Preoperative CT imaging as a tool to predict incisional hernia outcomes following abdominal wall reconstruction: A retrospective cohort analysis.
Ventral wall hernia often causes significant morbidity and requires complex abdominal wall reconstruction (AWR). This study aims to determine whether subcutaneous abdominal fat thickness (AFT) measured with preoperative CT scans could predict postoperative outcomes in patients undergoing AWR. A retrospective cohort study was conducted on all patients who underwent AWR at our institution between 2009 and 2021, with a minimum follow-up of 12 months. Using preoperative CT scans, AFT was measured at the xiphoid process, umbilicus, and pubic tubercle, as well as the hernia dimensions. Demographic, operative, and surgical outcome data were also collected and analyzed using statistical tests. The results showed that 9 of 101 patients (8.9%) experienced hernia recurrence. Smoking was associated with an increased risk of hernia recurrence (p < 0.001) with a predictive odds ratio (OR) of 18.27 (p = 0.041). Increased AFT at the xiphoid (p = 0.005), umbilicus (p < 0.001), and pubic tubercle (p < 0.001) were also associated with hernia recurrence and risk of infection. Only AFT at the pubic tubercle reached significance in the regression model predicting recurrence (OR=1.10; p = 0.030) and infection (OR=1.04; p = 0.021). A cut-off value of 67 mm was associated with a positive predictive value of 42.14% (sensitivity of 67% and specificity of 91%). Hernia defect area was not associated with risk of recurrence or infection. Smoking and increased AFT at the pubic tubercle are significant predictive factors for recurrence and infection in patients undergoing AWR, and preoperative optimization should focus on reducing these factors.


Lower Adherence to a Mediterranean Diet Is Associated with High Adiposity in Community-Dwelling Older Adults: Results from the Longevity Check-Up (Lookup) 7+ Project.
High adiposity impacts health and quality of life in old age, owing to its association with multimorbidity, decreased physical performance, and frailty. Whether a high adherence to a Mediterranean diet (Medi-Diet) is associated with reduced body adiposity in older adults is unclear. The present study was conducted to assess the prevalence of high adiposity in a large sample of community-dwelling older adults. We also explored the relationship between whole-body adiposity estimated through relative fat mass (RFM) and Medi-Diet adherence. Data were obtained from the Longevity Check-up 7+ (Lookup7+) project database. RFM was estimated from anthropometric and personal parameters using a validated equation. RFM was categorized as high if ≥40% in women and ≥30% in men. Information on diet was collected using a food frequency questionnaire, while Medi-Diet adherence was assessed through a modified version of the Medi-Lite scoring system. Analyses were conducted in 2092 participants (mean age 73.1 ± 5.9 years; 53.4% women). Mean RFM was 39.6 ± 5.14% in women and 29.0 ± 3.6% in men. High adiposity was found in 971 (46.4%) participants and was more frequent in those with a low (54.2%) or moderate (46.4%) Medi-Diet adherence compared with the high-adherence group (39.7%, p < 0.001). Logistic regression indicated that older adults with high Medi-Diet adherence were less likely to have a high RFM. Other factors associated with a greater risk of having high adiposity were older age, female sex, and physical inactivity. Our findings support an association between healthy lifestyles, including a greater adherence to a Mediterranean-style diet, and lower body adiposity in older adults.


Learning processes in the human newborn. Sensitization, habituation, and classical conditioning.
Data have been presented to document that the human newborn is a conditionable organism. Babies in the first days of life possess sensitivity to stimulation in all sensory modalities, an unconditioned repertoire of responses to some of these sensory stimuli, and a capacity for associating simultaneously presented stimuli. Thus a perceived but previously neutral stimulus with respect to the elicitation of some particular behavior can itself become an effective stimulus through paired associations with an effective stimulus, and may now produce a response similar to the initially effective stimulus. For such a phenomenon to occur, the organism must be capable of remembering. The duration of memory is empirically demonstrable through probes or tests with the neutral stimulus, at various time intervals following the last experience of the pairing. Besides engaging in classical conditioning involving transfer of elicitability from an effective stimulus to a previously ineffective stimulus (or its converse, as in extinction), demonstrating that human newborns do learn, babies are also demonstrably capable habituators. They exhibit diminution of response intensity or frequency to repetitively presented, and particularly closely spaced and essentially innocuous, stimuli. Newborns also exhibit generalized sensitization to stimulation such that, when neonates are aroused, stimuli will nondiscriminatively elicit behaviors. It is thus important that appropriate controls for nonconditioning processes, which may also involve change in behavior through experience, be included in any demonstrations that purport to show the conditionability of the newborn.


Experimental observations on the human arm motion planning under an elbow joint constraint.
This paper seeks to define the governing strategies by which the human central nervous system (CNS) finds optimal solutions for an arm reaching motion, when an elbow joint is constrained. The compensated arm reaching motion under the joint kinematic constraint is observed by human experiments. We present an experimental protocol, where subjects perform point-to-point reaching tasks with a lightweight elbow brace to restrict the elbow kinematics with minimal effect on the arm dynamics. The human compensatory strategy is analyzed in terms of hand path kinematics (i.e. spatial and temporal characteristics) and the arm postural configuration. The spatial and temporal characteristics of hand path are approximated by the Euclidean geodesic curves and the well known bell-shaped smooth profile, respectively. Furthermore, the contribution of each joint degree-of-freedom (DOF) motion is discussed and its relation to the arm posture selection is elaborated.


Morphology-guided radiosurgery treatment planning and optimization for multiple isocenters.
This work merges two distinct fields, 3D morphology and ionizing radiation dosimetry, to solve the problem of 3D-treatment planning and optimization in stereotactic radiosurgery. In Leksell Gamma Knife radiosurgery, dose delivery is based on the unit "shot," a dose distribution approximately spherical in shape. Multiple shots, or isocenters, are used in Gamma Knife treatment to deliver a conformal dose to an irregular radiosurgical target. The medial axis transformation, or skeleton, of the target, which uniquely characterizes the target volume and shape, is used to determine the optimal shot positions (isocenters), sizes (collimator helmet size and dosimetric weight), and the total number of shots that will deliver a conformal dose distribution to the target. The skeletonization approach reduces a complicated 3D-optimization problem to 1D searching with potential savings in computation time and mathematical complexity. In addition, optimization based on target shape replicates and automates manual treatment planning. This approach makes the process easily understandable. The relationship between skeleton discs and the dose distributions they predict is discussed. Results of optimal plans and corresponding dose distributions are presented. This approach is generally applicable to other types of multi-isocentric stereotactic radiosurgery techniques.


Benign clinical behavior of immature mediastinal teratoma in infancy and childhood: report of two cases and review of the literature.
Germ cell tumors of the mediastinum can be divided into three categories: 1) mature teratomas which have all elements at a mature level; 2) immature teratomas which are similar to the mature teratomas, but also contain immature epithelial or mesenchymal elements or blastema; and 3) embryonal tumors which contains elements which are recognized as dysgerminoma, embryonal carcinoma with or without yolk sac elements, and choriocarcinoma. Immature teratomas are the rarest type, accounting for only about 1% of mediastinal teratomas. Two cases of immature teratoma of the mediastinum occurring in infants are reported. One tumor was completely excised. The child is well without evidence of disease two years later. The other immature teratoma was unresectable. Biopsy showed it to be similar to the teratoma that was excised. No postoperative treatment was given. The tumor has not changed appreciably in size, but the child has grown normally for six years so that the tumor mass, which initially filled his chest, is now evidenced as mediastinal widening. A review of the reported cases of immature teratomas in the mediastinum shows that the prognostic value of the histologic appearance of these tumors has not been developed to the same degree as it has for teratomas in the ovary or the sacrococcygeal region. The immature teratomas that occur in infants behave as mass lesions as do the mature teratomas. Immature teratomas in the mediastinum of children in their late teens and in young adults behave as highly malignant tumors similar to the embryonal carcinomas.


Long-term follow-up after cancer rehabilitation using high-intensity resistance training: persistent improvement of physical performance and quality of life.
The short-term beneficial effects of physical rehabilitation programmes after cancer treatment have been described. However, little is known regarding the long-term effects. The purpose of this study was to investigate the long-term effects of high-intensity resistance training compared with traditional recovery. A total of 68 cancer survivors who completed an 18-week resistance training programme were followed for 1 year. During the 1-year follow-up, 19 patients dropped out (14 due to recurrence of cancer). The remaining 49 patients of the intervention group were compared with a group of 22 patients treated with chemotherapy in the same period but not participating in any rehabilitation programme. Outcome measures were muscle strength, cardiopulmonary function, fatigue, and health-related quality of life. One year after completion of the rehabilitation programme, the outcome measures in the intervention group were still at the same level as immediately after rehabilitation. Muscle strength at 1 year was significantly higher in patients who completed the resistance training programme than in the comparison group. High-intensity resistance training has persistent effects on muscle strength, cardiopulmonary function, quality of life, and fatigue. Rehabilitation programmes for patients treated with chemotherapy with a curative intention should include high-intensity resistance training in their programme.


Presetting of chromatin structure and transcription factor binding poise the human GADD45 gene for rapid transcriptional up-regulation.
GADD45 has been suggested to coordinate cell cycle regulation with the repair of DNA damage following ionizing radiation (IR). Although the GADD45 gene is transcriptionally up-regulated in response to IR, alterations in in vivo transcription factor (TF) binding or chromatin structure associated with up-regulation have not been defined. To understand how chromatin structure might influence TF binding and GADD45 up-regulation, key regulatory regions of the gene were identified by in vivo DNase I hypersensitivity (HS) analysis. Chromatin structure and in vivo TF binding in these regions were subsequently monitored in both non-irradiated and irradiated human ML-1 cells. In non-irradiated cells expressing basal levels of GADD45, the gene exhibited a highly organized chromatin structure with distinctly positioned nucleosomes. Also identified in non-irradiated cells were DNA-protein interactions at octamer binding motifs and a CCAAT box in the promoter and at consensus binding sites for AP-1 and p53 within intron 3. Upon irradiation and a subsequent 15-fold increase in GADD45 mRNA levels, neither the chromatin structure nor the pattern of TF binding in key regulatory regions was altered. These results suggest that the GADD45 gene is poised for up-regulation and can be rapidly induced independent of gross changes in chromatin structure or TF binding.


Production and Study of Immunochemical Properties of Stabilized Env Trimer of Recombinant Form CRF63_02A6 of HIV-1.
Stabilized trimers of the HIV-1 envelope glycoprotein Env are capable of inducing a potent and sustained broadly neutralizing antibody response in laboratory animals and therefore are attractive targets for anti-HIV vaccine development. In this work, a stable producer of the trimer Env recombinant form CRF63_02A6 of HIV-1 was derived from the CHO-K1 cell line. Using immunochemical assays, the trimers synthesized in CHO-K1 cells were shown to be recognized by both monoclonal broadly neutralizing antibodies and sera from HIV-positive patients. The resulting trimers of the recombinant form CRF63_02A6 of HIV-1 can be used both for structural studies and as a candidate vaccine immunogen against HIV-1.


A comparison of the bacteria found on the hands of 'homemakers' and neonatal intensive care unit nurses.
This prevalence study was conducted to compare the counts, types and antimicrobial resistance profiles of bacterial flora on the hands of individuals in the community to that of nurses at a nearby university teaching hospital, with an intense hand hygiene regimen. Hand cultures were obtained from 204 individuals during a home visit and 119 nurses in two neonatal intensive care units (NICUs). The mean total log counts of organisms were 5.73 and 5.24 for the homemakers [defined as the person (usually the mother) who is the primary person responsible for arranging childcare, cooking, cleaning etc] and nurse hands, respectively (P<0.0001). Significantly more homemakers had Acinetobacter lwoffii, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa, P. fluorescens/putida, and Staphylococcus aureus on their hands compared with the nurses (all P<0.05). However, significantly more nurses had Enterococcus faecalis, S. epidermidis, and S. warneri on their hands (P<0.05). Of note, the hands of nurses harboured significantly more S. epidermidis strains resistant to amoxicillin/clavulanate, cefazolin, clindamycin, erythromycin, and oxacillin and S. warneri resistant to amoxicillin/clavulanate, cefazolin, clindamycin, and oxacillin (P<0.05). Surprisingly, significantly more trimethoprim/sulfamethoxazole-resistant S. epidermidis and ciprofloxacin-resistant S. warneri was recovered from the hands of homemakers (P<0.05). This study demonstrates differences in prevalence, bacterial composition and antimicrobial resistance of hand flora of hospital personnel compared with homemakers. Moreover, the hands of homemakers may serve as community reservoirs for antimicrobial resistant strains of clinical importance.


The utility of surgical lung biopsy in immunocompromised children.
To determine the utility of lung biopsy in immunocompromised pediatric patients with suspected infectious lung disease and to evaluate the risks and benefits of biopsy in the era of minimally invasive thoracic surgery. We reviewed charts for 50 immunocompromised patients who underwent surgical lung biopsy between January 2000 and July 2011 at a free-standing, tertiary care, urban children's hospital. The primary outcome variable was "benefit from biopsy," defined as change in therapy based on biopsy results. The secondary outcome variable was survival to discharge. The χ(2) analysis was used for categorical variables and Student t test for continuous variables. Biopsy provided a definitive histopathologic or microbiologic diagnosis in 25 patients (50%), the most common diagnosis being fungal infection (22%). Diagnostic and nondiagnostic biopsy results yielded benefit in 25 surviving patients (50%) for whom the biopsy results were used to tailor treatment. Taking more than one biopsy specimen did not improve diagnostic yield. Six patients (12%) had a major morbidity including reinsertion of chest tube after initial chest tube removal (3), prolonged air leak (1), and a new requirement for mechanical ventilation postoperatively (2). Two patients died postoperatively, but the mortalities were not clearly related to surgery. Underlying diagnoses included hematologic malignancy (64%), primary immunodeficiency (12%), organ transplant recipient (12%), and solid malignancy (10%). Twelve patients (24%) had undergone stem cell transplantation. Lung biopsy in immunocompromised pediatric patients alters therapy in 50% of cases, but predictably carries identifiable morbidities. This study is limited by its retrospective nature.


Mobile Phone Interventions for the Secondary Prevention of Cardiovascular Disease.
Mobile health in the form of text messaging and mobile applications provides an innovative and effective approach to promote prevention and management of cardiovascular disease (CVD); however, the magnitude of these effects is unclear. Through a comprehensive search of databases from 2002-2016, we conducted a quantitative systematic review. The selected studies were critically evaluated to extract and summarize pertinent characteristics and outcomes. A large majority of studies (22 of 28, 79%) demonstrated text messaging, mobile applications, and telemonitoring via mobile phones were effective in improving outcomes. Some key factors associated with successful interventions included personalized messages with tailored advice, greater engagement (2-way text messaging, higher frequency of messages), and use of multiple modalities. Overall, text messaging appears more effective than smartphone-based interventions. Incorporating principles of behavioral activation will help promote and sustain healthy lifestyle behaviors in patients with CVD that result in improved clinical outcomes.


Safe and Efficient Sigma1 Ligand: A Potential Drug Candidate for Multiple Sclerosis.
Multiple Sclerosis (MS) is an autoimmune demyelinating and neurodegenerative disease of the central nervous system (CNS). Current management strategies suppress or modulate immune function, all with consequences and known side effects. They demonstrate a high level of success in limiting new relapses. However, the neurodegenerative process still affects both grey and white matter in the central nervous system. The sigma1 (S1R) ligand-regulated chaperone is implicated in many biological processes in various CNS-targeted diseases, acting on neural plasticity, myelination and neuroinflammation. Among the proteins involved in MS, S1R has therefore emerged as a promising new target. Standard and robust methods have been adopted to analyze the adsorption, distribution, metabolism, excretion (ADME) properties, safety pharmacology and toxicology of a previously synthetized simple benzamide-derived compound with nanomolar affinity for S1R, high selectivity, no cytotoxicity and good metabolic stability. The compound was also characterized as an agonist based on well-validated assays prior to in vivo investigations. Interestingly, we found that the oral administration of this compound resulted in an overall significant reduction in clinical progression in an MS experimental model. This effect is mediated through S1R action. Our results further suggest the potential use of this compound in the treatment of MS.


Evidence of cyclic GMP may regulate the association of myosin II heavy chain with the cytoskeleton by inhibiting its phosphorylation.
Previous studies have implicated cyclic GMP in the regulation of myosin II heavy chain (MHC) association with the cytoskeleton in Dictyostelium discoideum. Here we provide evidence that cyclic GMP may regulate MHC association with the cytoskeleton through MHC phosphorylation. Comparative data are presented of MHC phosphorylation in the wild-type strain NC4, the parental strain XP55 and streamer mutants NP368 and NP377. Using an anti-MHC monoclonal antibody to immunoprecipitate MHC from [32P]phosphate-labelled developing cells, we found that cyclic AMP stimulation of the wild-type strain NC4 and parental strain XP55 induced MHC phosphorylation in vivo. A peak of phosphorylation was observed at 30-40 s, followed by a gradual decrease to basal level at 160 s. In contrast, in both of the streamer mutants NP368 and NP377 (which have prolonged cyclic GMP accumulation and prolonged MHC association with the cytoskeleton), the phosphorylation of MHC was delayed and did not form a peak until 60-80 s after cyclic AMP stimulation. We also found that cytoskeletal MHC showed only minor phosphorylation, the majority of the phosphorylated MHC being found in the cytosol. We present a model to account for these results in which cyclic GMP regulates MHC association with the cytoskeleton by regulating the phosphorylation/dephosphorylation cycle of MHC in these cells.


[In vivo and in vitro suppression of lymphocyte function in paranasal sinus mycoses].
In about 10% of patients operated on a chronic sinusitis, an aspergilloma is found in the paranasal sinus. To detect possible underlying immunodeficiencies, patients with aspergilloma were subjected to an immunological screening programme. The data were compared with those of patients suffering from non-mycotic chronic sinusitis and healthy controls. Totale lymphocyte counts and immunological levels were normal in both groups of sinusitis. Leukocyte subset analyses by membrane fluorescence revealed a significant decrease of CD11+ cells, i.e. macrophages/monocytes and NK cells, in both types of sinusitis. Furthermore, a markedly enhanced frequency of CD25+-cells, i.e. IL 2-receptor bearing cells, was observed in patients with aspergilloma. Peripheral blood lymphocytes of both groups of patients showed a significant reduction in the proliferative response to both T and B-cell mitogens, the values for the mitogens ConA and PWM being significantly lower in aspergilloma patients than in those with non-mycotic sinusitis. This lack of lymphocyte stimulation in the aspergilloma group was also manifest in skin tests to recall antigens. These first data suggest an immunodeficiency in association with chronic sinusitis caused by Aspergillus fumigatus. Further studies are needed to clarify if this defect is cause or result of the mycotic infection.


The host-defense peptide piscidin P1 reorganizes lipid domains in membranes and decreases activation energies in mechanosensitive ion channels.
The host-defense peptide (HDP) piscidin 1 (P1), isolated from the mast cells of striped bass, has potent activities against bacteria, viruses, fungi, and cancer cells and can also modulate the activity of membrane receptors. Given its broad pharmacological potential, here we used several approaches to better understand its interactions with multicomponent bilayers representing models of bacterial (phosphatidylethanolamine (PE)/phosphatidylglycerol) and mammalian (phosphatidylcholine/cholesterol (PC/Chol)) membranes. Using solid-state NMR, we solved the structure of P1 bound to PC/Chol and compared it with that of P3, a less potent homolog. The comparison disclosed that although both peptides are interfacially bound and α-helical, they differ in bilayer orientations and depths of insertion, and these differences depend on bilayer composition. Although Chol is thought to make mammalian membranes less susceptible to HDP-mediated destabilization, we found that Chol does not affect the permeabilization effects of P1. X-ray diffraction experiments revealed that both piscidins produce a demixing effect in PC/Chol membranes by increasing the fraction of the Chol-depleted phase. Furthermore, P1 increased the temperature required for the lamellar-to-hexagonal phase transition in PE bilayers, suggesting that it imposes positive membrane curvature. Patch-clamp measurements on the inner Escherichia coli membrane showed that P1 and P3, at concentrations sufficient for antimicrobial activity, substantially decrease the activating tension for bacterial mechanosensitive channels. This indicated that piscidins can cause lipid redistribution and restructuring in the microenvironment near proteins. We conclude that the mechanism of piscidin's antimicrobial activity extends beyond simple membrane destabilization, helping to rationalize its broader spectrum of pharmacological effects.


Characterization of the ERp57-Tapasin complex by rapid cellular acidification and thiol modification.
Major histocompatibility complex (MHC) class I molecules bind and present short peptides to cells of the immune system. The oxidoreductase ERp57 is involved in the assembly of MHC class I molecules and is a component of the peptide loading complex, where it is found disulfide-bonded to tapasin. We have studied ERp57 and the ERp57-tapasin conjugate by rapid acidification of the intracellular environment with trichloroacetic acid (TCA), followed by thiol modification with the alkylating agent 4'-maleimidylstilbene-2,2'-disulfonic acid (AMS). By using TCA/AMS treatment, non-tapasin-associated ERp57 is shown to exist almost exclusively in a reduced state, suggesting that both thioredoxin-like CXXC motifs are exposed and reduced. A 110-kDa product is readily detected with this TCA/AMS protocol and is confirmed as an ERp57-tapasin conjugate by its absence from the tapasin-deficient .220 cell line and by immunoblotting with both ERp57- and tapasin-specific antisera. The ERp57-tapasin conjugate can also be modified with the oxidizing agent diamide, indicating that within the pool of ERp57-tapasin complexes the free, non-tapasin-linked CXXC motif exists in both oxidized and reduced states, suggesting availability to undergo redox reactions.


Rice chloroplast DNA molecules are heterogeneous as revealed by DNA sequences of a cluster of genes.
We describe the isolation of two rice chloroplast HindIII fragments (9.5 kb and 5.3 kb) each containing a gene cluster coding for the large subunit of ribulose-1,5-bisphosphate carboxylase (rbcL), beta and epsilon subunits of ATPase (atpB and atpE), tRNAmet (trnM) and tRNAval (trnV). All five genes contained in the 9.5 kb fragment are potentially functional, whereas in the 5.3 kb fragment, rbcL is truncated and atpB is frame-shift mutated. The copy number of the 9.5 kb fragment is 10 times that of the 5.3 kb fragment, indicating that the two fragments are probably located on different chloroplast genomes and represent two different (major and minor) genomic populations. Thus, the rice chloroplast genome appears to be heterogeneous, contrary to general belief. We also describe the isolation of a rice mitochondrial HindIII fragment (6.9 kb) which contains an almost complete transferred copy of this chloroplast gene cluster. In this transferred copy, the coding sequences of rbcL, atpE and trnM contain perfectly normal reading frames, whereas atpB has become grossly defective and trnV is truncated.


Meta-analysis identifies loci affecting levels of the potential osteoarthritis biomarkers sCOMP and uCTX-II with genome wide significance.
Research for the use of biomarkers in osteoarthritis (OA) is promising, however, adequate discrimination between patients and controls may be hampered due to innate differences. We set out to identify loci influencing levels of serum cartilage oligomeric protein (sCOMP) and urinary C-telopeptide of type II collagen (uCTX-II). Meta-analysis of genome-wide association studies was applied to standardised residuals of sCOMP (N=3316) and uCTX-II (N=4654) levels available in 6 and 7 studies, respectively, from TreatOA. Effects were estimated using a fixed-effects model. Six promising signals were followed up by de novo genotyping in the Cohort Hip and Cohort Knee study (N = 964). Subsequently, their role in OA susceptibility was investigated in large-scale genome-wide association studies meta-analyses for OA. Differential expression of annotated genes was assessed in cartilage. Genome-wide significant association with sCOMP levels was found for a SNP within MRC1 (rs691461, p = 1.7 × 10(-12)) and a SNP within CSMD1 associated with variation in uCTX-II levels with borderline genome-wide significance (rs1983474, p = 8.5 × 10(-8)). Indication for association with sCOMP levels was also found for a locus close to the COMP gene itself (rs10038, p = 7.1 × 10(-6)). The latter SNP was subsequently found to be associated with hip OA whereas COMP expression appeared responsive to the OA pathophysiology in cartilage. We have identified genetic loci affecting either uCTX-II or sCOMP levels. The genome wide significant association of MRC1 with sCOMP levels was found likely to act independent of OA subtypes. Increased sensitivity of biomarkers with OA may be accomplished by taking genetic variation into account.


Reversion of BRCA1/2 Germline Mutations Detected in Circulating Tumor DNA From Patients With High-Grade Serous Ovarian Cancer.
Purpose Germline BRCA1 or BRCA2 mutations in patients with high-grade serous ovarian cancer (HGSC) are associated with favorable responses to chemotherapy. However, secondary intragenic (reversion) mutations that restore protein function lead to clinically significant rates of acquired resistance. The goal of this study was to determine whether reversion mutations could be found in an unbiased manner in circulating cell-free DNA (cfDNA) to predict treatment response in HGSC. Patients and Methods Plasma and tumor samples were obtained from 30 patients with HGSC with either BRCA1 or BRCA2 germline mutation. Two cohorts were ascertained: patients with a malignancy before undergoing primary HGSC debulking surgery (n = 14) or patients at disease recurrence (n = 16). Paired tumor and plasma samples were available for most patients (24 of 30). Targeted amplicon, next-generation sequencing was performed using primers that flanked germline mutations, whose design did not rely on prior knowledge of reversion sequences. Results Five patients were identified with intragenic mutations predicted to restore BRCA1/2 open reading frames, including two patients with multiple independent reversion alleles. Reversion mutations were only detected in tumor samples from patients with recurrent disease (five of 16) and only in cfDNA from patients with a tumor-detected reversion (three of five). Findings from a rapid autopsy of a patient with multiple independent reversions indicated that reversion-allele frequency in metastatic sites is an important determinant of assay sensitivity. Abundance of tumor-derived DNA in total cell-free DNA, as measured by TP53 mutant allele frequency, also affected assay sensitivity. All patients with reversions detected in tumor-derived DNA were resistant to platin- or poly ADP ribose polymerase inhibitor-based chemotherapy. Conclusion Reversion mutations can be detected in an unbiased analysis of cfDNA, suggesting clinical utility for predicting chemotherapy response in recurrent HGSC.


Japanese encephalitis virus - exploring the dark proteome and disorder-function paradigm.
Japanese encephalitis virus (JEV) is one of the major causes of viral encephalitis all around the globe. Approximately 3 billion people in endemic areas are at risk of Japanese encephalitis. To develop a wholistic understanding of the viral proteome, it is important to investigate both its ordered and disordered proteins. However, the functional and structural significance of disordered regions in the JEV proteome has not been systematically investigated as of yet. To fill this gap, we used here a set of bioinformatics tools to analyze the JEV proteome for the predisposition of its proteins for intrinsic disorder and for the presence of the disorder-based binding regions (also known as molecular recognition features, MoRFs). We also analyzed all JEV proteins for the presence of the probable nucleic acid-binding (DNA and RNA) sites. The results of these computational studies are experimentally validated using JEV capsid protein as an illustrative example. In agreement with bioinformatic analysis, we found that the N-terminal region of the JEV capsid (residues 1-30) is intrinsically disordered. We showed that this region is characterized by the temperature response typical for highly disordered proteins. Furthermore, we have experimentally shown that this disordered N-terminal domain of a capsid protein has a noticeable 'gain-of-structure' potential. In addition, using DOPS liposomes, we demonstrated the presence of pronounced membrane-mediated conformational changes in the N-terminal region of JEV capsid. In our view, this disorder-centric analysis would be helpful for a better understanding of the JEV pathogenesis.


Analysis of complement-dependent antibody-mediated lysis of target cells acutely infected with measles.
A sensitive assay for the detection of complement-dependent cytolytic measles-antibodies in monkey and human sera is described. The high sensitivity of the technique is dependent upon the use of Vero or MA-104 cells acutely infected with a high-titered, non-syncitiogenic strain of attenuated measles virus. Cytolytic antibody titers of serum can be determined either by endpoint dilution in the presence of a standard dilution of heterologous (guinea pig) complement or by percentage of lysis of a specific number of target cells at a standard dilution of immune serum (1:32). The latter technique proved expedient in the comparison of cytolytic activities of large numbers of serum samples. Clearly, the alternative complement pathway is effective in lysis of these cells, but neither the classical nor the alternative pathway alone appears to be as effective as both pathways combined. No prozone effect occurred with homologous complement, and inhibition of lysis was eliminated by washing sensitized cells before addition of heterologous complement. Lysis of measles-infected cells untreated with measles antibody occurred in the presence of both normal and C4-deficient guinea pig serum at high concentrations, but no such activity occurred with non-immune human or rhesus serum. Antibody-mediated complement-dependent lysis of measles-infected cells may be an important immune defense against acute measles infection.


Trends and patterns of violence-related mortality in Nigeria: evidence from a 16-year analysis of secondary data.
Nigeria is one of the most terrorised countries due to terrorist attacks and violent clashes. There have been many fatalities resulting from this violence, which started in the late 1960s and has significantly increased recently. Violence in Nigeria has been studied, but not about Nigeria's mortality experience over time. This study described the patterns and trends of deaths related to violence in Nigeria over 16 years. Secondary data on lethal violence across Nigeria spanning from 2006 to 2021 were drawn from the Nigeria Watch database, an online database of lethal violence in Nigeria. Univariate analysis of the data was conducted to map the trends, patterns and sources of lethal violence across Nigeria. Nigeria recorded no fewer than 169 033 violent deaths between 2006 and 2021, with 2014 reporting the highest number (22, 873) and Borno State being the most affected, followed by Lagos, Kaduna, Zamfara, Plateau, Delta, Benue, Rivers and Adamawa. The highest number of deaths (51, 425) was attributed to crime, followed by insurgency (50, 252) and road crashes (27, 645). Other significant causes of death were political issues (8, 324) and cattle grazing (5, 501). Violence-related mortality is prevalent in Nigeria and significantly contributes to adult mortality. The government must develop strategies to identify, intervene in and end high-risk conflict situations to stop the growing contribution of violence to Nigeria's mortality experience.


Glucose-induced activation of glucose uptake in cells from the inner and outer blood-retinal barrier.
The purpose of this study was to elucidate in vitro the effect of elevated glucose on glucose uptake in the cells comprising the inner and outer blood-retinal barriers: human retinal pigment epithelial (hRPE) and human retinal vascular endothelial (hRVE) cells. Primary cultures of hRPE and hRVE cells grown in 5.5 or 22 mM glucose or in 22 mM mannitol were used to measure the rates of glucose uptake with [(3)H]-3-O-methyl glucose as a tracer. GLUT1 expression was measured by Northern and western blot analyses. Cellular fractionation was performed by differential centrifugation. GLUT1 overexpression was accomplished by adenoviral transduction. Increasing media glucose from 5.5 to 22 mM for 30 minutes caused a 1.9-fold increase in the V(max) of glucose uptake in hRPE cells and a 2.5-fold increase in hRVE cells. These increases were nonosmotic and glucose specific, in that the exposure to 22 mM mannitol did not affect the V(max) of glucose uptake. mRNA, total protein expression, and translocation of GLUT1, the glucose transporter predominantly expressed in hRPE and hRVE cells, were not affected by 22 mM glucose for up to 48 hours. High-glucose effects on V(max) were abolished with 10 microg/mL of the microtubule assembly inhibitor nocodazole. hRPE cells transduced to overexpress GLUT1 showed a 1.5-fold increase in the V(max) for glucose uptake versus control-transduced cells. However, the magnitude of glucose-induced increase in glucose uptake was the same in GLUT1- and control-transduced cells. High glucose induced 1.9- and 2.5-fold increases in the V(max) of glucose uptake in hRPE and hRVE cells, respectively. These increases were not due to an increase in GLUT1 expression. The increases were dependent on microtubule integrity, but not on GLUT1 translocation. The mechanism of the increases is unknown. GLUT1 regulating protein(s) and/or novel glucose transporter(s) may be involved in the regulation of glucose uptake by glucose in the cells that comprise the blood-retinal barrier.


Blood flow through vasa vasorum in arteries and veins: effects of luminal PO2.
We have examined effects of chronic reduction of intraluminal PO2 on blood flow through vasa vasorum, by comparing large arteries and veins, and effects of acute hypoxia on flow through vasa. Microspheres were used to measure flow in anesthetized dogs. Values obtained with different sizes of microspheres suggest that spheres 9 and 15 micron in diam, but not 50 micron, are appropriate for measurement of blood flow through vasa vasorum. Flow [expressed as ml X min-1 X 100 g-1 (SE)] through medial vasa was similar in the aorta (9.0 +/- 2.1) and pulmonary artery (9.3 +/- 1.1) although, on the basis of wall thickness and number of lamellae, one would predict much higher levels of flow to aortic media. Two veins that we studied have a thick muscular wall. Both veins had high levels of flow through medial vasa: 33 +/- 4.4 to the subdiaphragmatic inferior vena cava and 18 +/- 5.4 to the portal vein. Two other veins are apparently conduit vessels, with dense connective tissue and minimal smooth muscle. Both veins had minimal flow through medial vasa: 2.4 +/- 1.0 to superior vena cava, and 1.9 +/- 0.8 to supradiaphragmatic inferior vena cava. Thus, because flow through vasa differs greatly in different veins, structure of the vessel (as well as intraluminal PO2) is an important determinant of flow through vasa. Acute hypoxia increased conductance of medial vasa vasorum of arteries and veins when neurohumoral constrictor effects were blocked by phenoxybenzamine.(ABSTRACT TRUNCATED AT 250 WORDS)


[Home delivery as voiced by women: a perspective at the light of humanization].
This paper is a descriptive exploratory study developed with the objective of getting acquainted with life experiences, preparation,feelings and motivations of women who have chosen home childbirth. The subjects of the research comprised ten women who had at least one experience of home childbirth in Porto Alegre, in the last five years. The data was gathered through semi-structured interviews, which were analyzed according to Minayo's proposal. It indicates that the women who opted for home childbirth don't accept what the hospital system offers to women in labor at present time, but they do recognize that, for a few women, hospital delivery is the best choice, whether for reasons that involve personal decisions or health ones.


Clinical evaluation of class II Targis inlays: preliminary results after 1 year.
The aim of this study was to evaluate the clinical performance of a new generation of restorative resin, Targis (Vivadent), in class II inlay restorations. Forty class II Targis inlays were placed (18 premolars, 22 molars) in 26 patients (mean age=25.5). All test teeth were vital. All restorations were in occlusion and were placed adhesively using Variolink II high viscosity (Vivadent) in combination with Syntac adhesive system under rubber-dam by the same operator. The restorations were evaluated at baseline and after 6 months and 1 year, according to modified United States Public Health Service (USPHS) criteria by two examiners. The parameters evaluated were: anatomical form, marginal adaptation, marginal discoloration, colour match, surface finish, gingival index and secondary caries. Post-operative sensitivity was determined by direct questioning. Regarding all of the clinical evaluation criteria all 40 inlays exhibited clinically acceptable scores after 1-year evaluation period. Relying on these early 1-year results, the new restorative material (Targis) seems to be promising in class II inlays.


Mannose-Binding Lectin Inhibits the Motility of Pathogenic Salmonella by Affecting the Driving Forces of Motility and the Chemotactic Response.
Mannose-binding lectin (MBL) is a key pattern recognition molecule in the lectin pathway of the complement system, an important component of innate immunity. MBL functions as an opsonin which enhances the sequential immune process such as phagocytosis. We here report an inhibitory effect of MBL on the motility of pathogenic bacteria, which occurs by affecting the energy source required for motility and the signaling pathway of chemotaxis. When Salmonella cells were treated with a physiological concentration of MBL, their motile fraction and free-swimming speed decreased. Rotation assays of a single flagellum showed that the flagellar rotation rate was significantly reduced by the addition of MBL. Measurements of the intracellular pH and membrane potential revealed that MBL affected a driving force for the Salmonella flagellum, the electrochemical potential difference of protons. We also found that MBL treatment increased the reversal frequency of Salmonella flagellar rotation, which interfered with the relative positive chemotaxis toward an attractive substrate. We thus propose that the motility inhibition effect of MBL may be secondarily involved in the attack against pathogens, potentially facilitating the primary role of MBL in the complement system.


Anaemia in pregnant adolescent girls with malaria and practicing pica.
Pregnancy during the adolescent period is challenging mainly because of the nutritional demands of both the adolescent and pregnancy period. The risk for anaemia increases especially in developing countries such as Ghana where malaria is endemic and the practice of pica is common. In this study, we sought to determine the prevalence of anaemia, pica practice and malaria infection among pregnant adolescent girls and assess the extent to which these factors are associated. Two hundred and sixty five (265) pregnant adolescent girls were recruited from three hospitals in Accra. Haemoglobin levels, malaria infection and the practice of pica were assessed. Pearson's Chi squared tests were used to determine associations and logistic regression analysis was used to determine the odds of being anaemic. Significance was set at p≤0.05. Anaemia prevalence was 76% with severity ranging from mild (47.8%) to severe (0.8%). About 27.5% were moderately anaemic. Pica was practiced in only 9.1% of the girls. Malaria infection was prevalent in 17.7% of the girls. The logistic regression analysis indicated that pregnant girls with malaria infection were 3.56 times more likely to be anaemic when compared to those without malaria. Also, those who practiced pica were 1.23 times more likely to be anaemic when compared to those who did not practice pica. Anaemia is very prevalent in pregnant adolescent girls and is a public health problem. Drastic measures should be taken to reduce the high prevalence.


Joint effects of XRCC1 polymorphisms and polycyclic aromatic hydrocarbons exposure on sperm DNA damage and male infertility.
X-ray repair cross-complementing group 1 (XRCC1) plays a role in repairing polycyclic aromatic hydrocarbons (PAHs)-induced DNA damage. We examined the effects of exposure to PAHs and XRCC1 polymorphism, alone or combined, on sperm DNA integrity and male fertility. A total of 620 idiopathic infertile subjects and 273 fertile controls were recruited in this study. PAHs exposure was indicated by urinary 1-hydroxypyrene level. Genotypes were determined by PCR-RFLP, and sperm DNA damage was detected by Tdt-mediated dUTP nick end labelling assay using flow cytometry. A positive correlation was found between PAHs exposure and sperm DNA damage (beta coefficients = 0.183, p < 0.001), whereas there was no significant association between the XRCC1 polymorphisms and sperm DNA damage. However, when the patients were dichotomized for PAHs exposure, higher sperm DNA damage was found among 399Gln allele carriers compared with the wild-type homozygotes (p = 0.033). Further analysis based on a case-control study revealed the joint effect of XRCC1-399 polymorphism and PAHs exposure on the risk of male infertility (p interaction = 0.041). These findings provided the first evidence about potential joint effects of PAHs exposure and DNA repair gene polymorphisms on male reproductive system and may be helpful in improving our understanding of the etiology of male infertility.


Do children die? A retrospective review of deaths in a children's hospital.
We present a profile of deaths over two years in the medical departments of a children's hospital. The findings would help us better understand the individual dying experience of these patients. Service gaps and ways to optimise provision of supportive care were identified in the process. The inpatient notes of all children who died in the medical wards, including intensive care unit, were traced and reviewed by the investigators. Demographic data, diagnoses, length of stay and the care received were recorded. A total of 68 children died in the two years. They were representative of all deaths nationally in terms of diagnoses. Two-thirds of the children died in the intensive care unit after having stayed there for an average of five days. All but one patient had invasive ventilation till they died. Eight out of every ten cases were assessed to be actively dying while being cared for. Most had 'Do-Not-Resuscitate' status in place, but few had been offered the option to choose the place of care or death when it became clear that they would not survive. More efforts could be made to improve the care of dying children and their families. The Paediatric Palliative Service could assist in advance care planning at the end of life.


Implant use in growing patients. Treatment planning concerns.
The dynamic relationship of dental and craniofacial development to the use of dental implants in a growing patient must be understood before this treatment is initiated. This article describes the three dimensions of maxillary, mandibular, and skeletal growth and their relationship to the placement of dental implants. Recommendations are made for the use of dental implants in the growing individual predicated on the above parameters of growth and development.


Directional transneuronal spread of α-herpesvirus infection.
Most α-herpesviruses are pantropic, neuroinvasive pathogens that establish a reactivateable, latent infection in the PNS of their natural hosts. Various manifestations of herpes disease rely on extent and direction of the spread of infection between the surface epithelia and the nervous system components that innervate that surface. One aspect of such controlled spread of infection is the capacity for synaptically defined, transneuronal spread, a property that makes α-herpesviruses useful tools for determining the connectivity of neural circuits. The current understanding of intra-axonal transport and transneuronal spread of α-herpesviruses is reviewed, focusing on work with herpes simplex virus and pseudorabies virus, the available in vitro technology used to study viral transport and spread is evaluated and how certain viral mutants can be used to examine neural circuit architecture is described in this article.


The anatomical placode in reptile scale morphogenesis indicates shared ancestry among skin appendages in amniotes.
Most mammals, birds, and reptiles are readily recognized by their hairs, feathers, and scales, respectively. However, the lack of fossil intermediate forms between scales and hairs and substantial differences in their morphogenesis and protein composition have fueled the controversy pertaining to their potential common ancestry for decades. Central to this debate is the apparent lack of an "anatomical placode" (that is, a local epidermal thickening characteristic of feathers' and hairs' early morphogenesis) in reptile scale development. Hence, scenarios have been proposed for the independent development of the anatomical placode in birds and mammals and parallel co-option of similar signaling pathways for their morphogenesis. Using histological and molecular techniques on developmental series of crocodiles and snakes, as well as of unique wild-type and EDA (ectodysplasin A)-deficient scaleless mutant lizards, we show for the first time that reptiles, including crocodiles and squamates, develop all the characteristics of an anatomical placode: columnar cells with reduced proliferation rate, as well as canonical spatial expression of placode and underlying dermal molecular markers. These results reveal a new evolutionary scenario where hairs, feathers, and scales of extant species are homologous structures inherited, with modification, from their shared reptilian ancestor's skin appendages already characterized by an anatomical placode and associated signaling molecules.


Full color modulation of firefly luciferase through engineering with unified Stark effect.
The firefly luciferase has been a unique marking tool used in various bioimaging techniques. Extensive color modulation is strongly required to meet special marking demands; however, intentional and accurate wavelength tuning has yet to be achieved. Here, we demonstrate that the color shift of the firefly chromophore (OxyLH2-1) by internal and external fields can be described as a unified Stark shift. Electrostatic microenvironmental effects on fluorescent spectroscopy are modeled in vacuo through effective electric fields by using time-dependent density functional theory. A complete visible fluorescence spectrum of firefly chromophore is depicted, which enables one to control the emission in a specific color. As an application, the widely observed pH-correlated color shift is proved to be associated with the local Stark field generated by the trace water-ions (vicinal hydronium and hydroxide ions) at active sites close to the OxyLH2-1.


Mesoscale simulation of semiflexible chains. II. Evolution dynamics and stability of fiber bundle networks.
Network formation of associative semiflexible fibers and mixtures of fibers and colloidal particles is simulated for the Johnson-Kendall-Roberts model of elastic contacts, and a phase diagram in terms of particle elasticity and surface energy is presented. When fibers self-assemble, they form a network for sufficiently large fiber-solvent surface energy. If the surface energy is above the value where single particles crystallize, the adhesion forces drive diffusion-limited aggregation. Two mechanisms contribute to coarsening: non-associated chains joining existing bundles, and fiber bundles merging. Coarsening stops when the length of the network connections is roughly the persistence length, independent of surface energy. If the surface energy is below the value where single particles crystallize, a network can still be formed but at a much slower (reaction limited) rate. Loose (liquid-like) assemblies between chains form when they happen to run more-or-less parallel. These assemblies grow by diffusion and aggregation and form a loose network, which sets in micro-phase separation, i.e., syneresis. Only when the clusters crystallize, the coarsening process stops. In this case, the length of the network connections is larger than the persistence length of a single chain, and depends on the value of the surface energy. All networks of semiflexible homopolymers in this study show syneresis. Mixtures of fibers and colloid particles also form fiber bundle networks, but by choosing the colloid volume fraction sufficiently low, swelling gels are obtained. Applications of this model are in biological systems where fibers self-assemble into cell walls and bone tissue.


The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival.
The goals of this study were to describe the clinical and anatomic features of infants undergoing Kasai portoenterostomy (KPE) for biliary atresia (BA) and to examine associations between these parameters and outcomes. Infants enrolled in the prospective Childhood Liver Disease Research and Education Network, who underwent KPE were studied. Patients enrolled in a blinded, interventional trial were excluded from survival analysis. Primary endpoints were successful surgical drainage (total bilirubin less than 2 mg/dL within the first 3 months), transplant-free survival (Kaplan-Meier), and time to transplant/death (Cox regression). KPE was performed in 244 infants (54% female; mean age: 65 ± 29 days). Transplant-free survival was 53.7% and 46.7% at 1 and 2 years post-KPE. The risk of transplant/death was significantly lower in the 45.6% of patients who achieved successful bile drainage within 3 months post-KPE (HR: 0.08, P < 0.001). The risk of transplant/death was increased in patients with porta hepatis atresia (Ohi type II and III vs type I; HR: 2.03, P = 0.030), nonpatent common bile duct (Ohi subtype: b, c, and d vs a; HR: 4.31, P = 0.022), BA splenic malformation syndrome (HR: 1.92, P = 0.025), ascites > 20 mL (HR: = 1.90, P = 0.0230), nodular liver appearance compared to firm (HR: = 1.61, P = 0.008), and age at KPE ≥ 75 days (HR: 1.73, P < 0.002). Outcome was not associated with gestational age, gender, race, ethnicity, or extent of porta hepatis dissection. Anatomic pattern of BA, BASM, presence of ascites and nodular liver appearance at KPE, and early postoperative jaundice clearance are significant predictors of transplant-free survival.


Deaf adults' reasons for genetic testing depend on cultural affiliation: results from a prospective, longitudinal genetic counseling and testing study.
This article examines the relationship between cultural affiliation and deaf adults' motivations for genetic testing for deafness in the first prospective, longitudinal study to examine the impact of genetic counseling and genetic testing on deaf adults and the deaf community. Participants (n = 256), classified as affiliating with hearing, Deaf, or both communities, rated interest in testing for 21 reasons covering 5 life domains. Findings suggest strong interest in testing to learn why they are deaf, but little interest in using it for decisions about a partner or having children. Culturally mediated variation was also demonstrated. Deaf and both communities groups viewed testing as useful for more life domains than the hearing community group. Deaf and both communities had similar motivations related to further exploration, understanding, or strengthening of deafness. Motivations related to "hearing" were also relevant for both communities. We conclude that cultural affiliation is an important factor for constructing motivations for genetic testing.


Saline lavage after a "dry tap".
In patients with a "dry" aspiration during the investigation of prosthetic joint infection (PJI), saline lavage is commonly used to obtain a sample for analysis. The aim of this study was to investigate prospectively the impact of saline lavage on synovial fluid analysis in revision arthroplasty. Patients undergoing revision hip (THA) or knee arthroplasty (TKA) for any septic or aseptic indication were enrolled. Intraoperatively, prior to arthrotomy, the maximum amount of fluid possible was aspirated to simulate a dry tap (pre-lavage) followed by the injection with 20 ml of normal saline and re-aspiration (post-lavage). Pre- and post-lavage synovial white blood cell (WBC) count, percent polymorphonuclear cells (%PMN), and cultures were compared. A total of 78 patients had data available for analysis; 17 underwent revision THA and 61 underwent revision TKA. A total of 16 patients met modified Musculoskeletal Infection Society (MSIS) criteria for PJI. Pre- and post-lavage %PMNs were similar in septic patients (87% vs 85%) and aseptic patients (35% vs 39%). Pre- and post-lavage synovial fluid WBC count were far more disparate in septic (53,553 vs 8,275 WBCs) and aseptic (1,103 vs 268 WBCs) cohorts. At a cutoff of 80% PMN, the post-lavage aspirate had a sensitivity of 75% and specificity of 95%. At a cutoff of 3,000 WBCs, the post-lavage aspirate had a sensitivity of 63% and specificity of 98%. As the post-lavage synovial WBC count increased, the difference between pre- and post-lavage %PMN decreased (mean difference of 5% PMN in WBC < 3,000 vs mean difference 2% PMN in WBC > 3,000, p = 0.013). Of ten positive pre-lavage fluid cultures, only six remained positive post-lavage. While saline lavage aspiration significantly lowered the synovial WBC count, the %PMN remained similar, particularly at WBC counts of > 3,000. These findings suggest that in patients with a dry-tap, the %PMN of a saline lavage aspiration has reasonable sensitivity (75%) for the detection of PJI. Cite this article: Bone Joint J 2020;102-B(6 Supple A):138-144.


Tip-enhanced Raman spectroscopy of graphene-like and graphitic platelets on ultraflat gold nanoplates.
In this study, tip-enhanced Raman spectroscopy (TERS) is used to characterize graphene-like and graphitic platelets composed of a few layers of graphene. Specifically, gap-mode TERS geometry provides a larger enhancement of the local electromagnetic field at the junction formed by a gold sharp tip and a gold substrate. Graphene-like platelets are deposited onto ultra-flat thin gold nanoplates using a surfactant-assisted method. Au-coated atomic force microscopy (AFM) tips are used to probe specific substrate regions coated by the platelets. TERS spectra are collected on distinctive points on the graphene-like layers and surrounding substrate using radially or linearly polarized light, with an excitation wavelength of 632.8 nm. The position, width and intensity of G, D, and 2D Raman-active modes of graphene are discussed as a function of the incident light polarization and for distinct positions on the graphene layer. We report here on the nature of the collected TERS spectra focusing in particular on the edges of the graphene platelets.


Computer simulation models of pre-diabetes populations: a systematic review protocol.
Diabetes is a major public health problem and prediabetes (intermediate hyperglycaemia) is associated with a high risk of developing diabetes. With evidence supporting the use of preventive interventions for prediabetes populations and the discovery of novel biomarkers stratifying the risk of progression, there is a need to evaluate their cost-effectiveness across jurisdictions. In diabetes and prediabetes, it is relevant to inform cost-effectiveness analysis using decision models due to their ability to forecast long-term health outcomes and costs beyond the time frame of clinical trials. To support good implementation and reimbursement decisions of interventions in these populations, models should be clinically credible, based on best available evidence, reproducible and validated against clinical data. Our aim is to identify recent studies on computer simulation models and model-based economic evaluations of populations of individuals with prediabetes, qualify them and discuss the knowledge gaps, challenges and opportunities that need to be addressed for future evaluations. A systematic review will be conducted in MEDLINE, Embase, EconLit and National Health Service Economic Evaluation Database. We will extract peer-reviewed studies published between 2000 and 2016 that describe computer simulation models of the natural history of individuals with prediabetes and/or decision models to evaluate the impact of interventions, risk stratification and/or screening on these populations. Two reviewers will independently assess each study for inclusion. Data will be extracted using a predefined pro forma developed using best practice. Study quality will be assessed using a modelling checklist. A narrative synthesis of all studies will be presented, focussing on model structure, quality of models and input data, and validation status. This systematic review is exempt from ethics approval because the work is carried out on published documents. The findings of the review will be disseminated in a related peer-reviewed journal and presented at conferences. CRD42016047228.


Reduction of alcohol consumption and subsequent mortality in alcohol use disorders: systematic review and meta-analyses.
To determine whether a reduction in drinking in individuals with alcohol use disorders resulted in reduced mortality risk. Electronic searches were performed of MEDLINE, EMBASE, and ISI Web of Science and references of identified articles were searched up to May 2012 using these keywords: (alcohol dependence OR alcohol abuse) AND (mortality) AND (cohort OR follow-up). Only English-language articles were included. Sixteen cohort studies were identified that reported all-cause mortality risk by drinking groups measuring change in alcohol intake among people with alcohol use disorders. Numbers of participants and deaths in each group; odds ratios (ORs); and demographic, clinical, and methodological variables were extracted. In comparison to continued heavy drinking, a reduction below heavy levels of alcohol use (including abstention) was associated with a substantially reduced risk of mortality (random-effects pooled OR = 0.41; 95% CI, 0.34-0.50; P < .001). The OR was 0.35 (95% CI, 0.20-0.60; P < .001) for those who reached abstention and 0.61 (95% CI, 0.39-0.94; P = .026) for those who did not reach abstention but substantially reduced their consumption. The pooled OR for abstention compared to reduced consumption was 0.42 (95% CI, 0.19-0.92; P = .031). Meta-regression models did not reveal significant influences of study characteristics examined. Reduction of drinking in alcohol use disorders was associated with a marked reduction in mortality risk for those who reached abstinence or reduced drinking compared to continued heavy drinkers. Those who reached abstention showed the smallest mortality risk, lower than the risk for reduced consumption without abstinence.


Mechanism of D-cycloserine action: alanine racemase from Escherichia coli W.
The antibiotic d-cycloserine is an effective inhibitor of alanine racemase. The lack of inhibition by l-cycloserine of alanine racemase from Staphylococcus aureus led Roze and Strominger to formulate the cycloserine hypothesis. This hypothesis states that d-cycloserine has the conformation required of the substrates on the enzyme surface and that l-cycloserine cannot have this conformation. Alanine racemase from Escherichia coli W has been examined to establish whether these observations are a general feature of all alanine racemases. The enzyme (molecular weight = 95,000) has Michaelis-Menten constants of 4.6 x 10(-4)m and 9.7 x 10(-4)m for d- and l-alanine, respectively. The ratio of V(max) in the d- to l-direction is 2.3. The equilibrium constant calculated from the Haldane relationship is 1.11 +/- 0.15. Both d- and l-cycloserine are competitive inhibitors with constants (K(i)) of 6.5 x 10(-4)m and 2.1 x 10(-3)m, respectively. The ratio of K(m)d-alanine to K(i)d-cycloserine is 0.71, and the ratio of K(m)l-alanine to K(i)l-cycloserine is 0.46. Since l-cycloserine is an effective inhibitor, it is concluded that the cycloserine hypothesis does not apply to the enzyme from E. coli W.


Morphological variations of lingula and prevalence of accessory mandibular foramina in mandibles: A study.
The lingula is used for identifying the site for injection of local anesthetics and for excision of nerve in facial neuralgia. The relationship between lingula and lingual nerves may aid in risk associated with an impacted third molar. Due to its connection to nerve and vascular structures, the study of the lingula provides important information related to oral and maxillofacial surgical procedures, such as the sagittal split ramus osteotomy and the intraoral vertico-sagittal ramus osteotomy carried out to correct dento facial deformities. Intra-operative complications such as hemorrhage, fracture, and nerve injury may occur if lingula is not correctly identified. This study was conducted in the Department of Oral Medicine and Radiology, Career Post Graduate Institute of Dental Sciences and Hospital, Lucknow, U. P (India) on fifty (100 sides) dry adult human mandibles to determine the different shapes of lingula. The shapes of the lingula were classified as triangular, truncated, nodular, and assimilated types. The most common shape found in the study was the triangular (61.6%) while the least common shape was the assimilated (11.6%). All types of lingule were more prevalent unilaterally. The prevalence of accessory mandibular foramina (AMF) was 12% on the right side and 4% on the left side of the mandible. The present study provides information regarding different shapes of lingule and incidence of AMF in the populations of Lucknow and its surrounding areas (Uttar Pradesh) North India. The findings of the present study are very helpful to oro-dental surgeons, anthropologists, and forensic practice experts.


Preserving privacy for pediatric patients and families: use of confidential note types in pediatric ambulatory care.
This study evaluates and characterizes the use of a confidential clinic note type as part of the implementation of open notes at a free-standing children's hospital. We describe how this electronic health record feature which disables patient and family access to selected notes in the patient portal is used across our institution, which clinicians are using this feature, and the type of data our clinicians consider confidential. Through retrospective chart review, we have evaluated the use of a confidential note type over a 1-year period. We identified 402 964 clinic notes created during a 1-year period, of which 9346 (2.3%) were flagged as confidential. Use of this confidential note type was associated with female patient sex and increase in patient age. It was used most frequently by a small subset of providers. 922 (83.8%) of 1100 notes manually reviewed contained sensitive information. Reasons for confidential notes varied, but patient's mental health was most commonly identified. Our data demonstrate variability in the use of a confidential note type across specialties, patient ages, and types of confidential information. This note type is frequently utilized by a subset of providers who often manage sensitive patient and parent information. As vendors and institutions enable open notes, thoughtful implementation and provider education surrounding the use of this confidential feature is needed. A confidential clinic note feature is an integral aspect of pediatric open notes implementation. This feature supports protection of confidential information pertaining to our patients and their caregivers.


Long-term potentiation-dependent spine enlargement requires synaptic Ca2+-permeable AMPA receptors recruited by CaM-kinase I.
It is well established that long-term potentiation (LTP), a paradigm for learning and memory, results in a stable enlargement of potentiated spines associated with recruitment of additional GluA1-containing AMPA receptors (AMPARs). Although regulation of the actin cytoskeleton is involved, the detailed signaling mechanisms responsible for this spine expansion are unclear. Here, we used cultured mature hippocampal neurons stimulated with a glycine-induced, synapse-specific form of chemical LTP (GI-LTP). We report that the stable structural plasticity (i.e., spine head enlargement and spine length shortening) that accompanies GI-LTP was blocked by inhibitors of NMDA receptors (NMDARs; APV) or CaM-kinase kinase (STO-609), the upstream activator of CaM-kinase I (CaMKI), as well as by transfection with dominant-negative (dn) CaMKI but not dnCaMKIV. Recruitment of GluA1 to the spine surface occurred after GI-LTP and was mimicked by transfection with constitutively active CaMKI. Spine enlargement induced by transfection of GluA1 was associated with synaptic recruitment of Ca(2+)-permeable AMPARs (CP-AMPARs) as assessed by an increase in the rectification index of miniature EPSCs (mEPSCs) and their sensitivity to IEM-1460, a selective antagonist of CP-AMPARs. Furthermore, the increase in spine size and mEPSC amplitude resulting from GI-LTP itself was blocked by IEM-1460, demonstrating involvement of CP-AMPARs. Downstream signaling effectors of CP-AMPARs, identified by suppression of their activation by IEM-1460, included the Rac/PAK/LIM-kinase pathway that regulates spine actin dynamics. Together, our results suggest that synaptic recruitment of CP-AMPARs via CaMKI may provide a mechanistic link between NMDAR activation in LTP and regulation of a signaling pathway that drives spine enlargement via actin polymerization.


Identifying Barriers to Delivering the Awakening and Breathing Coordination, Delirium, and Early Exercise/Mobility Bundle to Minimize Adverse Outcomes for Mechanically Ventilated Patients: A Systematic Review.
Improved outcomes are associated with the Awakening and Breathing Coordination, Delirium, and Early exercise/mobility bundle (ABCDE); however, implementation issues are common. As yet, no study has integrated the barriers to ABCDE to provide an overview of reasons for less successful efforts. The purpose of this review was to identify and catalog the barriers to ABCDE delivery based on a widely used implementation framework, and to provide a resource to guide clinicians in overcoming barriers to implementation. We searched MEDLINE via PubMed, CINAHL, and Scopus for original research articles from January 1, 2007, to August 31, 2016, that identified barriers to ABCDE implementation for adult patients in the ICU. Two reviewers independently reviewed studies, extracted barriers, and conducted thematic content analysis of the barriers, guided by the Consolidated Framework for Implementation Research. Discrepancies were discussed, and consensus was achieved. Our electronic search yielded 1,908 articles. After applying our inclusion/exclusion criteria, we included 49 studies. We conducted thematic content analysis of the 107 barriers and identified four classes of ABCDE barriers: (1) patient-related (ie, patient instability and safety concerns); (2) clinician-related (ie, lack of knowledge, staff safety concerns); (3) protocol-related (ie, unclear protocol criteria, cumbersome protocols to use); and, not previously identified in past reviews, (4) ICU contextual barriers (ie, interprofessional team care coordination). We provide the first, to our knowledge, systematic differential diagnosis of barriers to ABCDE delivery, moving beyond the conventional focus on patient-level factors. Our analysis offers a differential diagnosis checklist for clinicians planning ABCDE implementation to improve patient care and outcomes.


Pulmonary alveolar proteinosis with peripheral adenocarcinom.
Background: Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease classified into congenital form, autoimmune form and secondary form. Secondary PAP is caused by underlying conditions including solid malignancies. Few cases reported PAP associated with lung cancers. Objective: To show the clinical features of PAP with adenocarcinom, tried to seek for possible mechanism to explain whole clinical course. Methods: Reported a case of PAP associated with lung adenocarcinom, and also reviewed the relevant literature on PAP. Results: The patient suffered from intermittent cough, fever, shortness of breath, thoracalgia or hemoptysis. Blood gas analysis showed hyoxemia. Spirometric abnormality is mildly restrictive defect. High-resolution computed tomography (HRCT) showed patchy, ground-glass opacities with interlobular septal thickening called as "crazy-paving" pattern. Positron emission tomography/computed tomography (PET/CT) revealed a nodule with characteristics of lobulation and spiculation in the right lung apex section and diffuse consolidation shadow spreading over rest of lung field. Bronchoalveolar lavage fluid (BALF) showed a large amount of amorphous red-dyed materials and a few alveolar macrophages scattered in endoalveolar space with PAS positive. Transbronchial lung biopsy found adenocarcinoma. Wedge resection with mediastinal lymphnode and then 2 cycles of postoperative chemotherapy was carried out. No ground-glass opacities were found in his chest CT pictures in the next nine months. This result may support the theory that lung cancer cells cause quantitative or functional damage to alveolar macrophages, which trend to secondary PAP. Conclusions: The patient had typical clinical features of PAP. PAP may be secondary to lung cancer. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 390-394).


Clinical characteristics and treatment outcomes of isolated myeloid sarcoma without bone marrow involvement: a single-institution experience.
Isolated myeloid sarcoma (MS) is a rare extramedullary tumor mass composed of malignant myeloid precursor cells without any evidence of leukemia in the peripheral blood and bone marrow. We describe the clinical characteristics and outcomes of patients diagnosed with isolated MS at our institution. We retrospectively reviewed 9 of 497 acute myeloid leukemia (AML) patients (1.8%) with isolated MS. Isolated MS patients were divided into 2 groups according to the first-line treatment strategy: systemic treatment only (S) or local treatment with or without systemic treatment (LS). The most common site of MS occurrence was the head and neck area (N=4, 44.4%), followed by the anterior mediastinum (N=2, 22.2%) and the gastrointestinal tract (N=2, 22.2%). The tumors of 4 patients (44.4%) eventually evolved to AML, in a median time of 13.4 months (range, 2.4-20.1 mo). The number of patients achieving complete remission after first-line treatment was higher in the LS group (N=5, 83.3%) than in the S group (N=1, 33.3%) (P =0.226). All patients in the LS group survived, but those in the S group died (P=0.012). Accurate and rapid diagnosis using various modalities and the early initiation of intensive combined treatment may be the optimal strategies to reduce the risk of isolated MS subsequently evolving to AML. To fully understand the characteristics of isolated MS, a larger number of patients from a multinational study is necessary.


[Transhepatic biliary drainage as a method in the diagnosis and treatment of obstructive jaundice].
Percutaneous transhepatic biliary drainage was performed on eleven jaundiced patients, who had obstruction of the bile duct, in order to determine the exact site and nature of the obstruction and to alleviate the jaundice. In the present series, six patients were treated with external biliary drainage. Four of them received this treatment prior to radical surgery. In the remaining two cases the external drainage was a palliative procedure. In five patients, the drainage catheter was internalized through the obstructed bile duct (internal biliary drainage). One of these patients was subsequently treated with radical surgery. In two cases, the internal biliary drainage was palliative. In the two remaining cases, intraluminal selective irradiation was introduced via Iridium 192 flexible wires. Severe hemobilia occurred in one patient, who was successfully treated by lithotomy and "T" tube drainage. We conclude that the simplicity and low cost of these drainage procedures recommend them as extremely useful for the diagnosis and treatment of obstructive jaundiced patients.


A complexity-scalable software-based MPEG-2 video encoder.
With the development of general-purpose processors (GPP) and video signal processing algorithms, it is possible to implement a software-based real-time video encoder on GPP, and its low cost and easy upgrade attract developers' interests to transfer video encoding from specialized hardware to more flexible software. In this paper, the encoding structure is set up first to support complexity scalability; then a lot of high performance algorithms are used on the key time-consuming modules in coding process; finally, at programming level, processor characteristics are considered to improve data access efficiency and processing parallelism. Other programming methods such as lookup table are adopted to reduce the computational complexity. Simulation results showed that these ideas could not only improve the global performance of video coding, but also provide great flexibility in complexity regulation.


Esketamine mitigates cognitive impairment following exposure to LPS by modulating the intestinal flora/subdiaphragmatic vagus nerve/spleen axis.
Susceptibility to secondary infection often increases after primary infection. Secondary infections can lead to more severe inflammatory injuries; however, the underlying mechanisms are not yet fully elucidated. To investigate whether esketamine treatment immediately after primary lipopolysaccharide (LPS) exposure could alleviate cognitive impairment caused by secondary infection. Mice were injected intraperitoneally (IP) with LPS (5 mg/kg) 10 days apart. Esketamine (10, 15, or 30 mg/kg) was administered IP immediately after the primary LPS injection. Splenectomy or subdiaphragmatic vagotomy (SDV) was performed 7 days before secondary LPS exposure or broad-spectrum antibiotic administration. Splenomegaly was observed after the primary LPS injection on Days 3 and 10. Splenomegaly was attenuated by treatment with 30 mg/kg esketamine. Esketamine treatment prevented increased plasma proinflammatory cytokines levels and cognitive dysfunction induced by secondary LPS exposure. Mice that underwent splenectomy or SDV had lower proinflammatory cytokines levels, higher hippocampal brain-derived neurotrophic factor (BDNF) levels, and improved cognitive function 1 day after secondary infection, which was not further improved by esketamine. Fecal microbiota transplantation (FMT) from endotoxic mice treated with esketamine attenuated hippocampal BDNF downregulation and cognitive dysfunction only in pseudo germ-free (PGF) mice without splenectomy. FMT with fecal suspensions from esketamine-treated endotoxic mice abrogated splenomegaly only in PGF mice without SDV. Blocking BDNF signaling blocked esketamine's ameliorating effects on secondary LPS exposure-induced cognitive dysfunction. The intestinal flora/subdiaphragmatic vagus nerve/spleen axis-mediated hippocampal BDNF downregulation significantly affected secondary LPS-induced systemic inflammation and cognitive dysfunction. Esketamine preserves cognitive function via this mechanism.


Do general practitioners' risk-taking propensities and learning styles influence their continuing medical education preferences?
US studies have shown that a clinician's risk-taking propensity significantly predicts clinical behaviour. Other US studies examining relationships between family practice doctors' preferences for CME and their Kolb learning style have described conflicting findings. The aim of the present study was to investigate GPs' learning styles, risk-taking propensities and CME preferences, and to explore links between them. A descriptive confidential cross-sectional postal questionnaire survey of the 304 general practitioner principals within Portsmouth and South East Hampshire Health Authority was conducted. Two hundred and seventy-four GPs returned questionnaires, a response rate of 90.1%. The Kolb learning style types were assimilators 43.8% (predominant learning abilities watching and thinking), divergers 21.1% (feeling and watching), convergers 18.3% (doing and thinking), and accommodators 16.8% (doing and feeling). The Pearson risk-taking propensities were 65.8% risk neutral, 19.4% risk seeking and 14.8% risk averse. Risk-seeking GPs were significantly more likely to be accommodators or convergers than divergers or assimilators (p = 0.006). Majorities of 54.9% stated that the present PGEA system works well, 85% welcomed feedback from their peers, and 76.8% stated that learning should be an activity for all the practice team. Further majorities would welcome help to decide their learning needs (63.8%) and are looking to judge CME effectiveness by changes in GP performance or patient care (54.8%). Further significant correlations and cross-tabulations were found between learning style and risk-taking and CME attitudes, experiences and preferences. It is concluded that risk seekers and accommodators (doing and feeling) prefer feedback, interaction and practical hands-on learning, and assimilators (watching and thinking) and the risk averse tend towards lectures, theoretical learning formats and less interactive activities. Sharing feelings in groups may be difficult for the risk averse and assimilators. The success of a combined educational strategy will depend on an inclusive philosophy, both recognizing and engaging the wide range of differences in learning style and risk taking for all the individuals who make up learning teams.


The emotional intelligence of pediatric residents - a descriptive cross-sectional study.
Emotional Intelligence (EI) is a type of social intelligence. Excellent scores are achieved by displaying high levels of empathy in interpersonal relationships, strong skills in managing stressful situations as well as other personal competencies. Many of the social competencies that EI describes may have a direct impact on patient care. The objective of this study was to describe EI of pediatric residents and to identify if there are EI skills that should be selected for targeted intervention. This was a cross-sectional study administering the EQ-i 2.0© psychometric instrument to pediatric residents at the University of Alberta. Thirty-five residents completed the EQ-i 2.0© (100% response rate). Their overall EI score was not significantly different than a normative group of college-educated professionals. Residents had relative strengths in the subcategories of Emotional expression, Interpersonal Relationships, Empathy, and Impulse Control (all p<0.05). Areas of relative weakness were in the subcategories of Stress Tolerance, Assertiveness, Independence, and Problem Solving (all p<0.05). The EI of pediatric residents is consistent with that of other professionals. Educational interventions may be useful in the areas of weakness to enhance the physician-patient relationship.


p16 gene methylation in colorectal cancer patients with long-term follow-up.
p16 gene plays an important role in the cell cycle regulation and is considered an important tumor suppressor gene. Several mechanisms of gene inactivation have been described; in this study we have focused on p16 gene promoter methylation. In colorectal cancer p16 gene methylation is a frequent event. 326 patients with sporadic colorectal cancer were included. DNA was extracted from tumor tissue samples obtained during the surgical procedure. Promoter methylation was analyzed using bisulfite modification and was detected by quantitative methylation-specific PCR. Frequency of p16 methylation was analyzed and compared with other clinicopathological variables. p16 gene methylation was detected in 24.8% of patients. Methylation was associated with differentiation grade and with tumor location: methylation was frequent in poorly differentiated tumors and had low frequency in distal colon. The p16 promoter methylation discriminated a subgroup of patients with better prognosis in poorly differentiated tumors. p16 methylation was a frequent event in our population and was able to induce differences in the overall survival of patients with poorly differentiated tumors.


The effect of extract of ginkgo biloba added to haloperidol on superoxide dismutase in inpatients with chronic schizophrenia.
The purpose of the study was to evaluate the effect of the classic antipsychotic haloperidol plus extract of ginkgo biloba (EGb) on treatment-resistant chronic schizophrenia and on blood superoxide dismutase (SOD) levels. Eighty-two patients with chronic refractory schizophrenia were studied. Forty-three patients were treated with haloperidol plus extract of ginkgo biloba (group 1), and 39 received haloperidol plus placebo (group 2). SOD levels of these patients were measured before and after treatment and were compared with SOD levels of 30 healthy volunteers. Therapeutic efficiency was equated with a change in clinical rating scores assessed by standardized measurement tools that included the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms (SANS) over this period. Patients in group 1 improved significantly as demonstrated by scores from these two assessment instruments; those in group 2 improved significantly only as shown by scores on SANS. SOD levels before treatment in all patients were significantly higher than those in healthy controls; after treatment, the SOD level decreased significantly in group 1 but not in group 2. These results suggest that EGb may enhance the efficiency of the classic antipsychotic haloperidol in patients with schizophrenia, especially on their positive symptoms, and that EGb may work through an antioxidant effect that is involved in the therapeutic mechanism in patients with chronic refractory schizophrenia.


Collective behaviour of the European minnow (Phoxinus phoxinus) is influenced by signals of differing acoustic complexity.
Collective behaviour, such as shoaling in fish, benefits individuals through a variety of activities such as social information exchange and anti-predator defence. Human driven disturbance (e.g. anthropogenic noise) is known to affect the behaviour and physiology of individual animals, but the disruption of social aggregations of fish remains poorly understood. Anthropogenic noise originates from a variety of activities and differs in acoustic structure, dominant frequencies, and spectral complexity. The response of groups of fish may differ greatly, depending on the type of noise, and how it is perceived (e.g. threatening or attractive). In a controlled laboratory study, high resolution video tracking in combination with fine scale acoustic mapping was used to investigate the response of groups of European minnows (Phoxinus phoxinus) to signals of differing acoustic complexity (sinewave tones vs octave band noise) under low (150 Hz) and high (2200 Hz) frequencies. Fish startled and decreased their mean group swimming speed under all four treatments, with low frequency sinewave tones having the greatest influence on group behaviour. The shoals exhibited spatial avoidance during both low frequency treatments, with more time spent in areas of lower acoustic intensity than expected. This study illustrates how noise can influence the spatial distribution and social dynamics within groups of fish, and owing to the high potential for freshwater aquatic environments to be influenced by anthropogenic activity, wider consequences for populations should be further investigated.


Hematoma risk after needle electromyography.
Although needle electromyography (EMG) appears to be a relatively safe procedure based primarily on clinical experience, no evidence-based guidelines exist for EMG procedures in patients taking anticoagulant or antiplatelet medications. We sought to determine whether there is an increased risk of hematoma formation after EMG of potentially high-risk muscles in patients taking anticoagulant or antiplatelet agents. After undergoing routine EMG, if any of seven predetermined high-risk muscles were tested, study subjects then underwent ultrasound to evaluate for hematoma formation. Patients were divided into three groups based on medication (warfarin, aspirin/clopidogrel, no blood-thinning medication), with at least 100 muscles examined per group. Two small, subclinical hematomas were seen on ultrasound; there was no difference in hematoma risk between groups (P = 0.43). Our findings suggest that hematoma formation from standard needle EMG is rare even in high-risk muscles, which have been avoided historically in anticoagulated patients.


Minimal in-school SARS-CoV-2 transmission with strict mitigation protocols at two independent schools in Nashville, TN.
The COVID-19 pandemic has greatly impacted school operations. To better understand the role of schools in COVID-19 transmission, we evaluated infections at two independent schools in Nashville, TN during the 2020-2021 school year. The cumulative incidence of COVID-19 within each school, age group, and exposure setting were estimated and compared to local incidence. Primary attack rates were estimated among students quarantined for in-school close contact. Among 1401 students who attended school during the study period, 98 cases of COVID-19 were reported, corresponding to cumulative incidence of 7.0% (95% confidence interval (CI): 5.7-8.5). Most cases were linked to household (58%) or community (31%) transmission, with few linked to in-school transmission (11%). Overall, 619 students were quarantined, corresponding to >5000 person-days of missed school, among whom only 5 tested positive for SARS-CoV-2 during quarantine (primary attack rate: 0.8%, 95% CI: 0.3, 1.9). Weekly case rates at school were not correlated with community transmission. These results suggest that transmission of COVID-19 in schools is minimal when strict mitigation measures are used, even during periods of extensive community transmission. Strict quarantine of contacts may lead to unnecessary missed school days with minimal benefit to in-school transmission.


Cats as an aid to teaching genetics.
I have used an exercise involving domestic cats in the General Genetics course at the University of Nebraska-Lincoln for the past 5 years. Using a coherent set of traits in an organism familiar to the students makes it easy to illustrate principles of transmission and population genetics. The one-semester course consists primarily of sophomores and juniors who have either taken a one-semester introductory biology course, a one-semester cell biology course, or have a strong high school biology background. The students are given a handout and asked to determine the genotype at seven unlinked loci of at least one cat. To fill out the form, the students have to grasp such concepts as dominance, incomplete dominance, temperature-sensitive mutations, epistatic interactions, sex linkage, and variable expressivity. Completing the form reinforces these concepts as they observe the cat's phenotype and fill in the genotype. I then analyze the collected data and use it in my lectures on population genetics to illustrate the Hardy-Weinberg equilibrium, calculate allele frequencies, and use statistics. This allows the students to look at population genetics in a very positive light and provides concrete examples of some often misunderstood principles.


Brain death and Islam: the interface of religion, culture, history, law, and modern medicine.
How one defines death may vary. It is important for clinicians to recognize those aspects of a patient's religious beliefs that may directly influence medical care and how such practices may interface with local laws governing the determination of death. Debate continues about the validity and certainty of brain death criteria within Islamic traditions. A search of PubMed, Scopus, EMBASE, Web of Science, PsycNet, Sociological Abstracts, DIALOGUE ProQuest, Lexus Nexus, Google, and applicable religious texts was conducted to address the question of whether brain death is accepted as true death among Islamic scholars and clinicians and to discuss how divergent opinions may affect clinical care. The results of the literature review inform this discussion. Brain death has been acknowledged as representing true death by many Muslim scholars and medical organizations, including the Islamic Fiqh Academies of the Organization of the Islamic Conference and the Muslim World League, the Islamic Medical Association of North America, and other faith-based medical organizations as well as legal rulings by multiple Islamic nations. However, consensus in the Muslim world is not unanimous, and a sizable minority accepts death by cardiopulmonary criteria only.


[Miller Fisher syndrome, internal and external ophthalmoplegia after flu vaccination].
Miller Fisher Syndrome (MFS) is the most frequent variant of the Guillain-Barré Syndrome. It is characterised by the classic triad of ophthalmoplegia, ataxia and areflexia. We present a case of a patient who developed these clinical findings 5 days after flu vaccination. Miller Fisher Syndrome is an unusual condition seen in ophthalmologic clinical practice. Although respiratory and digestive infections have been reported as antecedent infectious agents in MFS, it has not previously been described in relation to the flu vaccine.


Stimulation of creatine kinase activity by calcium-regulating hormones in explants of human amnion, decidua, and placenta.
We have used stimulation of the activity of the brain type creatine kinase (CK) isoenzyme as a response marker to examine the effects of vitamin D metabolites, PTH, and calcitonin in cultured explants of placenta, decidua, and amnion from normal human deliveries. We found a biological response to PTH in placenta and amnion and to vitamin D metabolites in all three tissues. In the amnion, CK activity increased 2.3-fold after 24 h of incubation in 2.5 nM 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], 3.8-fold when incubated with 12.5 nM 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] and 2.7-fold when incubated with 10 U/ml bovine PTH. In the decidua, 24,25-(OH)2D3, but not 1,25-(OH)2D3 or bPTH caused a 1.7-fold increase in CK activity. In contrast, the placenta responded to 1,25-(OH)2D3 with a 1.6-fold increase in CK activity and to bPTH, with a 1.7-fold increase but did not respond to 24,25-(OH)2D3. Bovine calcitonin (100 ng/ml) had no effect on CK activity in any of the three tissues. Nearly all CK in both the unstimulated and stimulated explants was the brain type isoenzyme. CK activity increased significantly between 1 and 4 h after hormonal treatment in all experiments. The enzyme activity rose steeply with dose and reached a significant increase, and usually a plateau, at hormone concentrations considered to be physiological in vivo. [3H]Thymidine incorporation into DNA increased in parallel to stimulation of CK activity in all experiments, except that PTH did not increase DNA synthesis in the placenta. PTH did cause an increase in cAMP production in explants of amnion (1.5-fold) and placenta (2.6-fold).


Haematological cancers: improving outcomes. A summary of updated NICE service guidance in relation to Specialist Integrated Haematological Malignancy Diagnostic Services (SIHMDS).
Haematological malignancies are a diverse group of cancers that affect the blood, bone marrow and lymphatic systems. Laboratory diagnosis of haematological malignancies is dependent on combining several technologies, including morphology, immunophenotyping, cytogenetics and molecular genetics correlated clinical details and classification according to the current WHO guidelines. The concept of the Specialised Integrated Haematological Malignancy Diagnostic Services (SIHMDS) has evolved since the UK National Institute for Health and Care Excellence (NICE) Improving Outcomes Guidance (IOG) in 2003 and subsequently various models of delivery have been established. As part of the 2016 update to the NICE IOG, these models were systematically evaluated and recommendations produced to form the basis for quality standards for future development of SIHMDS. We provide a summary of the systematic review and recommendations. Although the recommendations pertain to the UK National Health Service (NHS), they have relevance to the modern delivery of diagnostic services internationally.


Interleukin-10: a multi-faceted agent of pregnancy.
It is widely accepted that pregnancy constitutes a unique developmental event. Unprecedented intrauterine actions of angiogenesis, immunity, and neuroendocrine regulation are juxtaposed to mechanisms of senescence that enable fetal growth and protection. The suppressive and regulatory factors that facilitate healthy pregnancy are under investigation. In non-pregnant systems of infection and inflammation, the cytokine interleukin-10 (IL-10) has been widely investigated because of its potential as a key immunosuppressant in response to a multitude of inflammatory events. In the context of pregnancy, IL-10 levels increase markedly in women during early pregnancy and remain elevated well into the third trimester immediately prior to onset of labor. The role of IL-10 during pregnancy as a suppressor of active maternal immunity to allow acceptance of the fetal allograft has been a point of study. Moreover, secretion of IL-10 by a diverse set of maternal and fetal cells has proven to aid in the orchestration of normal processes of pregnancy. Interestingly, some of the more profound findings regarding the actions of IL-10 during pregnancy have manifested from research that focuses on aberrant pregnancy outcomes as a result of inflammation, hormonal imbalances, or gene-environment interactions. This review focuses on the role of IL-10 as a facilitator of successful pregnancy both as an immune suppressive agent and a mediator of cross talk between the placenta and the decidua. Importantly, we discuss investigations on adverse pregnancy conditions to further elucidate the multifarious role of IL-10 at the maternal-fetal interface.