled staining, anti-(U1)RNP antibodies and low serum complement levels. Complete remission was achieved in both with prednisolone. Anti-(U1)RNP may be a marker for a subset of SLE in which protein-losing enteropathy is a major manifestation.


Reactive oxygen species generators affect quality parameters and apoptosis markers differently in red deer spermatozoa.
Fe(2)(+)/ascorbate, hydrogen peroxide (H(2)O(2)), and hypoxanthine/xanthine oxidase (XOD) are commonly used for inducing oxidative stress on spermatozoa. A comparative study of these agents was carried out on thawed spermatozoa from red deer. First, we tested a high, medium, and low concentration of each agent: 100, 10, and 1 microM Fe(2)(+) (hydroxyl radical generator); 1 mM, 100, and 10 microM H(2)O(2); and 100, 10, and 1 mU/ml XOD (superoxide and H(2)O(2) generator), incubated at 37 degrees C for 180 min. Intracellular reactive oxygen species (ROS; H(2)DCFDA) increased with dose and time similarly for the three systems at each concentration level. Motility and mitochondrial membrane potential (Deltapsi(m)) were considerably decreased by H(2)O(2) (1 mM and 100 microM) and XOD (100 and 10 mU/ml). Only 1 mM H(2)O(2) reduced viability. The antioxidant Trolox (10 microM) reduced intracellular ROS, but could not prevent the H(2)O(2) or XOD effects. In a second experiment, YO-PRO-1 and M540 were used as apoptotic and membrane stability markers respectively. Only H(2)O(2) increased the proportion of apoptotic and membrane-destabilized spermatozoa. Catalase added to XOD prevented Deltapsi(m) loss, confirming that H(2)O(2) was the causative agent, not superoxide. In a third experiment, caspase activation was tested using the (FAM-VAD-FMK) probe. Viable spermatozoa with activated caspases could be detected in untreated samples, and only H(2)O(2) increased their proportion after 60 min. There were important differences between ROS generators, H(2)O(2) being the most cytotoxic. Although H(2)O(2) and XOD caused Deltapsi(m) dissipation, this was not reflected in increasing apoptotic markers.


Regulation of food intake by brown Leghorn cockerels in response to dietary dilution with kaolin.
The ability of adult Brown Leghorn cockerels to regulate food intake precisely was tested by measuring their responses to dietary dilutions with 100, 200, 300 and 400 g kaolin per kg diet. When changed from their original undiluted mash diet, cockerels continued gaining body weight with 100 and 200 g kaolin/kg dilutions, maintained weight with 300 g/kg and lost weight continuously with 400 g/kg. With all dilutions, the birds eventually adjusted weights of dry matter digested per day to the same levels as with the original basal diet. This took a few days with 100 g kaolin/kg, a week or more with 200 and 300 g/kg, and about three weeks with 400 g/kg. They achieved this mainly by increasing consumption of diluted food to maintain their original intake of basal diet. With 400 g kaolin/kg they were unable to compensate fully in amount eaten, but digestibility of the basal diet increased significantly. It is suggested that, given the right conditions, fowls may be able to compensate accurately when challenged with a range of dietary dilutions, the upper limit depending on the density of filler used.


Effects of rat urinary arginine esterases on rat kidney to release renin.
Urinary kallikrein has been reported to activate human plasma inactive renin. Our previous report suggests that rat urinary kallikrein releases active renin from rat renal cortical slices. Recently, McPartland et al. were able to separate the A esterase activity of male rat urine into two components: A1 and A2. To evaluate whether these other urine arginine esterases release renin from the kidney, esterases A1 and A2 were isolated from male rat urine using DEAE-Sephadex chromatography and superfused to rat renal cortical slices. The renin-stimulating action of these enzymes was compared to that of rat urinary kallikrein. Rat urinary kallikrein stimulated renin release in a dose-dependent fashion between 70--140 milliesterase units (mEU)/ml. Esterase A2 dose stimulated renin release significantly between 120--140 mEU/ml. However, esterase A1 did not stimulate renin release at concentrations between 70--140 mEU/ml. Although Trasylol completely abolished kallikrein and esterase A2 stimulated renin release, soybean trypsin inhibitor blocked only esterase A2-stimulated renin release. The physiological role and site of origin of the A1 and A2 esterases is unknown. However, similar to kallikrein, esterase A2 is a potent stimulator of renin release and may be physiologically important for the release and activation of renin in the kidney.


Hospital-Based Outpatient Direct Access to Physical Therapist Services: Current Status in Wisconsin.
Direct access to physical therapist services is available in all 50 states, with reported benefits including reduced health care costs, enhanced patient satisfaction, and no apparent compromised patient safety. Despite the benefits and legality of direct access, few data exist regarding the degree of model adoption, implementation, and utilization. The purposes of the study were: (1) to investigate the extent of implementation and utilization of direct access to outpatient physical therapist services in Wisconsin hospitals and medical centers, (2) to identify barriers to and facilitators for the provisioning of such services, and (3) to identify potential differences between facilities that do and do not provide direct access services. A descriptive survey was conducted. Eighty-nine survey questionnaires were distributed via email to the directors of rehabilitation services at Wisconsin hospitals and medical centers. The survey investigated facility adoption of the direct access model, challenges to and resources utilized during model implementation, and current barriers affecting model utilization. Forty-seven (52.8%) of the 89 survey questionnaires were completed and returned. Forty-two percent of the survey respondents (20 of 47) reported that their facility offered direct access to physical therapist services, but fewer than 10% of patients were seen via direct access at 95% of the facilities offering such services. The most frequently reported obstacles to model implementation and utilization were lack of health care provider, administrator, and patient knowledge of direct access; its legality in Wisconsin; and physical therapists' differential diagnosis and medical screening abilities. Potential respondent bias and limited generalizability of the results are limitations of the study. These findings apply to hospitals and medical centers located in Wisconsin, not to facilities located in other geographic regions. Respondents representing direct access organizations reported more timely access to physical therapist services, enhanced patient satisfaction, decreased organizational health care costs, and improved efficiency of resource utilization as benefits of model implementation. For organizations without direct access, not being an organizational priority, concerns from referral sources, and concerns that the physician-patient relationship would be negatively affected were noted as obstacles to model adoption.


Defining moments for conscious time and content.
The spatiotemporal scales of natural phenomena define the observational granularity needed for scientific characterization. In cognitive neurosciences, neural oscillations delineate temporal scales that may naturally provide the computational resolution for information processing in the brain. Do neural oscillations define moments for the perception of time?


In Vivo Effects of Retrobulbar Bimatoprost Injection on Orbital Fat.
Recent publications have reported the adverse effects of prostaglandin analogues on the periocular tissues. These medications may cause periorbital lipodystrophy, enophthalmos, and deepening of the superior sulcus deformity. While these effects may have adverse consequences for some patients, the atrophy of the periorbital fat may have a useful role in diseases that lead to orbital and periorbital fat hypertrophy such as thyroid eye disease. In this pilot study, the authors investigated the effects of retrobulbar bimatoprost injection on the intraocular pressure and orbital fat in a rat animal model. Three rats were sedated and intraocular pressure was measured. A 0.1 ml aliquot of bimatoprost was injected into the right orbit of all rats. In the left orbit, 0.1 ml of phosphate-buffered saline was injected as a control. Three weeks later, all rats were sedated and intraocular pressure was measured before euthanizing. Routine histologic staining was performed and thin sections through the intraconal orbital fat were obtained. Density of intraconal adipocytes was measured and adipocyte heterogeneity was determined using a computer image analysis algorithm. The specimens injected with bimatoprost demonstrated atrophy of orbital fat with significantly increased adipocyte density (p = 0.009) and heterogeneity (p = 0.008) when compared with control. Intraocular pressure was not significantly decreased at 3 weeks after injection of retrobulbar bimatoprost. In this pilot study, orbital injection of bimatoprost demonstrated atrophy of intraconal adipocytes when compared with control orbits injected with saline. The orbits injected with bimatoprost were noted to have smaller, more heterogeneous adipocytes that were densely packed in the intraconal space. The study limitations include the small sample size, which limited the ability for us to make conclusions about the effect on intraocular pressure. Nevertheless, the findings presented suggest that retrobulbar bimatoprost may present a nonsurgical alternative to induce atrophy of the orbital fat without inducing inflammation or hypotony.


Gastropericardial fistula as a delayed complication of a Nissen fundoplication.
A 41-year-old man presented to the emergency department with substernal chest pain and was found to have ST elevations in the inferior leads on his electrocardiogram. An emergent cardiac catheterization did not identify significant coronary narrowing. Computed tomography of the thorax demonstrated a pneumopericardium and a hiatal hernia. The patient had a complicated past surgical history, including a Nissen fundoplication and three additional surgeries for postoperative complications. An esophagram later revealed an ulcer and possible fistula, and the patient underwent gastropericardial fistula resection after the fistula failed to close with fibrin sealant application. Enteropericardial fistulas occur infrequently but have high morbidity and mortality rates. This possibility is much more likely in patients with prior gastroesophageal surgery, including laparoscopic Nissen fundoplication.


Thermal therapies in interventional MR imaging. Cryotherapy.
Cryotherapy of the brain is an old and well-established technique of functional and resective neurosurgery. With the use of modern imaging techniques such as MR imaging, which is ideally suited for diagnosis, planning, and monitoring of an ablation procedure, cryotherapy can become a modern alternative to other ablation techniques. In contrast to hyperthermal ablation tools such as laser or radiofrequency ablation, cryotherapy has specific potentials. First and most importantly, the freezing process ideally can be precisely monitored by MR imaging during the procedure without any specific temperature-sensitive pulse sequence. As shown in the experimental study, several techniques including conventional gradient echo sequences, ultrafast subsecond MR sequences, and MR fluoroscopy, are suited for monitoring the freezing process. Furthermore, the volume of the damaged tissue, as imaged by MR imaging, does not increase after completion of the ablation procedure. The extension of the ice corresponds well to the final, histologically confined necrosis and allows a high predictability of the resulting necrosis. Although not yet in clinical use, the combination of minimally invasive modern cryotherapy devices and ultrafast interventional MR techniques offer a promising alternative to other ablation techniques. In addition, it holds great promise for minimally invasive neurologic procedures in the near future. Further technical modifications and clinical studies, however, are necessary to establish the potential of this new treatment option.


GWAS meta-analyses clarify the genetics of cervical phenotypes and inform risk stratification for cervical cancer.
Genome-wide association studies (GWAS) have successfully identified associations for cervical cancer, but the underlying mechanisms of cervical biology and pathology remain uncharacterised. Our GWAS meta-analyses fill this gap, as we characterise the genetic architecture of cervical phenotypes, including cervical ectropion, cervicitis, cervical dysplasia, as well as up to 9229 cases and 490 304 controls for cervical cancer from diverse ancestries. Leveraging the latest computational methods and gene expression data, we refine the association signals for cervical cancer and propose potential causal variants and genes at each locus. We prioritise PAX8/PAX8-AS1, LINC00339, CDC42, CLPTM1L, HLA-DRB1 and GSDMB as the most likely candidate genes for cervical cancer signals, providing insights into cervical cancer pathogenesis and supporting the involvement of reproductive tract development, immune response and cellular proliferation/apoptosis. We construct a genetic risk score (GRS) that is associated with cervical cancer [hazard ratios (HR) = 3.1 (1.7-5.6) for the top 15% vs lowest 15% of individuals], and with other HPV- and immune-system-related diagnoses in a phenome-wide association study analysis. Our results propose valuable leads for further functional studies and present a GRS for cervical cancer that allows additional risk stratification and could potentially be used to personalise the conventional screening strategies for groups more susceptible to cervical cancer.


[HPLC using capillary monolithic column molecularly imprinted with composite metal organic frame for enrichment and detection of Ponceau 4R in Carthami flos].
To assess the performance of high-performance liquid chromatography (HPLC) combined with capillary monolithic column molecularly imprinted with metal organic frame (UiO-66-NH2@MIPs capillary monolithic column) for enrichment, purification and detection of Ponceau 4R in Carthami flos. UiO-66-NH2@MIPs monolithic columns were prepared via in situ polymerization, and the adsorption properties and morphology of the columns were characterized by HPLC, scanning electron microscopy (SEM) and infrared (IR) spectral analysis. HPLC with the prepared columns was performed for detecting the content of Ponceau 4R in Carthami flos samples. The UiO-66-NH2@MIPs system showed a good linearity for detecting Ponceau 4R over the concentration range of 0.1-10.0 μg/mL with a correlation coefficient > 0.9999 and a detection limit (S/N=3) of 2.7×10-4 μg/mL. The mean recovery of Ponceau 4R in Carthami flos samples ranged from 82.60% to 105.56%, and the intra-day and inter-day relative standard deviation (RSD) values ranged from 2.4% to 3.4%. The recycling experiment showed that the system could be reused for sensitive detection of Ponceau 4R in Carthami flos. The capacity of UiO-66-NH2@MIPs column was 0.178 μg/mg, which was superior to that of other monolithic columns (0.089, 0.080, and 0.111 μg/ mg), demonstrating that the addition of UiO-66-NH2 increased the adsorption capacity of the system. Under the optimized conditions, the UiO-66-NH2@MIPs-HPLC system had an enrichment factor of over 73 folds with obviously reduced interference by the impurity peaks. The UiO-66-NH2@MIPs column-HPLC system has much better performance for enrichment, purification and detection of Ponceau 4R in Carthami flos than direct HPLC.


Pattern of Care Before Presentation Among the Psychiatric Emergency Cases at a Tertiary Health Care Center in Nigeria.
To determine the pattern of care sought in cases of psychiatric emergency before presentation to a tertiary health care center. Consecutive recruitment of 180 emergency psychiatric cases, which comprised a total of 156 patients, presenting to the accident and emergency unit of the University of Benin Teaching Hospital (UBTH), Edo State, Nigeria, was conducted from June 2008 to January 2009. A structured instrument was used to gather the patients' information including their sociodemographic characteristics, their care before presentation, and the relations accompanying them to the hospital. The mean ± SD patient age was 33.82 ± 12.64 years, with an age range of 18-73 years and a modal age of 23 years. The male to female ratio was 1:1.05. Of the patients, 121 (77.6%) were not married, while 35 (22.4%) were married. Most identified as Christian (96.2%). The majority of the patients (70.0%) presented to the hospital through self-referral. Eighty (44.4%) of the patients had not sought any treatment before coming to UBTH. Forty-seven patients (26.1%) had sought care in churches, 39 (21.7%) had sought treatment in other hospitals, and 12 (6.7%) had sought traditional care before presenting to UBTH. Seventy-four patients (41.1%) were accompanied by parents and 44 (24.4%) were accompanied by siblings, while the spouse accompanied 23 (12.8%) patients. Most patients with psychiatric emergencies at UBTH prefer to present directly to the tertiary health care center in Benin City, and they are usually supported by their immediate family members.


A Natural Lipotrisaccharide and Its Derivatives Selectively Lyse Streptococcus pneumoniae via Interaction with Cell Membrane.
A natural lipotrisaccharide (NP000778, 1a), a new triglycosidic tri-O-substituted glycolipid isolated from the Morinda citrifolia plant, and its chemical derivatives were identified to be active against major Gram-positive pathogens, particularly Streptococcus pneumoniae. Additional evidence indicated that 1a and its synthetic derivatives exerted their bactericidal activities against S. pneumoniae by selectively targeting the bacterial membrane, leading to the rapid lysis of the pneumococci. Efficient synthesis of 1a and its derivatives was performed using an application of the intramolecular aglycon delivery (IAD) reaction to establish its structure-activity relationships (SARs). SAR analysis indicated that trisaccharide glycolipid compounds showed good selectivity and high potency against S. pneumoniae. These compounds contain a linear chain with a chain length from C3 to C9 at the 2-position (R1) and 4'-position (R3), as well as a 2-methyl butyryl group at the 3'-position (R2), without an aza substitution in the lipid chain. This is the first lipotrisaccharide identified with potent bactericidal activity via interaction with cell membrane. The results reported herein offer a valuable guideline for the design of glycolipid derivatives that selectively target pathogenic bacteria.


Thermodynamics of beta-amyloid fibril formation.
Amyloid fibers are aggregates of proteins. They are built out of a peptide called beta-amyloid (Abeta) containing between 41 and 43 residues, produced by the action of an enzyme which cleaves a much larger protein known as the amyloid precursor protein (APP). X-ray diffraction experiments have shown that these fibrils are rich in beta-structures, whereas the shape of the peptide displays an alpha-helix structure within the APP in its biologically active conformation. A realistic model of fibril formation is developed based on the 17 residues Abeta12-28 amyloid peptide, which has been shown to form fibrils structurally similar to those of the whole Abeta peptide. With the help of physical arguments and in keeping with experimental findings, the Abeta12-28 monomer is assumed to be in four possible states (i.e., native helix conformation, beta-hairpin, globular low-energy state, and unfolded state). Making use of these monomeric states, oligomers (dimers, tertramers, and octamers) were constructed. With the help of short, detailed molecular dynamics calculations of the three monomers and of a variety of oligomers, energies for these structures were obtained. Making use of these results within the framework of a simple yet realistic model to describe the entropic terms associated with the variety of amyloid conformations, a phase diagram can be calculated of the whole many-body system, leading to a thermodynamical picture in overall agreement with the experimental findings. In particular, the existence of micellar metastable states seem to be a key issue to determine the thermodynamical properties of the system.


Are elevated circulating intercellular adhesion molecule 1 levels more strongly predictive of diabetes than vascular risk? Outcome of a prospective study in the elderly.
The aim of this prospective study was to determine whether circulating intercellular adhesion molecule (ICAM) 1, as a potential surrogate of 'endothelial activation', is more strongly associated with risk of vascular events than with incident diabetes. We related baseline ICAM-1 levels to vascular events (866 CHD and stroke events in 5,685 participants) and incident diabetes (292 in 4,945 without baseline diabetes) in the elderly over 3.2 years of follow-up. ICAM-1 levels correlated positively with triacylglycerol but negatively with LDL- and HDL-cholesterol. ICAM-1 levels were higher in those who developed diabetes (388.6 +/- 1.42 vs 369.4 +/- 1.39 ng/ml [mean+/-SD], p = 0.011) and remained independently associated with new-onset diabetes (HR 1.84, 95% CI 1.26-2.69, p = 0.0015 per unit increase in log[ICAM-1] after adjusting for classical risk factors and C-reactive protein). By contrast, ICAM-1 levels were not significantly (p = 0.40) elevated in those who had an incident vascular event compared with those who remained event-free, and corresponding adjusted risk associations were null (HR 0.98, 95% CI 0.80-1.22, p = 0.89) in analyses adjusted for other risk factors. We show that elevated ICAM-1 levels are associated with risk of incident diabetes in the elderly at risk, despite no association with incident cardiovascular disease risk. We suggest that perturbations in circulating ICAM-1 levels are aligned more towards diabetes risk.


Performance intensification of constructed wetland technology: a sustainable solution for treatment of high-strength industrial wastewater.
The objectives of this study were to: (1) assess the intensification of chemical oxygen demand (COD) and phosphate (PO4-P) removal; and (2) generate a set of rate constants of COD degradation (kCOD) and phosphate (kPO4-P) removal for the treatment of industrial wastewater (WW) using intensified adsorption beds. Two horizontal subsurface flow constructed wetlands (HSSFCWs) filled with coal ash and alum sludge and two conventional HSSFCWs packed with gravels were operated with different loadings of COD and PO4-P at a hydraulic retention time (HRT) of 24 hrs at water depth of 0.40 m. The bed performance was analysed for COD and PO4-P removal efficiency. The intensified HSSFCWs outperformed the control beds by a mean COD and PO4-P removal efficiency of 43 and 49%, respectively. The progression of COD and PO4-P removal along the system was fitted into the first-order plug flow model (K-C model). In this study the kCOD values ranged from 0.36 to 0.65 m/d with a mean of 0.46 ± 0.08 m/d (n = 30). The kPO4-P values ranged from 0.74 to 1.76 m/d and averaged to 1.23 ± 0.37 m/d (n = 30), irrespective of the condition applied. Hence, these data can be used for future projects using HSSFCWs to treat industrial wastewater.


DJMol: An open-source modeling platform for computational chemistry and materials science with a Python interpreter.
We present a modular and extendable software suite, DJMol, for performing molecular simulations and it is demonstrated with DFTB+, Siesta, Atomic Simulation Environment, and OpenMD codes. It supports many of the standard features of an integrated development environment and consists of a structure builder and viewer, which could be connected with these electronic structure codes along with a set of data analyzers. This program comprises Java and Python modules and its libraries to carry out a different set of modeling tasks in materials science and chemistry. By adopting a Python interpreter into the software, a range of scriptable Python codes, such as Pymatgen can be incorporated into this programmable modeling platform. DJMol, through its common application programming interface (API), supports multiple modeling codes in the backend and several post-processing tools. It benefits an experienced user by increasing efficiency, while a nonexpert user by easy to use API.


Eukaryotic chromosome DNA replication: where, when, and how?
DNA replication is central to cell proliferation. Studies in the past six decades since the proposal of a semiconservative mode of DNA replication have confirmed the high degree of conservation of the basic machinery of DNA replication from prokaryotes to eukaryotes. However, the need for replication of a substantially longer segment of DNA in coordination with various internal and external signals in eukaryotic cells has led to more complex and versatile regulatory strategies. The replication program in higher eukaryotes is under a dynamic and plastic regulation within a single cell, or within the cell population, or during development. We review here various regulatory mechanisms that control the replication program in eukaryotes and discuss future directions in this dynamic field.


Arsenic trioxide treatment of rabbit liver VX-2 carcinoma via hepatic arterial cannulation-induced apoptosis and decreased levels of survivin in the tumor tissue.
To investigate the role of tumor apoptosis-inhibitory protein survivin in arsenic trioxide-induced apoptosis in VX-2 carcinoma in the rabbit liver by means of transcatheter arterial chemoembolization. Sixteen rabbits with 32 implanted hepatic VX-2 tumors were randomly divided into two groups. The experimental group received 2 mg of arsenic trioxide and 1 mL of ultra-fluid lipiodol co-injected via hepatic arterial cannulation and the control group received only 1 mL of lipiodol. Animals were sacrificed 3 weeks after trans-catheterial arterial chemoembolization. Tumor tissue and tumor-peripheral tissue were collected for analysis. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling staining was used to assess tumor cells apoptosis. Immunohistochemistry was used to assess the presence of survivin protein. Reverse transcription polymerase chain reaction was used to determine the expression of survivin gene. The number of apoptotic cells significantly increased in the tumor tissue (5.20 ± 0.60%) compared to tumor-peripheral tissue (1.29 ± 0.42%) of the arsenic trioxide-treated group. Survivin expression levels in the tumor tissue were significantly reduced in arsenic trioxide-treated group (7.68 ± 0.65) compared to the control group (35.30 ± 4.63). Transcatheter arterial chemoembolization with arsenic trioxide induced apoptosis of VX-2 carcinoma, in which tumor apoptosis-inhibitory protein survivin may have played a role.


Acute mechanical intestinal obstruction in children at zinder national hospital, Niger: Aetiologies and prognosis.
To describe the aetiological and prognostic aspects of acute mechanical intestinal obstruction (AMIO) in children at Zinder National Hospital (Niger). This was a cross-sectional study on a period to January 2013-June 2015. The database included all children under 15 years of age with a surgical diagnosis of mechanical intestinal obstruction. P < 0.05 was considered statistically significant for analysis. AMIOs represent 21.78% (n = 78) of child digestive surgical emergencies (n = 358). Median age was 12 months (range: 1 day-15 years). Fifteen (19.23%) were neonates and sixty children (76.92%) had ≤60 months. The sex ratio (male/female) was 2.8. The mean time from onset to presentation was 39.96 ± 36.22 h. Intussusception and strangulated hernias were the main causes of AMIO with, respectively, 43.59% (n = 34) and 29.48% (n = 23). Anorectal malformations represent 17.95% (n = 14) of cases of AMIO. Intestinal resection was made in 22.08% and colostomy in 19.23% of patients. The average length of hospital stay was 6.44 ± 4.30 days. The post-operative complications were recorded in 26 patients (33.33%), mostly surgical site infections. Overall mortality of AMIO was 15.38% (n = 12). It was higher in the neonates (33.33%) (P = 0.032). Deaths were associated with delay of admission (P = 0.0005) and waiting time for surgery (P = 0.019). Intussusception and strangulated hernia are the most common cause of AMIO in children. Diagnostic and therapeutic delays, lack of paediatric intensive care and post-operative complications are prognostic factors.


Assessment of the plasticizer exposure of hospital workers regularly handling medical devices: A pilot study.
Plastic medical devices, e.g. infusion sets, blood bags or tubing material, that are used manifold in the medical treatment of hospital patients, usually contain considerable amounts of plasticizers. Whereas several studies showed highly elevated inner plasticizer levels of patients treated with plasticized medical devices, little is known about the exposure situation of hospital staff. The present pilot study aimed to evaluate the urinary plasticizer metabolite levels of selected hospital workers of the blood bank (medical technical assistants, MTA) and of perfusionists that are regularly handling plasticized medical devices in order to estimate the work-related amount of the inner individual plasticizer exposure. The study subjects were asked to collect pre- and post-shift spot urine samples over the course of a working week, that were subsequently analyzed for selected urinary metabolites of the plasticizers DEHP, DINCH, DEHTP and TEHTM. Although the observed differences were rather low, a differentiated approach revealed a perceptible impact of the respective workplace environment on the individual urinary plasticizer metabolite levels. Thus, the group of blood bank MTA showed significantly elevated increment levels of urinary DEHP and DINCH metabolites, while the group of perfusionists, showed a considerable higher detection frequency of the main urinary TEHTM metabolite. All in all, however, it can be cautiously concluded by the results of the presented pilot study that a regular handling of plasticized medical devices by hospital employees (via inhalation or dermal contact) contributes demonstrably but yet only marginally to the individual internal plasticizer exposure.


Leukaemia inhibitory factor modulates the differentiation of granulosa cells during sheep in vitro preantral to antral follicle development and improves oocyte meiotic competence.
In vitro follicle development from cryopreserved ovarian tissue could become an invaluable assisted reproduction technology for women with early ovarian failure. The challenge lies in producing, from small follicles present in the ovarian cortex, high-quality mature oocytes able to sustain embryo development. In vivo, an optimal combination of hormones and other factors coordinates the development of follicles and their enclosed oocyte. We have investigated the effect of the leukaemia inhibitory factor (LIF) cytokine, alone or in combination with FSH, on sheep in vitro follicle development from the preantral stage onwards. LIF did not alter follicle growth or antrum formation, but it modulated the differentiation of granulosa cells, as revealed by decreased production of anti-Müllerian hormone and abolished FSH-induced stimulation of oestradiol secretion. This modulatory role was also reflected in the abundance of mRNA from 35 genes, analysed by reverse-transcription coupled to microfluidic quantitative PCR. LIF stimulated or at least maintained the expression of genes involved in the dialogue between the oocyte and granulosa cells, through gap junctions (GJA4 encoding connexin 37) or paracrine signalling (Bone morphogenetic protein 15, KIT ligand and their receptors). Finally, the presence of both LIF and FSH during follicle growth strongly improved oocyte meiotic competence: most oocytes (56%) underwent subsequent nuclear maturation, a significant increase compared with their counterparts from follicles of similar size (550-900 µm) cultured with FSH only (28%) or developed in vivo (9%). Their ability to sustain embryo development remains to be evaluated. Combined supplementation with FSH and LIF certainly merits investigation with human follicles.


Suppression of WDM four-wave mixing crosstalk in fibre optic parametric amplifier using Raman-assisted pumping.
We perform an extensive numerical analysis of Raman-Assisted Fibre Optical Parametric Amplifiers (RA-FOPA) in the context of WDM QPSK signal amplification. A detailed comparison of the conventional FOPA and RA-FOPA is reported and the important advantages offered by the Raman pumping are clarified. We assess the impact of pump power ratios, channel count, and highly nonlinear fibre (HNLF) length on crosstalk levels at different amplifier gains. We show that for a fixed 200 m HNLF length, maximum crosstalk can be reduced by up to 7 dB when amplifying 10x58Gb/s QPSK signals at 20 dB net-gain using a Raman pump of 37 dBm and parametric pump of 28.5 dBm in comparison to a standard single-pump FOPA using 33.4 dBm pump power. It is shown that a significant reduction in four-wave mixing crosstalk is also obtained by reducing the highly nonlinear fibre interaction length. The trend is shown to be generally valid for different net-gain conditions and channel grid size. Crosstalk levels are additionally shown to strongly depend on the Raman/parametric pump power ratio, with a reduction in crosstalk seen for increased Raman pump power contribution.


Validating accelerometry estimates of energy expenditure across behaviours using heart rate data in a free-living seabird.
Two main techniques have dominated the field of ecological energetics: the heart rate and doubly labelled water methods. Although well established, they are not without their weaknesses, namely expense, intrusiveness and lack of temporal resolution. A new technique has been developed using accelerometers; it uses the overall dynamic body acceleration (ODBA) of an animal as a calibrated proxy for energy expenditure. This method provides high-resolution data without the need for surgery. Significant relationships exist between the rate of oxygen consumption (V̇O2 ) and ODBA in controlled conditions across a number of taxa; however, it is not known whether ODBA represents a robust proxy for energy expenditure consistently in all natural behaviours and there have been specific questions over its validity during diving, in diving endotherms. Here, we simultaneously deployed accelerometers and heart rate loggers in a wild population of European shags (Phalacrocorax aristotelis). Existing calibration relationships were then used to make behaviour-specific estimates of energy expenditure for each of these two techniques. Compared with heart rate-derived estimates, the ODBA method predicts energy expenditure well during flight and diving behaviour, but overestimates the cost of resting behaviour. We then combined these two datasets to generate a new calibration relationship between ODBA and V̇O2 that accounts for this by being informed by heart rate-derived estimates. Across behaviours we found a good relationship between ODBA and V̇O2 Within individual behaviours, we found useable relationships between ODBA and V̇O2 for flight and resting, and a poor relationship during diving. The error associated with these new calibration relationships mostly originates from the previous heart rate calibration rather than the error associated with the ODBA method. The equations provide tools for understanding how energy constrains ecology across the complex behaviour of free-living diving birds.


Physiological Response to Opioids.
The clinical setting in which women's health physicians practice, whether as generalist, obstetricians and gynecologists, or subspecialists, dictates our frequent clinical interaction with "pain." Opioid-containing medications are frequently prescribed within our specialty as a means of immediate pain relief. Opioid-containing medication causes a deep physiological alteration of several systems resulting in potential harm to acute and chronic opioid users. This article includes a thorough system-based review of opioid-containing medications on physiological systems. Women's health providers should have an in-depth understanding of such reverberations on patients' wellbeing to maintain the safest level of care. A solid grasp of physiological repercussions of opioid use would encourage physicians to seek alternative treatment options. Such practice is essential in curbing the opioid epidemic our patients are facing.


A novel hybrid tobacco product that delivers a tobacco flavour note with vapour aerosol (Part 1): Product operation and preliminary aerosol chemistry assessment.
Vapour products have demonstrated potential to be a lower-risk alternative to cigarettes. The present study describes a novel hybrid tobacco product that combines a warm aerosol stream generated by an electronic vaporisation mechanism with tobacco top flavour from cut tobacco. During operation, the aerosol stream released from the vapour cartomiser is passed through a bed of blended cut tobacco by the puffing flow, elevating the tobacco temperature and eluting volatile tobacco flavour components. A preliminary but comprehensive analysis of the aerosol composition of the hybrid tobacco product found that emissions were dominated by the control vapour formulation. In non-targeted chemical screening, no detectable difference in GC scans was observed between the hybrid tobacco product and the control vapour product. However, a sensorially elevated tobacco flavour was confirmed by a consumer sensory panel (P < 0.05). In a targeted analysis of 113 compounds, either identified by regulatory bodies as potential toxicants in cigarette smoke or formed from electronic vapour products, only 26 were quantified. The novel action of tobacco heating and liquid aerosolisation produced classes and levels of toxicants that were similar to those of the control vapour product, but much lower than those of a Kentucky 3R4F reference cigarette. For nine toxicants mandated by the WHO Study Group on Tobacco Product Regulation for reduction in cigarette emissions, the levels were 91%-99% lower per puff in the hybrid tobacco product aerosol than in 3R4F smoke. Overall, the novel hybrid tobacco product provides a sensorially enhanced tobacco flavour, but maintains a toxicant profile similar to its parent vapour product with relatively low levels of known cigarette smoke toxicants.


The Effect of Guided Growth Surgery on Langenskiold Stage and Mechanical Axis in Early-Onset Blount Disease: A Retrospective Case Series.
Our understanding of the efficacy of guided growth surgery with tension-band plating (TBP) in early-onset Blount disease is evolving. Preliminary work has demonstrated that TBP can normalize the mechanical axis, yet its effect on Langenskiöld stage (LS) has not previously been reported. The primary outcome of this study was improvement in LS after TBP. Secondary outcomes were improvement in LS at most recent follow-up and improvement in mechanical axis deviation (MAD), mechanical medial proximal tibial angle, and mechanical lateral distal femoral angle at treatment completion and most recent follow-up. A retrospective review was done of patients with early-onset Blount disease treated with TBP between January 1, 2010, and December 31, 2019, across two institutions. Inclusion criteria were a radiographic diagnosis of early-onset Blount disease (LS changes present), surgery with TBP, and follow-up beyond implant removal. Radiographs before surgery, at removal of hardware (ROH), and at most recent follow-up were evaluated. Twenty-five limbs in 16 children who underwent TBP at a mean age of 5.8 ± 2.3 years were included. Implants were in situ a mean of 1.9 ± 0.7 years. The mean follow-up after ROH was 3.6 ± 1.4 years. LS ranged from 1 to 5 preoperatively with 14 of 25 limbs (56%) staged ≥3. LS improved in 15 of 25 limbs (60%) at ROH and in 21 of 25 limbs (84%) at most recent follow-up. Langenskiöld changes resolved in 7 of 25 limbs (28%) at most recent follow-up. Preoperatively, the MAD was varus in all limbs, but at ROH, the MAD had improved in 22 of 23 limbs with neutral or valgus alignment in 20 of 23 limbs (87%). At most recent follow-up, 16 of 23 limbs (70%) maintained improved alignment. There was improvement/resolution of LS and varus deformity in early-onset Blount disease in most patients who underwent TBP. Based on these results, TBP for early-onset Blount disease should be the first-line surgical treatment. IV.


Electron Paramagnetic Resonance Study of the Free Radical Scavenging Capacity of Curcumin and Its Demethoxy and Hydrogenated Derivatives.
The quantitative free radical scavenging capacity of curcumin and its demethoxy derivatives (demethoxycurcumin (Dmc) and bisdemethoxycurcumin (Bdmc)) and hydrogenated derivatives (tetrahydrocurcumin (THC), hexahydrocurcumin (HHC) and octahydrocurcumin (OHC)) towards 1,1-diphenyl-2-picryl hydrazyl (DPPH), nitric oxide radical (NO), hydroxyl radical (HO(·)) and superoxide anion radical (O2(·)) were investigated by electron paramagnetic resonance (EPR) spectroscopy. One mole of the hydrogenated derivatives scavenged about 4 mol of the DPPH radical, while curcumin and Dmc scavenged about 3 mol of the DPPH radical. Curcumin and THC showed moderate scavenging activity towards NO, yielding 200 mmol of NO scavenged per 1 mol of the scavenger. In contrast, curcumin and its derivatives showed very low scavenging activity towards HO(·) and O2(·), yielding approximately only 3-12 mmol scavenged per 1 mol of the tested compounds. Our results suggest that curcumin and its derivatives principally act as chain breaking antioxidants rather than as direct free radical scavengers. Furthermore, we showed that the ortho-methoxyphenolic group and the heptadione linkage of these molecules greatly contributed to their DPPH and NO scavenging activity.


Multiple evidences reveal new species and a new record of smelly Gymnopus (Agaricales, Omphalotaceae) from China.
Gymnopus sect. Impudicae is a poorly studied group around the world. However, it is well known for its pungent smell-a total of five species from China belonging to sect. Impudicae were recorded, and included four species new to science-G. epiphyllus, G. cystidiosus, G. subdensilamellatus, and G. subpolyphyllus-which were delimited and proposed based on morphological and molecular evidences, and one new record from Henan, Jiangxi, and Gansu Province, China-G. densilamellatus. Detailed descriptions and illustrations were presented as well as comparisons to similar species. Phylogenetic analysis inferred from the ITS and nLSU dataset supported the Gymnopus as a monophyletic genus which was defined by Oliveira et al., and the novel species grouped as separate lineages within it. A Key to the reported species of Gymnopus sect. Impudicae is also provided.


Receptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1.
Gene-based therapies represent a promising therapeutic paradigm for the treatment of HIV-1, as they have the potential to maintain sustained viral inhibition with reduced treatment interventions. Such an option may represent a long-term treatment alternative to highly active antiretroviral therapy. Methods: We previously described a therapeutic approach, referred to as transcriptional gene silencing (TGS), whereby small noncoding RNAs directly inhibit the transcriptional activity of HIV-1 by targeting sites within the viral promoter, specifically the 5' long terminal repeat (LTR). TGS differs from traditional RNA interference (RNAi) in that it is characterized by concomitant silent-state epigenetic marks on histones and DNA. To deliver TGS-inducing RNAs, we developed functional RNA conjugates based on the previously reported dual function of the gp120 (A-1) aptamer conjugated to 27-mer Dicer-substrate anti-HIV-1 siRNA (dsiRNA), LTR-362. Results: We demonstrate here that high levels of processed guide RNAs localize to the nucleus in infected T lymphoblastoid CEM cell line and primary human CD4+ T-cells. Treatment of the aptamer-siRNA conjugates induced TGS with an ~10-fold suppression of viral p24 levels as measured at day 12 post infection. To explore the silencing efficacy of aptamer-siRNA conjugates in vivo, HIV-1-infected humanized NOD/SCID/IL2 rγnull mice (hu-NSG) were treated with the aptamer-siRNA conjugates. Systemic delivery of the A-1-stick-LTR-362 27-mer siRNA conjugates suppressed HIV-1 infection and protected CD4+ T cell levels in viremia hu-NSG mice. Principle conclusions: Collectively these data suggest that the gp120 aptamer-dsiRNA conjugate design is suitable for systemic delivery of small RNAs that can be used to suppress HIV-1.