Serum HER-2 extracellular domain: relationship with clinicobiological presentation and prognostic value before and after primary treatment in 701 breast cancer patients.
To determine the clinical correlations and prognostic value of serum HER-2 (sHER-2) before and after primary breast cancer treatment. sHER-2 from 701 consecutive patients with stage I-III tumors (median follow-up 7.7 years) was assayed by an enzyme-linked immunosorbent assay (Immuno 1, Bayer Diagnostics). The median pretreatment sHER-2 concentration was 8.30 ng/mL (range 3.15-82.00 ng/mL). Forty-seven patients (6.7%) had sHER-2 concentrations >12 ng/mL (cutoff level). Pretreatment sHER-2 correlated positively with CA 15.3 (p=0.0169), pathological tumor size (p=0.0082), number of invaded lymph nodes (pN, p=0.0160) and histological grading (p=0.0086). Kaplan-Meier analyses indicated that pretreatment sHER-2 was of prognostic value for contralateral breast cancer (p=0.0018), metastasis-free survival (MFS) (p=0.0008) - particularly lung (p=0.0082) and liver metastases (p=0.0035) - and overall disease-specific survival (DSS) (p=0.0020). According to pN status, pretreatment sHER-2 was of prognostic value only for pN-positive patients (p=0.0017). When combined with estradiol or progesterone receptor status, patients with elevated sHER-2 and receptor-negative tumors had a significantly shorter DSS (p<0.0001 for both receptors). Post-treatment sHER-2 also had individual prognostic value for MFS (p=0.0144) and DSS (p=0.0212). In multivariate analysis, only sHER-2 after primary treatment was an independent prognostic variable for MFS and DSS (p=0.0078 and p=0.0058, respectively). sHER-2 elevation in early breast cancer correlates with the principal criteria of tumor aggressiveness, thus permitting selection of patients with a high risk of visceral metastases and contralateral breast tumors. Post-treatment sHER-2 is an independent prognostic factor enabling to identify patients likely to benefit from aggressive adjuvant treatments.


Femoral-facial syndrome: Prenatal diagnosis and clinical features. Report of three cases.
The objective of our article is to illustrate the earliest prenatal sonographic diagnosis of femoral-facial syndrome (FFS) and to illustrate the spectrum of clinical manifestations of this condition. We present serial sonographic evaluation with 3D evaluation in two fetuses diagnosed prenatally with FFS and the postnatal findings in three patients (one fetus following pregnancy interruption and two newborns one of whom was diagnosed prenatally) with FFS. The two patients with prenatally diagnosed FFS were found to have femoral shortening and characteristic facial features, one 12 weeks of gestation, and one at 15 weeks of gestation. The sonographic findings in the two prenatally diagnosed patients were confirmed after delivery. We also present a third patient who was diagnosed at delivery in whom the diagnosis was missed at a routine prenatal sonogram at 19 weeks of gestation. The patients reported herein expand the clinical spectrum of FFS. The utility of sonographic evaluation in diagnosis of the facial appearance and of the bony abnormalities in this condition is emphasized.


Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress.
Cells coordinate interphase-to-mitosis transition, but recurrent cytogenetic lesions appear at common fragile sites (CFSs), termed CFS expression, in a tissue-specific manner after replication stress, marking regions of instability in cancer. Despite such a distinct defect, no model fully provides a molecular explanation for CFSs. We show that CFSs are characterized by impaired chromatin folding, manifesting as disrupted mitotic structures visible with molecular fluorescence in situ hybridization (FISH) probes in the presence and absence of replication stress. Chromosome condensation assays reveal that compaction-resistant chromatin lesions persist at CFSs throughout the cell cycle and mitosis. Cytogenetic and molecular lesions are marked by faulty condensin loading at CFSs, a defect in condensin-I-mediated compaction, and are coincident with mitotic DNA synthesis (MIDAS). This model suggests that, in conditions of exogenous replication stress, aberrant condensin loading leads to molecular defects and CFS expression, concomitantly providing an environment for MIDAS, which, if not resolved, results in chromosome instability.


Translation of Pur-α is targeted by cellular miRNAs to modulate the differentiation-dependent susceptibility of monocytes to HIV-1 infection.
The postentry restriction of HIV-1 replication in monocytes can be relieved when they differentiate to dendritic cells (DCs) or macrophages. Multiple mechanisms have been proposed to interpret the differentiation-dependent susceptibility of monocytes to HIV-1 infection, and the absence of host-cell-encoded essential factors for HIV-1 completing the life cycle may provide an explanation. We have analyzed the gene expression profile in monocytes by mRNA microarray and compared it with that of differentiated DCs. We demonstrated that purine-rich element binding protein α (Pur-α), a host-cell-encoded ubiquitous, sequence-specific DNA- and RNA-binding protein, showed inadequate expression in monocytes, and the translation of Pur-α mRNA was repressed by cell-expressed microRNA (miRNA). These Pur-α-targeted miRNAs modulated the differentiation-dependent susceptibility of monocytes/DCs to HIV-1 infection, because rescue of Pur-α expression by transfection of miRNA inhibitors relieved the restriction of HIV-1 infection in monocytes, and ectopic input of miRNA mimics significantly reduced HIV-1 infection of monocyte-derived DCs (MDDCs). Collectively, our data emphasized that inadequate host factors contribute to HIV-1 restriction in monocytes, and cellular miRNAs modulate differentiation-dependent susceptibility of host cells to HIV-1 infection. Elaboration of HIV-1 restriction in host cells facilitates our understanding of viral pathogenesis and the search for a new antiviral strategy.


Stochastic models for the Earth's relief, the shape and the fractal dimension of the coastlines, and the number-area rule for islands.
The degree of irregularity in oceanic coastlines and in vertical sections of the Earth, the distribution of the numbers of islands according to area, and the commonality of global shape between continents and islands, all suggest that the Earth's surface is statistically self-similar. The preferred parameter, one which increases with the degree of irregularity, is the fractal dimension, D, of the coastline; it is a fraction between 1 (limit of a smooth curve) and 2 (limit of a plane-filling curve). A rough Poisson-Brown stochastic model gives a good first approximation account of the relief, by assuming it to be created by superposing very many, very small cliffs, placed along straight faults and statistically independent. However, the relative area predicted for the largest islands is too small, and the irregularity predicted for the relief is excessive for most applications; so is indeed the value of the dimension, which is D = 1.5. Several higher approximation self-similar models are described. Any can be matched to the empirically observed D, and can link all the observations together, but the required self-similarity cannot yet be fully explained.


Formal representation of ambulatory assessment protocols in HTML5 for human readability and computer execution.
Ambulatory assessment (AA) is a research method that aims to collect longitudinal biopsychosocial data in groups of individuals. AA studies are commonly conducted via mobile devices such as smartphones. Researchers tend to communicate their AA protocols to the community in natural language by describing step-by-step procedures operating on a set of materials. However, natural language requires effort to transcribe onto and from the software systems used for data collection, and may be ambiguous, thereby making it harder to reproduce a study. Though AA protocols may also be written as code in a programming language, most programming languages are not easily read by most researchers. Thus, the quality of scientific discourse on AA stands to gain from protocol descriptions that are easy to read, yet remain formal and readily executable by computers. This paper makes the case for using the HyperText Markup Language (HTML) to achieve this. While HTML can suitably describe AA materials, it cannot describe AA procedures. To resolve this, and taking away lessons from previous efforts with protocol implementations in a system called TEMPEST, we offer a set of custom HTML5 elements that help treat HTML documents as executable programs that can both render AA materials, and effect AA procedures on computational platforms.


The Profile of Microorganisms Responsible for Port-Related Bacteremia in Pediatric Hemato-Oncological Patients.
Patients with pediatric cancer face an increased risk of infections. In most cases, these infections are associated with the use of a long-term central venous catheter. This study describes the epidemiology of a port-associated bacteremia as well as a profile of microorganisms responsible for port-associated bloodstream infections (PABSIs) in pediatric patients with cancer treated in a single center. The retrospective analysis included patients with cancer who had implanted a port, hospitalized between 2010 and 2015 at the Department of Pediatric Oncology, Hematology and Bone Marrow Transplantation, Poznan University of Medical Sciences. The medical records of patients were reviewed for demographic characteristics, diagnosis, port-related complications, and their management. Data were collected from patients' electronic medical records containing complete information on medical examinations and supplementary tests, diagnosis, timing, and type of port-associated complications. In a study period, 277 ports were inserted to 241 patients. A total of 183 094 catheter days were analyzed. Sixteen patients had more than 1 insertion of a port. The commonest observed complication was PABSI (40.07%) and the incidence density was 0.6 per 1000 port-days. Staphylococcus was the most commonly isolated organisms from patients with PABSI. From all port-associated complications, bloodstream infections and mechanical complications were the most often observed complications. The commonest pathogens responsible for PABSI were coagulase-negative staphylococci. Pathogens resistant to standard antibiotic treatment play an important role in PABSI, with methicillin-resistant Staphylococcus epidermidis being the predominant pathogen. Port-associated bloodstream infections are a common reason for preterm removal of a port.


Consensus statement on dementia education and training in Europe.
The aim of the current statement is to agree on: (1) what is the current situation with education and training on dementia in Europe; (2) what are the minimum educational requirements for professionals (neurologists, psychiatrists, primary care providers, nurses, biologists, neuroradiologists, etc.) regarding Alzheimer's disease and dementia, and (3) how to start a course of action for the future. In 2005, a simple questionnaire was sent to members of the European Alzheimer's Disease Consortium (EADC) concerning the education and training on dementia in their countries. Fourteen universities of the respective countries responded to this simple questionnaire. The answers varied, and the conclusion of this effort was that little was done concerning the training of students and health professionals on dementia. In 2008, another more structured and specified questionnaire was sent to professors in different universities of the same countries. The answers obtained were different from those of the previous questionnaire and demonstrated that it is very difficult to know about training and education in the field of dementia in every European country. From the data collected, it seems that although in the recent past little had been done concerning training on dementia, nowadays training has been developed in most European countries, and relevant educational projects exist both for medical students and doctors during their specialty training. Our main purpose is to develop training material or develop specific courses to improve the professional knowledge about dementia so that best medical and non-medical practice is implemented.


Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations.
Herein, the thermodynamic properties of solutions evolving from the non-sink dissolution of amorphous solid dispersions (ASDs) containing two or more drugs have been evaluated, focusing on the maximum achievable supersaturation and tendency of the system to undergo liquid-liquid phase separation (LLPS). Ritonavir (RTV) and atazanavir (ATV) were co-formulated with polyvinylpyrrolidone to produce ASDs with different molar ratios of each drug, and the dissolution profile of each drug was studied under non-sink conditions. The phase behavior of the supersaturated solutions generated by ASD dissolution was compared to that of supersaturated solutions generated by antisolvent addition. Dissolution of an ASD containing RTV, ATV and lopinavir (LPV) was also investigated. A thermodynamic model was used to predict the maximum achievable supersaturation for ASDs containing two and three drugs. In addition, a transport study with Caco-2 cells was conducted to evaluate the impact of co-addition of drugs on membrane transport. It was found that the formulation containing a 1:1 molar ratio of RTV and ATV achieved only 50% of the supersaturation attained by dissolution of the single drug systems. The maximum achievable concentration of ATV decreased linearly as the mole fraction of ATV in the formulation decreased and a similar trend was observed for RTV. For the dispersion containing a 1:1:1 molar ratio of RTV, ATV and LPV, the maximum concentration of each drug was only one third of that achieved for the single drug formulations. The decrease in the achievable supersaturation was well-predicted by the thermodynamic model for both the binary and ternary drug combinations. These observations can be explained by a decrease in the concentration at which the drugs undergo LLPS in the presence of other miscible drugs, thereby reducing the maximum achievable supersaturation of each drug. The reduced free drug concentration was reflected by a decreased flux across Caco-2 cells for the drug combinations compared to drug alone. This study sheds light on the complex dissolution and solution phase behavior of multicomponent amorphous dosage forms, in particular those containing poorly water soluble drugs, which may undergo supersaturation in vivo.


Oxalate quantification in hemodialysate to assess dialysis adequacy for primary hyperoxaluria.
Patients with primary hyperoxaluria (PH) overproduce oxalate which is eliminated via the kidneys. If end-stage kidney disease develops they are at high risk for systemic oxalosis, unless adequate oxalate is removed during hemodialysis (HD) to equal or exceed ongoing oxalate production. The purpose of this study was to validate a method to measure oxalate removal in this unique group of dialysis patients. Fourteen stable patients with a confirmed diagnosis of PH on HD were included in the study. Oxalate was measured serially in hemodialysate and plasma samples in order to calculate rates of oxalate removal. HD regimens were adjusted according to a given patient's historical oxalate production, amount of oxalate removal at dialysis, residual renal clearance of oxalate, and plasma oxalate levels. After a typical session of HD, plasma oxalate was reduced by 78.4 ± 7.7%. Eight patients performed HD 6 times/week, 2 patients 5 times/week, and 3 patients 3 times/week. Combined oxalate removal by HD and the kidneys was sufficient to match or exceed endogenous oxalate production. After a median period of 9 months, pre-dialysis plasma oxalate was significantly lower than initially (75.1 ± 33.4 vs. 54.8 ± 46.6 mmol/l, p = 0.02). This methodology can be used to individualize the dialysis prescription of PH patients to prevent oxalosis during the time they are maintained on HD and to reduce risk of oxalate injury to a transplanted kidney.


The Effect of UK Nursing Policy on Higher Education Wound Care Provision and Practice: A Critical Discourse Analysis.
In the United Kingdom, significant ongoing inconsistency exists in wound care nursing education provision and practice. Health economists have identified this to be a major cause of the burgeoning economic and personal cost of successfully, and equitably, healing chronic wounds. While numerous wound care educational resources exist, policies intended to implement a program of reform or change are for some reason not filtering down to, or being implemented by, those who need them most. Policy making processes do not appear to be operating as efficiently as they should, and this merits further scrutiny. A critical discourse analysis of two UK professional body wound care policies provided an innovative insight into the effect of policy production to the research problem. The overarching construct of "Aspiration and Resolution" and its subconstructs were identified. Links between data, analysis, and conclusions were established using Greckhamer and Cilesiz's (2014) framework to address criticisms over lack of transparency in critical discourse analysis methodology. Findings indicate wound care policy makers must adopt an active, not passive, approach to policy making. An active position, compared with the inertia that appears to currently exist, would take into consideration the capacity to implement policy and not merely increase awareness or disseminate. Wound healing policy making agencies need to make decisions on how to disseminate and implement policy. Active policy making would also adopt target audiences' decisions to implement policy, instigate activities to improve knowledge and skills, facilitate change, and ensure continued use of policy as part of organizational operations.


Treatment of Mpox with Suspected Tecovirimat Resistance in Immunocompromised Patient, United States, 2022.
Reports of tecovirimat-resistant mpox have emerged after widespread use of antiviral therapy during the 2022 mpox outbreak. Optimal management of patients with persistent infection with or without suspected resistance is yet to be established. We report a successfully treated case of severe mpox in California, USA, that had suspected tecovirimat resistance.


Rofecoxib 12.5 mg, rofecoxib 25 mg, and celecoxib 200 mg in the treatment of symptomatic osteoarthritis: results of two similarly designed studies.
To compare the efficacy of rofecoxib and celecoxib for the treatment of knee or hip OA over 6 weeks. Two similarly designed, multicenter, randomized, double-blind, placebo-controlled studies. Patients were randomly assigned 3:3:3:1 in Study 1 to once daily (QD) rofecoxib 12.5 mg (N = 456), rofecoxib 25 mg (N = 459), celecoxib 200 mg (N = 456), or placebo (N = 150) and 3:3:1 in Study 2 to QD rofecoxib 25 mg (N = 471), celecoxib 200 mg (N = 460), or placebo (N = 151). There was no rofecoxib 12.5 mg arm in Study 2. The primary outcome measure of both studies was pain at night over 6 weeks for rofecoxib 25 mg vs. celecoxib 200 mg. Efficacy comparisons with rofecoxib 12.5 mg in Study 1 were included as pre-specified study objectives but not as pre-specified study hypotheses. Secondary endpoints included Patient Global Assessment of Response to Therapy (PGART) over 6 weeks and over 1 week. Safety was evaluated through the assessment of spontaneously reported adverse experiences (AEs), evaluation of vital signs, and laboratory data reported by investigators and patients. For the primary endpoint, reduction in pain at night over 6 weeks in Study 1 was not significantly different between active treatments; in Study 2 rofecoxib 25 mg significantly (p = 0.023) reduced pain at night compared with celecoxib 200 mg over 6 weeks. For the secondary endpoints, in both studies, significantly (p < 0.05) more patients treated with rofecoxib 25 mg than celecoxib 200 mg had a good or excellent PGART over 6 weeks, and over the first week (p < 0.01). In both studies, there were no significant differences between active medications in the incidence of reported overall, serious, or drug-related AEs. The reported AE rates with the active treatments were generally similar to those with placebo in the two studies. Rofecoxib 25 mg was significantly better than celecoxib 200 mg in relieving night pain at 6 weeks in one study; this was not confirmed in the accompanying study.


Linear biocompatible glyco-polyamidoamines as dual action mode virus infection inhibitors with potential as broad-spectrum microbicides for sexually transmitted diseases.
The initial steps of viral infections are mediated by interactions between viral proteins and cellular receptors. Blocking the latter with high-affinity ligands may inhibit infection. DC-SIGN, a C-type lectin receptor expressed by immature dendritic cells and macrophages, mediates human immunodeficiency virus (HIV) infection by recognizing mannose clusters on the HIV-1 gp120 envelope glycoprotein. Mannosylated glycodendrimers act as HIV entry inhibitors thanks to their ability to block this receptor. Previously, an amphoteric, but prevailingly cationic polyamidoamine named AGMA1 proved effective as infection inhibitor for several heparan sulfate proteoglycan-dependent viruses, such as human papilloma virus HPV-16 and herpes simplex virus HSV-2. An amphoteric, but prevailingly anionic PAA named ISA23 proved inactive. It was speculated that the substitution of mannosylated units for a limited percentage of AGMA1 repeating units, while imparting anti-HIV activity, would preserve the fundamentals of its HPV-16 and HSV-2 infection inhibitory activity. In this work, four biocompatible linear PAAs carrying different amounts of mannosyl-triazolyl pendants, Man-ISA7, Man-ISA14, Man-AGMA6.5 and Man-AGMA14.5, were prepared by reaction of 2-(azidoethyl)-α-D-mannopyranoside and differently propargyl-substituted AGMA1 and ISA23. All mannosylated PAAs inhibited HIV infection. Both Man-AGMA6.5 and Man-AGMA14.5 maintained the HPV-16 and HSV-2 activity of the parent polymer, proving broad-spectrum, dual action mode virus infection inhibitors.


Early cardiac dysfunction in obese adolescents with Down syndrome or autism.
Obesity in adolescents with intellectual and developmental disabilities) occurs at twice the frequency as their typically developing peers. Typically developing adolescents with obesity have abnormal cardiac function (as measured by strain echocardiography) and cardiac mass, but the effects of obesity on cardiac health in adolescents with Down syndrome or autism spectrum disorder are unknown. The purpose of this study was to evaluate the impact of body mass index on cardiac function in adolescents with Down syndrome or autism. Adolescents (age 12-21 years) with Down syndrome (n = 28), autism (n = 33), and age-/sex-matched typically developing controls (n = 15) received an echocardiogram optimised for strain analysis at a single timepoint. Measures of ventricular function, mass, and size were collected. Regression modelling evaluated the impact of body mass index and intellectual and developmental disabilities diagnosis on these cardiac measures. In regression modelling, an elevated body mass index z-score was associated with diminished systolic biventricular function by global strain (left ventricular longitudinal strain β 0.87, P < 0.001; left ventricular circumferential strain β 0.57, p 0.003; right ventricular longitudinal strain β 0.63, P < 0.001). Diminished left ventricular diastolic function by early diastolic strain rate was also associated with elevated body mass index (global longitudinal end-diastolic strain rate β -0.7, P < 0.001). No association was found between traditional (non-strain) measures of systolic and diastolic ventricular function and body mass index z-score. Obesity in adolescents with Down syndrome or autism negatively impacts cardiac function as measured by echocardiographic strain analysis that was not detected by traditional parameters.


Neuropeptide Y overexpression in the preweanling Zucker (fa/fa) rat.
Hypothalamic preproNPY overexpression in the Zucker fatty (fa/fa) rat was examined. In situ hybridization was used to determine the relative level of preproNPY mRNA in the arcuate nucleus of +/+, +/fa, and fa/fa pups aged postnatal day 2 (P2), 5, 9, 12, or 25. The relative optical density (ROD) of probe hybridization in the arcuate, the area of hybridization (A), and the product of ROD x A (a measure of total arcuate preproNPY mRNA hybridization) were measured. Values were normalized to the mean +/fa value within each litter. Initial analysis showed that preproNPY mRNA hybridization (ROD x A) in fa/fa pups was significantly higher than +/fa and +/+ pups on P9, 12, and 25, and significantly higher than +/fa on P5. No significant difference between lean (+/+ and +/fa) genotypes, however, were observed at any age tested. Values from the lean genotypes were, therefore, pooled, and data were normalized to the mean value of lean animals for analysis. This analysis revealed that preproNPY mRNA hybridization in fa/fa pups was higher than lean littermates as early as P2.


Cell geometry regulates tissue fracture.
In vascular plants, the epidermal surfaces of leaves and flower petals often display cells with wavy geometries forming intricate jigsaw puzzle patterns. The prevalence and diversity of these complex epidermal patterns, originating from simple polyhedral progenitor cells, suggest adaptive significance. However, despite multiple efforts to explain the evolutionary drivers behind these geometrical features, compelling validation remains elusive. Employing a multidisciplinary approach that integrates microscopic and macroscopic fracture experiments with computational fracture mechanics, we demonstrate that wavy epidermal cells toughen the plants' protective skin. Through a multi-scale framework, we demonstrate that this energy-efficient patterning mechanism is universally applicable for toughening biological and synthetic materials. Our findings reveal a tunable structural-mechanical strategy employed in the microscale design of plants to protect them from deleterious surface fissures while facilitating and strategically directing beneficial ones. These findings hold implications for targeted plant breeding aimed at enhancing resilience in fluctuating environmental conditions. From an engineering perspective, our work highlights the sophisticated design principles the plant kingdom offers to inspire metamaterials.


Development of a multiplex PCR for the identification of major pathogenic bacteria of post-partum endometritis in dairy cows.
Post-partum period has an important role in cows' breeding due to its effects on reproductive efficiency and subsequent pregnancy. Escherichia coli, Trueperella pyogenes (Arcanobacterium pyogenes), Fusobacterium necrophorum and Prevotella melaninogenicus are recognized as major pathogens associated with uterine endometrial lesions. The objective of this study was to identify these pathogens using the polymerase chain reaction (PCR) as a culture-independent sensitive method. A total of 172 cows were examined 25-35 days post-partum, and 128 cows were examined at 2 weeks later (39-49 days post-partum). Uterine discharges were collected by covered plastic infusion pipettes. The prevalence of endometritis was greater in the first examination than the second (35.5% vs. 16%). E. coli was detected in eight of the samples, T. pyogenes was detected in 13 of the samples and F. necrophorum was detected in 11 of the samples. There was no positive sample of P. melaninogenicus. Uterine contamination by T. pyogenes and F. necrophorum in the first examination was higher than the second examination. T. pyogenes affected as a tendency the prevalence of clinical endometritis in first examination. Primiparous cows showed 4.02 times higher odds of clinical endometritis compared with second-parity cows in first examination. A multiplex PCR protocol as a simple, less expensive, fast assay was introduced to identify E. coli, T. pyogenes and F. necrophorum.


Patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation: trends in survival during the past two decades.
It remains unclear how specific innovations in allogeneic hematopoietic cell transplantation (HCT) attained over the past decades have contributed to improvement in transplantation outcomes. To address this question, we conducted a registry-based study of adults with acute myeloid leukemia in first or second complete remission who underwent allogeneic HCT between 1994 and 2013 from a sibling (N = 1600) or unrelated (N = 2113) donor matched at the antigen level for HLA-A, -B, and -DR. Preliminary analysis led us to focus on comparisons between the 1994-2006 and 2007-2013 periods. Significant improvement in survival was observed in the later cohort compared to the earlier cohort for unrelated HCT (P = 0.004), but not for related HCT (P = 0.767). The improvement in unrelated HCT was solely due to diminished non-relapse mortality (P = 0.001), while incidence of relapse did not change over time (P = 0.934). The percentage of patients receiving transplants from 8/8-matched unrelated donors was significantly higher in the later cohort (P < 0.001), and their survival was significantly better than that of those undergoing mismatched unrelated HCT (P = 0.022). These findings suggest that advances in HLA-typing technology have been vital for improvement in transplantation outcomes.


Minimal pre-operative leg length discrepancy as a risk factor of post-operative leg length discrepancy after total hip arthroplasty: a retrospective study of patients with non-traumatic osteonecrosis of the femoral head.
Leg length discrepancy (LLD) is one of the troublesome complications of total hip arthroplasty (THA). Previously, several risk factors have been suggested, but they were subjected to their inherent limitations. By controlling confounding variables, we hypothesized that known risk factors be re-evaluated and novel ones be discovered. This study aimed to analyze the independent risk factors for LLD after primary THA in patients with non-traumatic osteonecrosis of the femoral head (ONFH). We retrospectively reviewed patients with non-traumatic ONFH who underwent unilateral THA between 2014 and 2021. All patients were operated by one senior surgeon using a single implant. Demographic data, surgical parameters, and radiological findings (pre-operative LLD, Dorr classification, and femoral neck resection) were analyzed to identify the risk factors of ≥ 5 mm post-operative LLD based on radiological measurement and to calculate odds ratios by logistic regression analysis. Post hoc power analysis demonstrated that the number of analyzed patients was sufficient with 80% power. One hundred and eighty-six patients were analyzed, including 96 females, with a mean age of 58.8 years at the time of initial THA. The average post-operative LLD was 1.2 ± 2.9 mm in the control group and 9.7 ± 3.2 mm in the LLD group, respectively. The LLD group tended to have minimal pre-operative LLD than the control group (-3.2 ± 5.1 mm vs. -7.9 ± 5.8 mm p = 2.38 × 10- 8). No significant difference was found between the groups in age, gender, body mass index, femoral cortical index, and implant size. Mild pre-operative LLD is associated with an increased risk of post-operative LLD after primary THA in patients with ONFH. Thus, surgeons should recognize pre-operative LLD to achieve an optimal outcome and must inform patients about the risk of developing LLD.


The Combined Effect of Common Genetic Risk Variants on Circulating Lipoproteins Is Evident in Childhood: A Longitudinal Analysis of the Cardiovascular Risk in Young Finns Study.
Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are modifiable risk factors for cardiovascular disease. Several genetic loci for predisposition to abnormal LDL-C, HDL-C and TG have been identified. However, it remains unclear whether these loci are consistently associated with serum lipid levels at each age or with unique developmental trajectories. Therefore, we assessed the association between genome wide association studies (GWAS) derived polygenic genetic risk scores and LDL-C, HDL-C, and triglyceride trajectories from childhood to adulthood using data available from the 27-year European 'Cardiovascular Risk in Young Finns' Study. For 2,442 participants, three weighted genetic risk scores (wGRSs) for HDL-C (38 SNPs), LDL-C (14 SNPs) and triglycerides (24 SNPs) were computed and tested for association with serum lipoprotein levels measured up to 8 times between 1980 and 2011. The categorical analyses revealed no clear divergence of blood lipid trajectories over time between wGRSs categories, with participants in the lower wGRS quartiles tending to have average lipoprotein concentrations 30 to 45% lower than those in the upper-quartile wGRS beginning at age 3 years and continuing through to age 49 years (where the upper-quartile wGRS have 4-7 more risk alleles than the lower wGRS group). Continuous analyses, however, revealed a significant but moderate time-dependent genetic interaction for HDL-C levels, with the association between HDL-C and the continuous HDL-C risk score weakening slightly with age. Conversely, in males, the association between the continuous TG genetic risk score and triglycerides levels tended to be lower in childhood and become more pronounced after the age of 25 years. Although the influence of genetic factors on age-specific lipoprotein values and developmental trajectories is complex, our data show that wGRSs are highly predictive of HDL-C, LDL-C, and triglyceride levels at all ages.


Designing Activities to Teach Higher-Order Skills: How Feedback and Constraint Affect Learning of Experimental Design.
Active learning approaches to biology teaching, including simulation-based activities, are known to enhance student learning, especially of higher-order skills; nonetheless, there are still many open questions about what features of an activity promote optimal learning. Here we designed three versions of a simulation-based tutorial called Understanding Experimental Design that asks students to design experiments and collect data to test their hypotheses. The three versions vary the experimental design task along the axes of feedback and constraint, where constraint measures how much choice students have in performing a task. Using a variety of assessments, we ask whether each of those features affects student learning of experimental design. We find that feedback has a direct positive effect on learning. We further find that small changes in constraint have only subtle and mostly indirect effects on learning. This work suggests that designers of tools for teaching higher-order skills should strive to include feedback to increase impact and may feel freer to vary the degree of constraint within a range to optimize for other features such as the ability to provide immediate feedback and time-on-task.


Pancreatic fluid collections: Clinical manifestations, diagnostic evaluation and management.
Pancreatic fluid collections (PFC), including pancreatic pseudocysts and walled-off pancreatic necrosis, are a known complication of severe acute pancreatitis. A majority of the PFCs remain asymptomatic and resolve spontaneously. However, some PFCs persist and can become symptomatic. Persistent PFCs can also cause further complications such as the gastric outlet, intestinal, or biliary obstruction and infection. Surgical interventions are indicated for the drainage of symptomatic sterile and infected PFCs. Management of PFCs has evolved from a primarily surgical or percutaneous approach to a less invasive endoscopic approach. Endoscopic interventions are associated with improved outcomes with lesser chances of complications, faster recovery time, and lower healthcare utilization. Endoscopic ultrasound-guided drainage of PFCs using lumen-apposing metal stents has become the preferred approach for the management of symptomatic and complicated PFCs.


Impact of after-hours telemedicine on hospitalizations in a skilled nursing facility.
Skilled nursing facilities (SNFs) are increasingly being called upon to prevent avoidable hospitalizations. Primary care provider (PCP) bedside assessment for change of condition in SNF patients is believed to improve care and reduce unnecessary hospitalizations, but PCPs are not always available on site in an SNF. This study addresses the potential clinical and financial impacts of an after-hours physician coverage service enabled by technology, TripleCare (TC), to prevent avoidable hospitalizations. TC was launched in a 365-bed SNF in Brooklyn, New York, in March 2015. Outcomes were tracked and evaluated for the initial year. Avoided hospitalizations were identified as such by the covering physicians and confirmed by the facility's medical director. Of the 313 patients cared for by the telemedicine-enabled covering physicians during the year of service, 259 (83%) were treated on site, including 91 who avoided hospitalizations as verified by a third party, and 54 were transferred to the hospital. It is estimated that the associated cost savings to Medicare and other payers exceeded $1.55 million, approximately $500,000 of which went to a managed care Medicare payer, in this 1 SNF during this period. Medicare would annually save $500,000 in an average 120-bed facility, or $4167 per bed. Use of a dedicated virtual after-hours physician coverage service in an SNF demonstrated a significant reduction in avoidable hospitalizations.


Endovascular treatment of iliac and common femoral arteries disease by the transradial access: A prospective, feasibility study.
To report feasibility and safety of endovascular interventions on iliac and common femoral arteries, using the transradial access (TRA). 100 consecutive patients (19 women; mean age 71, range 37-90years) with critical limb ischemia (30%) or claudication, and TASC A-D lesions in iliac or common femoral arteries, were prospectively enrolled, from January 2013 to June 2015, to be treated via the TRA. Exclusion criteria included no palpable radial arteries (RA) and the presence of a fistula for hemodialysis. Patients were evaluated for procedural technical success, in-hospital complications, and 30days clinical success (defined as improvement of at least one grade in the Rutherford classification of symptoms). A total of 131 iliac and common femoral arteries lesions were treated (58 in common iliac arteries, 38 in external iliac arteries and 35 in common femoral arteries). Ninety-two stents were deployed in 58 patients. Procedural technical success was achieved in 91% of the lesions; with 95% technical success rate in common iliac arteries, 87% in external iliac arteries and 89% in common femoral arteries; with 72% technical success rate in occlusions and 98% in stenosis. No in-hospital complications were observed. At 30days, 93 patients (93%) had an improvement of at least one category in the Rutherford classification of symptoms (clinical success rate 93%); 12 patients (12%) had an asymptomatic occlusion of the RA. TRA can be used to treat iliac and common femoral arteries lesions with a high grade of technical success and a low rate of complications.


Conjugated docosahexaenoic acid suppresses KPL-1 human breast cancer cell growth in vitro and in vivo: potential mechanisms of action.
The present study was conducted to examine the effect of conjugated docosahexaenoic acid (CDHA) on cell growth, cell cycle progression, mode of cell death, and expression of cell cycle regulatory and/or apoptosis-related proteins in KPL-1 human breast cancer cell line. This effect of CDHA was compared with that of docosahexaenoic acid (DHA). KPL-1 cell growth was assessed by colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; cell cycle progression and mode of cell death were examined by flow cytometry; and levels of expression of p53, p21Cip1/Waf1, cyclin D1, Bax, and Bcl-2 proteins were examined by Western blotting analysis. In vivo tumor growth was examined by injecting KPL-1 cells subcutaneously into the area of the right thoracic mammary fat pad of female athymic mice fed a CDHA diet. CDHA inhibited KPL-1 cells more effectively than did DHA (50% inhibitory concentration for 72 hours: 97 micromol/l and 270 micromol/l, respectively). With both CDHA and DHA growth inhibition was due to apoptosis, as indicated by the appearance of a sub-G1 fraction. The apoptosis cascade involved downregulation of Bcl-2 protein; Bax expression was unchanged. Cell cycle progression was due to G0/G1 arrest, which involved increased expression of p53 and p21Cip1/Waf1, and decreased expression of cyclin D1. CDHA modulated cell cycle regulatory proteins and apoptosis-related proteins in a manner similar to that of parent DHA. In the athymic mouse system 1.0% dietary CDHA, but not 0.2%, significantly suppressed growth of KPL-1 tumor cells; CDHA tended to decrease regional lymph node metastasis in a dose dependent manner. CDHA inhibited growth of KPL-1 human breast cancer cells in vitro more effectively than did DHA. The mechanisms of action involved modulation of apoptosis cascade and cell cycle progression. Dietary CDHA at 1.0% suppressed KPL-1 cell growth in the athymic mouse system.


Excitation-contraction coupling in cardiac Purkinje fibers. Effects of cardiotonic steroids on the intracellular [Ca2+] transient, membrane potential, and contraction.
The [Ca2+]-activated photoprotein aequorin was used to measure [Ca2+] in canine cardiac Purkinje fibers during the positive inotropic and toxic effects of ouabain, strophanthidin, and acetylstrophanthidin. The positive inotropic effect of these substances was associated with increases in the two components of the aequorin signal, L1 and L2. On the average, strophanthidin at 10(-7) M produced steady, reversible increases in L1, L2, and peak twitch tension of 20, 91, and 240%, respectively. This corresponds to increases in the upper-limit spatial average [Ca2+] from 1.9 X 10(-6) M to 2.1 X 10(-6) M at L1 and from 1.4 X 10(-6) M to 1.8 X 10(-6) M at L2. Elevation of diastolic luminescence above the control level was not detected. At higher concentrations (5 X 10(-7) M), strophanthidin produced aftercontractions, diastolic depolarization, and transient depolarizations, all of which were associated with temporally similar changes in [Ca2+]. During these events, diastolic [Ca2+] rose from the normal level of approximately 3 X 10(-7) M up to 1-2 X 10(-6) M. The negative inotropic effect of 5 X 10(-7) M strophanthidin was not associated with a corresponding decrease in the [Ca2+] transient but was associated with a change in the relationship between [Ca2+] and tension. Assuming the Na+-lag mechanism of cardiotonic steroid action, we conclude the following: at low concentrations of drug, increased Ca2+ uptake by the sarcoplasmic reticulum prevents a detectable rise in cytoplasmic [Ca2+] during diastole, but this increased Ca2+ uptake results in increased release of Ca2+ during the action potential. At higher drug concentrations, observable [Ca2+] changes during diastole activate tension and membrane conductance changes.


Robust Principal Component Analysis and Geographically Weighted Regression: Urbanization in the Twin Cities Metropolitan Area of Minnesota.
In this paper, we present a hybrid approach, robust principal component geographically weighted regression (RPCGWR), in examining urbanization as a function of both extant urban land use and the effect of social and environmental factors in the Twin Cities Metropolitan Area (TCMA) of Minnesota. We used remotely sensed data to treat urbanization via the proxy of impervious surface. We then integrated two different methods, robust principal component analysis (RPCA) and geographically weighted regression (GWR) to create an innovative approach to model urbanization. The RPCGWR results show significant spatial heterogeneity in the relationships between proportion of impervious surface and the explanatory factors in the TCMA. We link this heterogeneity to the "sprawling" nature of urban land use that has moved outward from the core Twin Cities through to their suburbs and exurbs.


Forecast and control of epidemics in a globalized world.
The rapid worldwide spread of severe acute respiratory syndrome demonstrated the potential threat an infectious disease poses in a closely interconnected and interdependent world. Here we introduce a probabilistic model that describes the worldwide spread of infectious diseases and demonstrate that a forecast of the geographical spread of epidemics is indeed possible. This model combines a stochastic local infection dynamics among individuals with stochastic transport in a worldwide network, taking into account national and international civil aviation traffic. Our simulations of the severe acute respiratory syndrome outbreak are in surprisingly good agreement with published case reports. We show that the high degree of predictability is caused by the strong heterogeneity of the network. Our model can be used to predict the worldwide spread of future infectious diseases and to identify endangered regions in advance. The performance of different control strategies is analyzed, and our simulations show that a quick and focused reaction is essential to inhibiting the global spread of epidemics.


Transformer-Based Representation of Organic Molecules for Potential Modeling of Physicochemical Properties.
In this work, we study the use of three configurations of an autoencoder neural network to process organic substances with the aim of generating meaningful molecular descriptors that can be employed to develop property prediction models. A total of 18,322,500 compounds represented as SMILES strings were used to train the model, demonstrating that a latent space of 24 units is able to adequately reconstruct the data. After AE training, an analysis of the latent space properties in terms of compound similarity was carried out, indicating that this space possesses desired properties for the potential development of models for forecasting physical properties of organic compounds. As a final step, a QSPR model was developed to predict the boiling point of chemical substances based on the AE descriptors. 5276 substances were used for the regression task, and the predictive ability was compared with models available in the literature evaluated on the same database. The final AE model has an overall error of 1.40% (1.39% with augmented SMILES) in the prediction of the boiling temperature, while other models have errors between 2.0 and 3.2%. This shows that the SMILES representation is comparable and even outperforms the state-of-the-art representations widely used in the literature.


Comparative effectiveness of different acupuncture therapies for neck pain.
Neck pain is a common musculoskeletal symptom that has negative effects on quality of life and work productivity. Acupuncture has been widely used for neck pain, and a number of randomized controlled trials (RCTs) and systematic reviews (SRs) have evaluated its effectiveness. However, previous studies have obtained inconsistent results regarding the effects of acupuncture for neck pain, and there is no SR for the comparative efficacy and safety of various types of acupuncture. Therefore, we herein conducted a SR and network meta-analysis to compare and rank different types of acupuncture with respect to their effectiveness in treating neck pain. We searched 9 electronic databases for relevant RCTs published from their inception to July 1, 2021. Pairwise meta-analyses and network meta-analysis were performed with R software using the frequentist framework. Change of pain intensity was assessed as the primary outcome, and change of pain-related disability and efficacy rate were assessed as secondary outcomes. The Cochrane risk of bias tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) instrument were used to evaluate the quality of the included RCTs and the certainty of the evidence. A total of 65 RCTs involving 5266 participants and 9 interventions were included. Three network meta-analyses were constructed for the following: pain intensity (42 RCTs, 3158 participants), pain-related disability (21 RCTs, 1581 participants), and efficacy rate (40 RCTs, 3512 participants). The results indicated that fire acupuncture, electroacupuncture, and warm acupuncture were more effective than manual acupuncture in terms of pain intensity reduction and efficacy rate, and that electroacupuncture decreased pain-related disability more effectively than manual acupuncture. Fire acupuncture ranked first among the 9 interventions. The overall q of evidence was very low according to the GRADE assessment. The reported adverse events were not serious. Fire acupuncture, warm acupuncture, acupoint catgut embedding, and electroacupuncture ranked higher than other interventions (usual care, sham acupuncture, no treatment) in reducing the pain and disability index scores and the efficacy rate. However, the included trials were evaluated as being of low quality; thus, we recommend additional well-designed RCTs with larger sample sizes to confirm these findings. PROSPERO, CRD42021235274.


Evolving Challenges in Diagnosis of Renal Vasculitis.
Renal-limited vasculitis is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis that presents only with a renal manifestation in the absence of other organs involvement. In this report, a 50-year-old female presented with nonspecific symptoms and anemia, who was subsequently discovered to have renal-limited vasculitis. After receiving a combination of steroid and immunosuppressive therapy, she recovered uneventfully without further relapse. A wide range of nonspecific presenting symptoms and the insidious nature of renal disease often delay in early recognition of renal-limited vasculitis. Keeping a lower threshold of initiating vasculitis workup helps detect the earlier diagnosis which is crucial in management with improved renal outcome.


Structure-activity relationships for chemical and glutathione S-transferase-catalysed glutathione conjugation reactions of a series of 2-substituted 1-chloro-4-nitrobenzenes.
Glutathione S-transferases (GSTs) constitute an important class of phase II (de)toxifying enzymes, catalysing the conjugation of glutathione (GSH) with electrophilic compounds. In the present study, Km, kcat and kcat/Km values for the rat GST 1-1-, 3-3-, 4-4- and 7-7-catalysed conjugation reactions between GSH and a series of 10 different 2-substituted 1-chloro-4-nitrobenzenes, and the second-order rate constants (ks) of the corresponding base-catalysed reactions, were correlated with nine classical physicochemical parameters (electronic, steric and lipophilic) of the substituents and with 16 computer-calculated molecular parameters of the substrates and of the corresponding Meisenheimer complexes with MeS- as a model nucleophile for GS- (charge distributions and several energy values), giving structure-activity relationships. On the basis of an identical dependence of the base-catalysed as well as the GST 1-1- and GST 7-7-catalysed reactions on electronic parameters (among others, Hammett substituent constant sigma p and charge on p-nitro substituents), and the finding that the corresponding reactions catalysed by GSTs 3-3 and 4-4 depend to a significantly lesser extent on these parameters, it was concluded that the Mu-class GST isoenzymes have a rate-determining transition state in the conjugation reaction between 2-substituted 1-chloro-4-nitrobenzenes and GSH which is different from that of the other two GSTs. Several alternative rate-limiting transition states for GST 3-3 and 4-4 are discussed. Furthermore, based on the obtained structure-activity relationships, it was possible to predict the kcat/Km values of the four GST isoenzymes and the ks of the base-catalysed GSH conjugation of 1-chloro-4-nitrobenzene.


Assessment of cardiac functions in fetuses of gestational diabetic mothers.
We investigated cardiac function in 67 fetuses of gestational diabetic mothers (FGDMs) and 122 fetuses of healthy mothers between 24 and 36 weeks of gestation. Cardiac functions were evaluated by M-mode, pulsed-wave, and tissue Doppler echocardiography. Fetal echocardiograms were performed at 24, 28, 32, and 36 weeks of gestation. Glycated hemoglobin (HbA1c) levels were obtained from all pregnant women at 24 weeks of gestation. The mean age of diabetic pregnant women was significantly greater than that of controls. Serum HbA1c values of both groups were within normal limits, but they were significantly greater in the diabetic group (p = 0.003). The increase in peak aortic and pulmonary artery velocities were greater in FGDM (p < 0.001). No pathological interventricular septal (IVS) hypertrophy was observed. There was a significant increase in IVS thickness in FGDM compared with controls, which was more prominent at the end of the third trimester (p < 0.001). During the course of pregnancy, mitral E-wave (p < 0.001), A-wave (p = 0.007), tricuspid E-wave (p < 0.001) and A-wave (p = 0.002) velocities were greater in FGDM. The increases in mitral E/A and tricuspid E/A ratios were lower in FGDM with advancing gestation. The E a-wave (p = 0.02), A a-wave (p = 0.04), and S a-wave (p < 0.001) velocities of the right-ventricular (RV) free wall and the E a (p = 0.02) and A a (p = 0.01) velocities of the left-ventricle (LV) posterior wall were greater in FGDM during the course of pregnancy. The E a/A a ratio of the RV posterior wall was greater in FGDM with advancing gestation (p < 0.03). LV and RV E/E a ratios were similar in both groups. The LV myocardial performance index measured by pulsed-wave Doppler was greater in FGDM (p < 0.001). We detected diastolic dysfunction in FGDM. The data suggest that gestational diabetes mellitus may impair ventricular diastolic functions without causing pathological fetal myocardial hypertrophy. We detected subclinical diastolic dysfunction using both pulsed-wave and tissue Doppler imaging in FGDM.


[Viagra, cialis, impase--which of them, to whom, when and how?].
The study has been performed of the efficacy in the treatment of erectile dysfunction (ED) of oral drugs affecting nitric oxide: impase and phosphodiesterase-5 (PDE-5) inhibitors--sildenafil citrate (viagra), tadalafil (sialis)--alone and in combination with impase. A total of 218 ED patients aged 21-73 years (mean age 58.1 +/- 13.2 years) were divided into 3 groups comparable by the number of the patients, age, suspected etiology, pathogenesis and ED severity. Group 1 (n = 81) took viagra in the individually adjusted dose for 6 months; group 2 (n = 64) received sialis in a dose 20 mg for 6 months; group 3 (n = 73) took impase 1 tablet each other day sublingually for 6 months. Overall efficacy made up 77.8, 81.3 and 56.2% for viagra, sialis and impase, respectively. In view of different mechanism of action of PDE-5 inhibitors (viagra, sialis) and impase we combined the drugs in those who failed monotherapy or had drastic side effects. The combination raised efficacy of pharmacotherapy from 56.2 to 92.2%. We came to the conclusion that in psychogenic, isolated neurogenic, compensated and subcompensated arteriogenic ED of a mild or moderate degree, the treatment can be started with impase. If it was uneffective, in severe ED or moderate venoocclusive ED it is better to use PDE-5 inhibitors (viagra, sialis). If one of the latter fails, the other should be administered. If the inhibitors have low efficacy or in side effects, it is indicated to use their combination with impase.


Comparison of endometrial cancer risk in patients with endometrial precancerous lesions: WHO 1994 vs EIN classification.
Our aim was to investigate the frequency of concurrent endometrial cancer in patients with endometrial precancerous lesions (PCLs) using World Health Organization 1994 (WHO94) and endometrial intraepithelial neoplasia (EIN) systems. We retrospectively investigated patients that underwent surgery for endometrial PCLs according to WHO94 or EIN systems at Hacettepe University Gynecology Clinic between January 2002 and June 2014. Of the 267 patients, 189 (70.9%) were in the WHO94 group, 78 (29.2%) were in the EIN group. Mean age of patients was 50.2 years. Sixteen patients (8.5%) in WHO94 group and 15 (%19.2) patients in the EIN group had EC (p = 0.013). In WHO94 group, EC rate in patients with atypical EH (32.6%) was significantly more than patients with non-atypical EH (1.4%) (p < .001). Atypical EH and EIN are actual PCLs which could be accompanied by EC. Therefore, atypical EH and EIN should be treated surgically if there is no desire for fertility. IMPACT STATEMENTWhat is already known on this subject? Endometrial hyperplasias are precursors lesion in the pathogenesis of endometrium adenocarcinomas. There are two classification systems: World Health Organization System and endometrial intraepithelial neoplasia system (WHO and EIN).What do the results of this study add? In this paper, we report on endometrial precancerous lesions. Controversy continues over the endometrial precancerous lesion classification. We also share our experiences in this regard. We concluded that the EIN system was superior in determining concurrent cancer risk.What are the implications of these findings for clinical practice and / or further research? The paper should be of interest to readers in the areas of gynecology.It is important to clarify the classifications of precancerous lesions in order to guide clinicians in the treatment of patients with endometrial precancerous lesions. In this context, it could be suggested to use the EIN system more widely.


What is the educational value and clinical utility of artificial intelligence for intraoperative and postoperative video analysis? A survey of surgeons and trainees.
Surgical complications often occur due to lapses in judgment and decision-making. Advances in artificial intelligence (AI) have made it possible to train algorithms that identify anatomy and interpret the surgical field. These algorithms can potentially be used for intraoperative decision-support and postoperative video analysis and feedback. Despite the very early success of proof-of-concept algorithms, it remains unknown whether this innovation meets the needs of end-users or how best to deploy it. This study explores users' opinion on the value, usability and design for adapting AI in operating rooms. A device-agnostic web-accessible software was developed to provide AI inference either (1) intraoperatively on a live video stream (synchronous mode), or (2) on an uploaded video or image file (asynchronous mode) postoperatively for feedback. A validated AI model (GoNoGoNet), which identifies safe and dangerous zones of dissection during laparoscopic cholecystectomy, was used as the use case. Surgeons and trainees performing laparoscopic cholecystectomy interacted with the AI platform and completed a 5-point Likert scale survey to evaluate the educational value, usability and design of the platform. Twenty participants (11 surgeons and 9 trainees) evaluated the platform intraoperatively (n = 10) and postoperatively (n = 11). The majority agreed or strongly agreed that AI is an effective adjunct to surgical training (81%; neutral = 10%), effective for providing real-time feedback (70%; neutral = 20%), postoperative feedback (73%; neutral = 27%), and capable of improving surgeon confidence (67%; neutral = 29%). Only 40% (neutral = 50%) and 57% (neutral = 43%) believe that the tool is effective in improving intraoperative decisions and performance, or beneficial for patient care, respectively. Overall, 38% (neutral = 43%) reported they would use this platform consistently if available. The majority agreed or strongly agreed that the platform was easy to use (81%; neutral = 14%) and has acceptable resolution (62%; neutral = 24%), while 30% (neutral = 20%) reported that it disrupted the OR workflow, and 20% (neutral = 0%) reported significant time lag. All respondents reported that such a system should be available "on-demand" to turn on/off at their discretion. Most found AI to be a useful tool for providing support and feedback to surgeons, despite several implementation obstacles. The study findings will inform the future design and usability of this technology in order to optimize its clinical impact and adoption by end-users.


Sensory impairment: a feature of chronic venous insufficiency.
Clinical and microscopic evidence suggests the existence of sensory neuropathy in patients with severe chronic venous insufficiency (CVI). A clinical evaluation was conducted to determine whether a sensory neuropathy was present and, if so, to determine its extent and distribution. The study was performed in a university-affiliated Veterans Affairs Medical Center. Twenty-three limbs were studied in 14 male veterans with mild or moderate CVI. The exclusions included diabetes, previous ipsilateral extremity surgery, or other diseases associated with neuropathy. Sensory thresholds in the limbs with CEAP class 2 disease (n = 11) were compared with the thresholds in the limbs with CEAP class 5 disease (n = 12) at nine different sites on the foot, ankle, calf, thigh, and palm. Thenar and hypothenar thresholds were measured as internal controls. Thresholds were determined by a pressure aesthesiometer consisting of 20 graduated filaments that ranged from 1.65 to 6.65 (log(10)mg)(10) of pressure. A complete, sensory motor assessment of the limb was performed by an experienced neurosurgeon who specialized in peripheral nerve evaluation. The clinical variables assessed were deep tendon reflexes, vibration, proprioception, and light touch. Venous reflux was determined with duplex ultrasound scanning and air plethysmography. Sensory thresholds at the most common site of venous ulceration-just proximal to the medial malleolus--were significantly (P <.05) different between mild (class 2) and severe (class 5) CVI. Sensory abnormalities coincided with the extent of trophic changes and did not reflect specific dermatomal or cutaneous nerve distributions. In addition to light touch or pinprick, vibration sense and deep tendon reflexes were also significantly worse in those with severe CVI. Sensory neuropathy is a feature of severe CVI, and its distribution is coincident with trophic changes. Because this is often unappreciated by the patient, it probably contributes to the propensity for deterioration from minor trauma.


[Malalignment following injuries of the distal tibia and epiphysis of the fibula].
If the correct treatment is applied, growth disturbances following epiphyseal fractures of the distal tibia are rare. Even if the prognosis is good after the correct treatment of epiphyseal fractures of the distal tibia, the parents and child may have to be informed about growth disturbances. Most frequent is a varus deformity after asymmetric closure of the medial growth plate. If at least 2 years of growth can be expected, a callus resection according to Langenskjöld is indicated. If this procedure fails, the ideal timing for a correction is the end of the growth. Imminent contractures can be an indication for early correction even if a recurrent deformity can be expected. An open-wedge osteotomy permits all three procedures to be carried out: callus resection, axis correction and leg-length correction. If an incongruence of the joint is present, the closed wedge technique using an external fixator is indicated; correction of the leg length can be postponed. Joint incongruence reacts well to axis alignment. The pre-arthrotic joint can remain free of symptoms for years. We never encountered epiphyseal fractures of the distal fibula, but we did see one case of deformity of the ankle joint as a result of closure of the proximal fibular growth plate.


Novel mutation of topoisomerase I in rendering cells resistant to camptothecin.
To identify mechanisms of camptothecin (CPT) resistance and the relationship between CPT-resistant cells and other anticancer agents, a CPT-resistant cell line (CPT30) and its partial revertant cell line (CPT30R) were established from a human nasopharyngeal carcinoma cell line (HONE-1). CPT30 and CPT30R cells displayed a 14- and 3.5-fold resistance to CPT compared with HONE-1 cells, respectively. The resistant and partial revertant cell lines showed cross-resistance to topotecan and increased sensitivity to cisplatin, carboplatin, and 1,3-bis(chloroethyl)-1-nitrosurea. The topoisomerase (Top) I catalytic activity of CPT30 and CPT30R cells was 30% and 200%, respectively, compared with that of HONE-1 cells. The expression of Top I protein and mRNA levels in CPT30 cells was 40% and 30% less than that in HONE-1 cells, respectively, whereas in CPT30R cells, the levels of Top I protein and mRNA were 50% and 20% higher, respectively, than that in HONE-1 cells. Both the resistant and revertant cell line whole-cell lysates demonstrated different levels of sensitivity to CPT in in vitro assays in comparison with that of HONE-1 cells. Furthermore, CPT exhibited 15- and 7-fold better binding affinity in stabilizing protein-linked DNA breaks in HONE-1 cells than in CPT30 and CPT30R cells, respectively. Direct DNA sequencing of the reverse transcription-PCR product and genomic DNA revealed a point mutation resulting in E418K mutation in the Top I of both CPT30 and CPT30R cells. Wild-type Top I RNA and genomic DNA were also detected in these two cell lines. A yeast system was used to examine whether this mutation could be responsible for CPT resistance. Our results showed that a single amino acid change (E418K) resulted in CPT resistance. Therefore, quantitative and qualitative changes in Top I were responsible for CPT resistance in CPT30 cells. CPT resistance in CPT30R cells was caused by mutation of Top I.


Thrombin generation after the abrupt cessation of intravenous unfractionated heparin among patients with acute coronary syndromes: potential mechanisms for heightened prothrombotic potential.
The purpose of this study was to determine the mechanistic basis for thrombin generation and increased prothrombotic potential after the abrupt cessation of intravenous (i.v.) unfractionated heparin among patients with acute coronary syndromes. A "rebound" increase in prothrombotic potential has been observed biochemically and clinically after the abrupt cessation of unfractionated heparin (UFH) among patients with acute coronary syndromes. Although the mechanism is unknown, tissue factor and the extrinsic coagulation cascade, both operative in atherosclerotic vascular disease and arterial thrombosis, are thought to be centrally involved. In a single-center, pilot study, 30 patients with either unstable angina or non-ST segment elevation myocardial infarction who had received a continuous i.v. infusion of UFH for 48 h were randomly assigned to: 1) abrupt cessation, 2) i.v. weaning over 12 h or 3) subcutaneous weaning over 12 h. Thrombin generation (prothrombin fragment 1.2) was evident within 1 h of UFH cessation, increased progressively (by nearly two-fold) at 24 h (p = 0.002) and correlated inversely with tissue factor pathway inhibitor concentration (r = -0.61). Thrombin generation was greatest among patients randomized to abrupt cessation (1.6-fold increase at 24 h) and least in those with i.v. weaning. Thrombin generation after the abrupt cessation of UFH may represent a drug-induced impairment of physiologic vascular thromboresistance in response to locally generated tissue factor. A dosing strategy of abbreviated i.v. weaning attenuates but does not prevent heparin rebound among patients with acute coronary syndromes.


Non-invasive prediction of hemoglobin levels by principal component and back propagation artificial neural network.
To facilitate non-invasive diagnosis of anemia, specific equipment was developed, and non-invasive hemoglobin (HB) detection method based on back propagation artificial neural network (BP-ANN) was studied. In this paper, we combined a broadband light source composed of 9 LEDs with grating spectrograph and Si photodiode array, and then developed a high-performance spectrophotometric system. By using this equipment, fingertip spectra of 109 volunteers were measured. In order to deduct the interference of redundant data, principal component analysis (PCA) was applied to reduce the dimensionality of collected spectra. Then the principal components of the spectra were taken as input of BP-ANN model. On this basis we obtained the optimal network structure, in which node numbers of input layer, hidden layer, and output layer was 9, 11, and 1. Calibration and correction sample sets were used for analyzing the accuracy of non-invasive hemoglobin measurement, and prediction sample set was used for testing the adaptability of the model. The correlation coefficient of network model established by this method is 0.94, standard error of calibration, correction, and prediction are 11.29g/L, 11.47g/L, and 11.01g/L respectively. The result proves that there exist good correlations between spectra of three sample sets and actual hemoglobin level, and the model has a good robustness. It is indicated that the developed spectrophotometric system has potential for the non-invasive detection of HB levels with the method of BP-ANN combined with PCA.


Navigating personal and relational concerns: the quest for equilibrium.
The authors' personal-relational equilibrium model suggests that people come to seek equilibrium in their dedication to personal and relational concerns in that these 2 important needs cannot always be gratified simultaneously. The authors proposed that the experience of personal-relational disequilibrium motivates attempts to restore equilibrium and that achieving equilibrium promotes life satisfaction. Four studies revealed good support for the model. In Study 1, a manipulation of anticipated future disequilibrium (vs. equilibrium) as a result of overdedication to either the personal or relational domain caused reduced motivation to address concerns in that domain and increased motivation toward the complementary domain. In Study 2, narratives describing disequilibrium experiences (vs. equilibrium experiences) exhibited increased motivation to restore equilibrium and reduced life satisfaction. In Study 3, diary reports of everyday disequilibrium were associated with increased same-day motivation to restore equilibrium, reduced same-day life satisfaction, and increased next-day dedication of effort to the complementary domain. In Study 4, experiences of disequilibrium predicted reduced well-being 6 months later. Collectively, these findings extend knowledge of how people regulate themselves toward equilibrium in pursuing 2 fundamental human concerns.


Cardiac surgery with cardiopulmonary bypass markedly lowers SARS-COV-2 antibody titer.
This study aims to investigate the effect of cardiopulmonary bypass on antibody titers in patients vaccinated against the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) undergoing cardiac surgery with cardiopulmonary bypass. Between October 2021 and October 2022, a total of 70 patients (44 males, 26 females; mean age 59.9±10.3; range, 26 to 79 years) who completed their recommended COVID-19 vaccinations and underwent elective cardiac surgery with cardiopulmonary bypass were prospectively included. Serum samples for antibody titer measurements were taken at anesthesia induction and the end of cardiopulmonary bypass after decannulation. The SARS-CoV-2 total immunoglobulin antibodies against N-protein were measured. The antibody titer measurements at anesthesia induction and at the end of cardiopulmonary bypass were compared in all patients. The median levels after cardiopulmonary bypass were lower than the preoperative levels (1,739.0 vs. 857.0, respectively; p<0.001). There was a drop of 40.0% (21.2%-62.6%) in the antibody titers among all patients. The decrease in antibody titers was consistent regardless of the number of vaccine doses or whether the last dose was received within the last three months. Among the studied factors, no parameter was significantly associated with a lesser or higher decrease in antibody titers. Cardiac surgery with cardiopulmonary bypass causes a decrease in SARS-CoV-2 antibody titers at the end of cardiopulmonary bypass. Revaccination after cardiac operations may be considered in this patient group that is highly vulnerable due to their comorbidities and lowered antibody levels.


Anaesthetic National Teaching Programme for Students (ANTPS).
The COVID-19 pandemic has significantly undermined undergraduate anaesthetic teaching in spite of the vital role of the specialty against the pandemic. Anaesthetic National Teaching Programme for Students (ANTPS) was designed to meet the evolving needs of undergraduates and tomorrow's doctor by standardising anaesthetic training, preparing for final exams and equipping competencies vital for doctors of all grades and specialties. Our Royal College of Surgeons England-accredited University-College-Hospital-affiliated programme consisted of six-biweekly sessions were delivered online by anaesthetic trainees. Prerandomised and postrandomised session-specific multiple-choice questions (MCQs) assessed students' improvement in knowledge. Anonymous feedback forms were provided to students after each session and 2 months following the programme. 3743 student feedback forms (92.2% of attendees) across 35 medical-schools were recorded. There was a mean improvement in test score (0.94±1.27, p<0.001). 313 students completed all six sessions. Based on 5-point Likert scale, students who completed the programme showed an improvement in their confidence in knowledge and skills to face common foundation challenges (1.59±1.12, p<0.001) and thus felt better prepared for life as junior doctors (1.60±1.14, p<0.001). With an increase in confidence in students to pass their MCQs, Observed Structured Clinical Examinations and case-based discussion assessments, 3525 students stated they would recommend ANTPS to other students. Unprecedented COVID-19 factors impacting training, positive student feedback and extensive recruitment, demonstrate that our programme is an indispensable learning resource which standardises anaesthetic undergraduate education nationally, prepares undergraduates for their anaesthetic and perioperative exams and lays strong foundations for implementation of clinical skills required by all doctors, to optimise training and patient care.


High-reliability SAW bandpass filters for space applications.
High-reliability surface-acoustic-wave (SAW) bandpass filters have been developed for use in transponders for more than 25 earth-orbital and deep-space satellite programs. SAW filters have been incorporated in several NASA standard TTandC transponders and NASA standard tracking and data relay satellite system (TDRSS) user transponders. The author gives examples of the electrical performance, summarizes the manufacturing processes, and discusses qualification testing for these SAW devices. He identifies reliability problems encountered and their solutions.


Treating schizophrenia now and developing strategies for the next decade.
This paper focuses on treatments for schizophrenia (SZ)--treatments we have now and those we hope to have in the future. The treatments we have are based on serendipity, but are effective nonetheless. Pharmacologic characteristics of the most-prescribed drugs are reviewed. It is apparent that a spectrum of effective drugs exist to support individualized therapy. With a view to future discovery, a strategy is proposed for rational antipsychotic drug development. A few concrete examples from the author's own laboratory illustrate an application of the proposal. These data would support the existence of a drug target in the anterior cingulate and/or hippocampal cortex. The studies suggest a focus on the limbic cortex for SZ pathophysiology. It would depend on future discovery to test whether this proposal will be productive. For sure, the rapid advance of basic neuroscience provides untold promise for the future


Associations between Short-Term Exposure to Ambient Air Pollution and Influenza: An Individual-Level Case-Crossover Study in Guangzhou, China.
Influenza imposes a heavy burden on public health. Little is known, however, of the associations between detailed measures of exposure to ambient air pollution and influenza at an individual level. We examined individual-level associations between six criteria air pollutants and influenza using case-crossover design. In this individual-level time-stratified case-crossover study, we linked influenza cases collected by the Guangzhou Center for Disease Control and Prevention from 1 January 2013 to 31 December 2019 with individual residence-level exposure to particulate matter (PM2.5 and PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3) and carbon monoxide (CO). The exposures were estimated for the day of onset of influenza symptoms (lag 0), 1-7 d before the onset (lags 1-7), as well as an 8-d moving average (lag07), using a random forest model and linked to study participants' home addresses. Conditional logistic regression was developed to investigate the associations between short-term exposure to air pollution and influenza, adjusting for mean temperature, relative humidity, public holidays, population mobility, and community influenza susceptibility. N=108,479 eligible cases were identified in our study. Every 10-μg/m3 increase in exposure to PM2.5, PM10, NO2, and CO and every 5-μg/m3 increase in SO2 over 8-d moving average (lag07) was associated with higher risk of influenza with a relative risk (RR) of 1.028 (95% CI: 1.018, 1.038), 1.041 (95% CI: 1.032, 1.049), 1.169 (95% CI: 1.151, 1.188), 1.004 (95% CI: 1.003, 1.006), and 1.134 (95% CI: 1.107, 1.163), respectively. There was a negative association between O3 and influenza with a RR of 0.878 (95% CI: 0.866, 0.890). Our findings suggest that short-term exposure to air pollution, except for O3, is associated with greater risk for influenza. Further studies are necessary to decipher underlying mechanisms and design preventive interventions and policies. https://doi.org/10.1289/EHP12145.


Proneness of TLR5 deficient mice to develop colitis is microbiota dependent.
Alterations in the gut microbiota have been implicated to play a role in potentiating inflammatory bowel diseases in both humans and mice. Mice lacking the flagellin receptor, toll-like receptor 5 (TLR5), are prone to develop spontaneous gut inflammation, but are significantly protected when treated with antibiotics or maintained in germ-free conditions. However, given that the incidence of spontaneous inflammation in TLR5KO mice is quite variable in conventional conditions (typically ∼10% show clear colitis), this result is far from definitive and does not rule out that TLR5KO mice might be prone to develop inflammation even in the absence of a microbiota. Herein, we demonstrate that neutralization of IL10 signaling induces colitis in 100% of TLR5KO mice which provide a more rigorous approach to evaluate the role of microbiota in gut inflammation. Mice treated with antibiotics or maintained in germ-free condition are substantially protected against IL-10R neutralization-induced colitis, underscoring that gut inflammation in TLR5KO mice is dependent upon the presence of a gut microbiota.


Combination treatment of melasma with pulsed CO2 laser followed by Q-switched alexandrite laser: a pilot study.
Melasma is very difficult to treat and often refractory to treatment with topical creams and pigmented-lesion lasers. Pulsed CO2 laser alone is compared with the combination of pulsed CO2 laser followed by Q-switched alexandrite laser in the treatment of dermal-type melasma. This combination is proposed to be effective by first destroying the abnormal melanocytes with the pulsed CO2 laser and then selectively eliminating the dermal melanin with the alexandrite laser. Four patients were randomly chosen for each treatment arm. There were multiple follow-up visits for examination by an objective blinded investigator. All patients in the combination laser group showed complete resolution, and two patients in the CO2 laser only group had peripheral hyperpigmentation in the long-term follow-up evaluation. These laser therapies are safe, as there was no scarring and no infection. The combination laser therapy was highly effective in removing the hyperpigmentation and all patients in this group showed complete resolution without any peripheral hyperpigmentation.


Survivorship and the second epidemiological transition in industrial-era London.
The second epidemiological transition describes a shift in predominant causes of death from infectious to degenerative (non-communicable) diseases associated with the demographic transition from high to low levels of mortality and fertility. In England, the epidemiological transition followed the Industrial Revolution, but there is little reliable historical data on cause of death beforehand. Because of the association between the demographic and epidemiological transitions, skeletal data can potentially be used to examine demographic trends as a proxy for the latter. This study uses skeletal data to examine differences in survivorship in London, England in the decades preceding and following initial industrialization and the second epidemiological transition. We use data (from n = 924 adults) from London cemeteries (New Churchyard, New Bunhill Fields, St. Bride's Lower Churchyard, and St. Bride's Church Fleet Street) in use prior to and during industrialization (c. 1569-1853 CE). We assess associations between estimated adult age at death and time period (pre-industrial vs. industrial) using Kaplan-Meier survival analysis. We find evidence of significantly lower adult survivorship prior to industrialization (c. 1569-1669 and 1670-1739 CE) compared to the industrial period (c. 1740-1853 CE) (p < 0.001). Our results are consistent with historical evidence that, in London, survivorship was improving in the later 18th century, prior to the recognized beginning of the second epidemiological transition. These findings support the use of skeletal demographic data to examine the context of the second epidemiological transition in past populations.


Procedural characteristics and adverse events in diagnostic and interventional catheterisations in paediatric and adult CHD: initial report from the IMPACT Registry.
To report procedural characteristics and adverse events on data collected in the registry. The IMPACT--IMproving Paediatric and Adult Congenital Treatment--Registry is a catheterisation registry of paediatric and adult patients with CHD undergoing diagnostic and interventional cardiac catheterisation. We are reporting the procedural characteristics and adverse events of patients undergoing diagnostic and interventional catheterisation procedures from January, 2011 to March, 2013. Demographic, clinical, procedural, and institutional data elements were collected at the participating centres and entered via either a web-based platform or software provided by American College of Cardiology-certified vendors, and were collected in a secure, centralised database. Centre participation was voluntary. During the time frame of data collection, 19,797 procedures were entered into the IMPACT Registry. Procedures were classified as diagnostic only (35.4%); one of six specific interventions (23.8%); other or multiple interventions (40.7%); and were further broken down into four age groups. Anaesthesia was used in 84.1% of diagnostic procedures and 87.8% of interventional ones. Adverse events occurred in 10.0% of diagnostic and 11.1% of interventional procedures. The IMPACT Registry is gathering data to set national benchmarks for diagnostic and certain specific interventional procedures. We are seeing little differences in procedural characteristics or adverse events in diagnostic procedures compared with interventional procedures overall, but there is significant variation in adverse events amongst age categories. Risk stratification and patient acuity scores will be required for further analysis of these differences.


A new risk management paradigm for managed care.
The long-term outlook for managed care may be threatened by current capitation-rate-development methods that adjust risk for age, gender, geographic area, income level, and occupation, but not health status. Not only provider payments, but also patient access may be compromised as a result. New risk-adjustment methods that categorize patients into groups based on their current health status and anticipated disease progression allow fairer distribution of the essential components of costs to deliver healthcare services to the at-risk population, and improve upon HCFA's adjusted average per capita cost (AAPCC) rates and recently implemented principal inpatient diagnostic cost group (PIP-DCG) risk-adjustment methodology.


The peroneus quartus muscle. Anatomy and clinical relevance.
Whilst a few studies have associated various symptoms with the presence of a peroneus quartus muscle in the peroneal compartment of the leg, little is known of the clinical relevance of this muscle. We dissected 102 cadaver legs and reviewed the magnetic resonance images of 80 patients with symptoms from the ankle. The peroneus quartus, with a number of different attachments, was present in 6.6% of the legs. It most commonly arose from the peroneus brevis muscle and inserted into the retrotrochlear eminence of the calcaneum. Associated pathology included a longitudinal tear in the tendon of peroneus brevis, possible peroneal tendon subluxation or dislocation, and a prominent retrotrochlear eminence. On the MR scans its presence was associated with pain and weakness of the ankle. Orthopaedic surgeons and radiologists should be aware of the possible presence of the peroneus quartus muscle, not only because of possible associated pathology, but also for its potential use for surgical reconstruction.


Clinical Study on the Thoracodorsal Artery Perforator Flap in Breast-Conserving Reconstruction of T2 Breast Cancer.
Breast-conserving surgery combined with oncoplastic breast surgery has become the standard surgical treatment for early breast cancer. The purpose of this study was to investigate the safety and efficacy of the thoracodorsal artery perforator flap (TDAPF) in breast-conserving reconstruction of T2 breast cancer. Thirty patients with T2 breast cancer admitted to our hospital from January 2019 to December 2020 were enrolled to receive pedicled TDAPF for repairing breast defects after breast-conserving surgery. Intraoperative conditions, postoperative complications, and shape satisfaction after breast reconstruction were recorded. The operation was successfully completed in all 30 patients, with an operation time of 177.77 ± 24.39 min, bleeding of 44.17 ± 7.67 mL, and length of hospital stay of 5.23 ± .97 d. There was no deformity or seroma at the donor site. Breast shape recovered well after operation. After operation, one patient had fat liquefaction in the recipient site, which healed well after wound treatment. The incidence of postoperative complications was 3.33%. Postoperative follow-up lasted 16-28 months, with a median of 22 months. The Breast-Q score for breast satisfaction was 61.83 ± 12.87 at 6 months after operation, compared to 62.07 ± 11.78 before operation (P > .05). TDAPF, featuring a high survival rate, moderate flap area, fewer postoperative complications, and high satisfaction with breast shape after operation. For east asian women with moderate breast size, TDAPF is a safe, effective choice for repairing defects in breast-conserving surgery for T2 breast cancer.


Leucocyte migration test with autologous colonic mucosa as antigen in patients with ulcerative colitis.
The leucocyte migration agarose technique (LMAT) was applied in a study of the migration of peripheral leucocytes in 16 patients with ulcerative colitis using three different autologous types of tissue as antigen: rectal mucosa, skin and buccal mucosa. In all cases the migration indices were within normal limits, and they did not differ from a group of control patients suffering from peptic ulcer, irritable colon, or haemorrhoidal tumours. The present study does not support the theory of cellular hypersensitivity against colonic mucosa in patients with ulcerative colitis.


Neonatal screening for Duchenne muscular dystrophy: a novel semiquantitative application of the bioluminescence test for creatine kinase in a pilot national program in Cyprus.
The objectives of this study were to evaluate a novel semiquantitative application of the bioluminescence test for screening newborns for Duchenne muscular dystrophy (DMD) and to use this technique in a pilot national program. The study was performed on the island of Cyprus, which provides ideal conditions for maximizing the prevention rate due to the small size of the country, the well-defined population, and the high degree of awareness of the public concerning genetic diseases. Guthrie spots were obtained through the national screening center for phenylketonuria and congenital hypothyroidism. The bioluminescence method for measuring creatine kinase (CK) in dried blood spots was adapted for use in a semiquantitative way. During the first 6 years of the program (1992-1997), we screened 30,014 samples and found 43 with initially high CK values. We were able to obtain repeat specimens in 35 cases. Of the repeat samples, 30 were found to have normal activity, giving a false-positive rate of 0.10%. Five boys had persistent CK elevations and were confirmed to be DMD or Becker (BMD) cases by DNA analysis and/or dystrophin analysis. The semiquantitative application of the bioluminescence assay of CK that we have introduced has proved to be a fast and reliable method for screening large numbers of samples for DMD. It has a low rate of false positives, which compares favorably with that of other DMD screening programs. Although it is early to evaluate its impact fully, the program seems to be bringing about the anticipated benefits to affected families.


Reconstitution of neurotoxin-modulated ion transport by the voltage-regulated sodium channel isolated from the electroplax of Electrophorus electricus.
The functional reconstitution of the voltage-regulated Na channel purified from the electroplax of Electrophorus electricus is described. Reconstitution was achieved by removing detergent with Bio-Beads SM-2 followed by freeze-thaw-sonication in the presence of added liposomes. This preparation displayed heat-stable binding of 3H-labeled tetrodotoxin (TTX) (Kd = 33 nM). 22Na+ influx was stimulated 2- to 5-fold by alkaloid neurotoxins and blocked by TTX. Veratridine activated Na+ influx with a K1/2 of 18 microM, and this activation was blocked by TTX precisely in parallel with specific [3H]TTX binding. Batrachotoxin stimulated 22Na+ flux more effectively than did veratridine. No effect of the peptide anemone toxin II was found. Insertion of the Na channel into membranes resulted in 60-70% of the TTX-binding sites facing the vesicle exterior. Thus, external TTX partially inhibited flux, whereas blockade was complete when TTX was also equilibrated with the vesicle interior. The lipid-soluble local anesthetics tetracaine and dibucaine inhibited flux completely. QX-222, a charged derivative of lidocaine, blocked only a fraction of the channels, apparently those oriented inside-out. Purified samples were predominantly composed of the Mr 260,000-300,000 glycopeptide but contained variable quantities of smaller peptides. Veratridine-dependent flux and peptide compositions were determined on fractions across a gel filtration column profile. Stimulated flux codistributed only with the large peptide.


Nonlinear Y-Like Receptive Fields in the Early Visual Cortex: An Intermediate Stage for Building Cue-Invariant Receptive Fields from Subcortical Y Cells.
Many of the neurons in early visual cortex are selective for the orientation of boundaries defined by first-order cues (luminance) as well as second-order cues (contrast, texture). The neural circuit mechanism underlying this selectivity is still unclear, but some studies have proposed that it emerges from spatial nonlinearities of subcortical Y cells. To understand how inputs from the Y-cell pathway might be pooled to generate cue-invariant receptive fields, we recorded visual responses from single neurons in cat Area 18 using linear multielectrode arrays. We measured responses to drifting and contrast-reversing luminance gratings as well as contrast modulation gratings. We found that a large fraction of these neurons have nonoriented responses to gratings, similar to those of subcortical Y cells: they respond at the second harmonic (F2) to high-spatial frequency contrast-reversing gratings and at the first harmonic (F1) to low-spatial frequency drifting gratings ("Y-cell signature"). For a given neuron, spatial frequency tuning for linear (F1) and nonlinear (F2) responses is quite distinct, similar to orientation-selective cue-invariant neurons. Also, these neurons respond to contrast modulation gratings with selectivity for the carrier (texture) spatial frequency and, in some cases, orientation. Their receptive field properties suggest that they could serve as building blocks for orientation-selective cue-invariant neurons. We propose a circuit model that combines ON- and OFF-center cortical Y-like cells in an unbalanced push-pull manner to generate orientation-selective, cue-invariant receptive fields. A significant fraction of neurons in early visual cortex have specialized receptive fields that allow them to selectively respond to the orientation of boundaries that are invariant to the cue (luminance, contrast, texture, motion) that defines them. However, the neural mechanism to construct such versatile receptive fields remains unclear. Using multielectrode recording, we found a large fraction of neurons in early visual cortex with receptive fields not selective for orientation that have spatial nonlinearities like those of subcortical Y cells. These are strong candidates for building cue-invariant orientation-selective neurons; we present a neural circuit model that pools such neurons in an imbalanced "push-pull" manner, to generate orientation-selective cue-invariant receptive fields.


Glycocalyx Shedding is Enhanced by Age and Correlates with Increased Fluid Requirement in Patients with Major Burns.
Massive fluid shift after severe burn injury leads to edema and intravascular fluid loss that may result in burn-induced compartment syndrome (BICS) when corrected by aggressive fluid resuscitation. Factors causing this fluid shift remain unclear. Because glycocalyx regulates endothelial permeability, we hypothesized that glycocalyx shedding would increase fluid requirements in burn patients. This prospective cohort study aimed to identify relationships between shedding of the glycocalyx and fluid requirements after burn injury. Patients aged more than 18 years with burn injury over more than 20% total body surface area (TBSA) were enrolled. Patient background factors including age, sex, burn size, and inhalation injury were recorded at patient enrollment. Serum syndecan-1, known as a biomarker of glycocalyx shedding, was serially measured on admission, day 1, days 3 to 5, around 1 and 2 weeks, and 1 month after the injury to observe postburn injury kinetics of syndecan-1. As biomarkers of endothelial damage, soluble thrombomodulin, antithrombin III, and plasminogen activator inhibitor-1 were also measured. We determined the relationship between syndecan-1 and initial 24-h fluid requirements and between syndecan-1 and morbidity/mortality. We enrolled 39 patients (median age, 55 years; median burn size, 35%TBSA): 16 developed BICS, and 10 patients died. Syndecan-1 level on admission was significantly higher than that in healthy volunteers and remained so. Syndecan-1 level on admission was associated with patient age (ρ = 0.50, P = 0.001) but not burn size (ρ = 0.08, P = 0.63), and antithrombin III level on admission was negatively associated with burn size (ρ = -0.48, P = 0.002). The syndecan-1 level on admission was significantly associated with fluid requirement (mL/kg) (ρ = 0.38, P = 0.017). After adjustment for age, sex, %TBSA, and inhalation injury, syndecan-1 was an independent parameter for the increase in fluid requirement (P = 0.04) and development of BICS (P = 0.03) by multivariable regression analysis. These findings suggested that glycocalyx shedding increased in an age-dependent manner, whereas antithrombin III decreased according to burn size. Glycocalyx shedding occurs soon after burn injury in an age-dependent manner. To reduce fluid-related complications such as BICS, new strategies to protect glycocalyx in burn patients are needed.