Traditional versus blended CPR training program: A randomized controlled non-inferiority study.
Cardiopulmonary resuscitation (CPR) training and its quality are critical in improving the survival rate of cardiac arrest. This randomized controlled study investigated the efficacy of a newly developed CPR training program for the public in a Taiwanese setting. A total of 832 adults were randomized to either a traditional or blended (18-minute e-learning plus 30-minute hands-on) compression-only CPR training program. The primary outcome was compression depth. Secondary outcomes included CPR knowledge test, practical test, quality of CPR performance, and skill retention. The mean compression depth was 5.21 cm and 5.24 cm in the blended and traditional groups, respectively. The mean difference in compression depth between groups was -0.04 (95% confidence interval -0.13 to infinity), demonstrating that the blended CPR training program was non-inferior to the traditional CPR training program in compression depth after initial training. Secondary outcome results were comparable between groups. Although the mean compression depth and rate were guideline-compliant, only half of the compressions were delivered with adequate depth and rate in both groups. CPR knowledge and skill retained similarly in both groups at 6 and 12 months after training. The blended CPR training program was non-inferior to the traditional CPR training program. However, there is still room for improvement in optimizing initial skill performance as well as skill retention. Clinical Trial Registration: NCT03586752; www.clinicaltrial.gov.


Functional specialization of monocot DCL3 and DCL5 proteins through the evolution of the PAZ domain.
Monocot DICER-LIKE3 (DCL3) and DCL5 produce distinct 24-nt small interfering RNAs (siRNAs), heterochromatic siRNAs (hc-siRNAs) and phased secondary siRNAs (phasiRNAs), respectively. The former small RNAs are linked to silencing of transposable elements and heterochromatic repeats, and the latter to reproductive processes. It is assumed that these DCLs evolved from an ancient 'eudicot-type' DCL3 ancestor, which may have produced both types of siRNAs. However, how functional differentiation was achieved after gene duplication remains elusive. Here, we find that monocot DCL3 and DCL5 exhibit biochemically distinct preferences for 5' phosphates and 3' overhangs, consistent with the structural properties of their in vivo double-stranded RNA substrates. Importantly, these distinct substrate specificities are determined by the PAZ domains of DCL3 and DCL5, which have accumulated mutations during the course of evolution. These data explain the mechanism by which these DCLs cleave their cognate substrates from a fixed end, ensuring the production of functional siRNAs. Our study also indicates how plants have diversified and optimized RNA silencing mechanisms during evolution.


Do poly(lactic acid) microplastics instigate a threat? A perception for their dynamic towards environmental pollution and toxicity.
Fears concerning microplastics (MPs) environmental fate and persistence are progressively expanding on a global basis, with the emphasis given to manufacturing bioplastics for substituting petro-derived plastics extensively growing. Among them, poly(lactic acid) (PLA) holds a pioneering role towards the replacement of conventional polymeric materials, owing to its multifunctional properties, enclosing superior mechanical properties, low cost, renewability, great biocompatibility, transparency, and thermoplasticity launching many fields of application. Due to the wide applicability of PLA in several sectors of everyday life, its waste to be released into the environment is expected to follow a growing tendency during the upcoming years. Even though PLA is a biodegradable polyester, it actually degrades under specific composting environments, including a rich oxygen environment with high temperatures (58-80 °C), high humidity (>60% moisture) as well as the presence of micro-organisms (thermophilic bacteria). Additionally, in various studies it has been implied that PLA displays slower degradation performance when found in blends with other conventional polymers, underlining the unspecified effects on PLA degradation profile, keeping thus the information about PLA degradation from a blur standpoint. Therefore, a deepened understanding of the fate and dynamic effects of PLA MPs is of primary importance. Nevertheless, the current examination of the effects of PLA MPs in terms of sorption capacities and toxicity is so far limited and broadly unexplored since the current scientific emphasis has been merely centered on the conventional MPs' behavior. In this light, the present review provides an inclusive overview of the ongoing research of poly(lactic acid) in the framework of microplastics' pollution, while the future trends and missing points in this context are highlighted.


Macrocyclic aromatic tetrasulfonamides with a stable cone conformation.
Aromatic tetrasulfonamide macrocycles carrying alkoxy side chains adopt a stable cone conformation in both the solid state and solution.


A hospital payment system with incentives for improvement in quality of care: first lessons.
A demonstration program of five member hospitals of the Rochester Area Hospitals Corporation in Rochester, New York, is introducing two major changes into traditional quality assurance programs in hospitals: (1) a shift of focus from structure and process to outcomes and (2) replacement of punitive approaches with a positive, reward-oriented approach. Relying on the MedisGroups information system to measure outcomes and on statistical techniques to identify variations in hospitals' performance, the demonstration offers financial awards in the form of a payment adjustment incorporated into the hospital reimbursement system, based on each hospital's outcomes compared to both an external and a local standard. The authors report the first experiences with the demonstration and the prospects for continuous improvement of quality of care.


Secondary osteoporosis: underlying disease and the risk for glucocorticoid-induced osteoporosis.
Chronic diseases of many organ systems require long-term (>or=1 year) treatment with glucocorticoids. Owing to the catabolic activity of glucocorticoid therapy, osteoporosis is a potential complication. This review discusses glucocorticoid-induced bone loss and the factors, including underlying disease, that increase the risk for osteoporosis. Therapeutic options for the prevention and treatment of glucocorticoid-induced osteoporosis (GIO) also are reviewed. A review of the English-language literature was conducted using the MEDLINE database and proceedings from scientific meetings. Search terms including glucocorticoid-induced osteoporosis, bone loss, and fracture were used to refine the search, and preference was given to studies published after 1990. Long-term glucocorticoid treatment causes bone loss that is most precipitous in the first 6 months. Patients treated with glucocorticoids have additional risk factors for bone loss and osteoporosis that are associated with their primary disease. Chronic diseases can cause changes in bone metabolism, leading to bone loss in addition to that induced by glucocorticoids alone. Bone loss can be minimized through proper nutrition, weight-bearing exercise, calcium and vitamin D supplementation, and, where indicated, bisphosphonate treatment. The American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis guidelines recommend bisphosphonates for minimizing bone loss and fracture risk in patients at risk for GIO. Risedronate is indicated for the prevention and treatment of GIO, and alendronate is indicated for its treatment. Both risedronate and alendronate increase bone mineral density in patients at risk for GIO. Risedronate significantly reduces the incidence of vertebral fractures after 1 year of treatment (P<0.05). The effectiveness and tolerability of the bisphosphonates have not been established in pregnant women or pediatric patients. Men and women initiating long-term glucocorticoid treatment and those with GIO should be concomitantly treated with effective osteoporosis therapy to reduce fracture risk and counseled on preventive lifestyle changes.


Comparison of potassium and sodium binding in vivo and in agarose samples using TQTPPI pulse sequence.
Potassium and sodium specific binding in vivo were explored at 21.1T by triple quantum (TQ) magnetic resonance (MR) signals without filtration to achieve high sensitivities and precise quantifications. The pulse sequence used time proportional phase increments (TPPI). During simultaneous phase-time increments, it provided total single quantum (SQ) and TQ MR signals in the second dimension at single and triple quantum frequencies, respectively. The detection of both TQ and SQ signals was performed at identical experimental conditions and the resulting TQ signal equals 60±3% of the SQ signal when all ions experience sufficient time for binding. In a rat head in vivo the TQ percentage relative to SQ for potassium is 41.5±3% and for sodium is 16.1±1%. These percentages were compared to the matching values in an agarose tissue model with MR relaxation times similar to those of mammalian brain tissue. The sodium TQ signal in agarose samples decreased in the presence of potassium, suggesting a competitive binding of potassium relative to sodium ions for the same binding sites. The TQTPPI signals correspond to almost two times more effective binding of potassium than sodium. In vivo, up to ∼69% of total potassium and ∼27% of total sodium can be regarded as bound or experiencing an association time in the range of several milliseconds. Experimental data analyses show that more than half of the in vivo total sodium TQ signal could be from extracellular space, which is an important factor for quantification of intracellular MR signals.


Evaluation of the correlation between gaze avoidance and schizophrenia psychopathology with deep learning-based emotional recognition.
To investigate the correlation between gaze avoidance and psychopathology in patients with schizophrenia through eye movement measurements in real-life interpersonal situations. We enrolled 52 clinically stable patients with schizophrenia. Psychopathology was evaluated using the Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale. After presenting a visual stimulus, eye movements were measured with Tobii Pro Wearable Glasses 2, and deep learning-based emotional recognition using the residual masking network was used for neutral stimulus verification. Statistical analyses were performed using Pearson's correlation and regression analyses. Data of 45 participants with verified stimulus neutrality by deep learning image recognition were used for analysis. The first dwelling time was negatively correlated with the PANSS positive syndrome subscale (p = 0.028), general psychopathology subscale (p = 0.008), total score (p = 0.008), 5-factor positive symptoms (p = 0.035), and 5-factor depression/anxiety symptoms (p = 0.043). The baseline-area of interest (AOI) pupil diameter change was positively correlated with PANSS 5-factor positive symptom scores (p = 0.039). After adjusting for additional variables, the same items had a significant effect on the first dwelling time and baseline-AOI pupil diameter change. Psychopathology, particularly positive symptoms, was associated with gaze avoidance and pupil diameter in patients with schizophrenia. Evaluating the characteristics of eye movements in patients with schizophrenia will enable better understanding of their symptoms.


Interpretations of Examinations Outside of Radiologists' Fellowship Training: Assessment of Discrepancy Rates Among 5.9 Million Examinations From a National Teleradiology Databank.
BACKGROUND. In community settings, radiologists commonly function as multispecialty radiologists, interpreting examinations outside of their area of fellowship training. OBJECTIVE. The purpose of this article was to compare discrepancy rates for preliminary interpretations of acute community-setting examinations that are concordant versus discordant with interpreting radiologists' area of fellowship training. METHODS. This retrospective study used the databank of a U.S. teleradiology company that provides preliminary interpretations for client community hospitals. The analysis included 5,883,980 acute examinations performed from 2012 to 2016 that were preliminarily interpreted by 269 teleradiologists with a fellowship of neuroradiology, abdominal radiology, or musculoskeletal radiology. When providing final interpretations, client on-site radiologists voluntarily submitted quality assurance (QA) requests if preliminary and final interpretations were discrepant; the teleradiology company's QA committee categorized discrepancies as major (n = 8444) or minor (n = 17,208). Associations among examination type (common vs advanced), relationship between examination subspecialty and the teleradiologist's fellowship (concordant vs discordant), and major and minor discrepancies were assessed using three-way conditional analyses with generalized estimating equations. RESULTS. For examinations with a concordant subspecialty, the major discrepancy rate was lower for common than for advanced examinations (0.13% vs 0.26%; relative risk [RR], 0.50, 95% CI, 0.42-0.60; p < .001). For examinations with a discordant subspecialty, the major discrepancy rate was lower for common than advanced examinations (0.14% vs 0.18%; RR, 0.81; 95% CI, 0.72-0.90; p < .001). For common examinations, the major discrepancy rate was not different between examinations with concordant versus discordant subspecialty (0.13% vs 0.14%; RR, 0.90; 95% CI, 0.81-1.01; p = .07). For advanced examinations, the major discrepancy rate was higher for examinations with concordant versus discordant subspecialty (0.26% vs 0.18%; RR, 1.45; 95% CI, 1.18-1.79; p < .001). The minor discrepancy rate was higher among advanced examinations for those with concordant versus discordant subspecialty (0.34% vs 0.29%; RR, 1.17; 95% CI, 1.00-1.36; p = .04), but not different for other comparisons (p > .05). CONCLUSION. Major and minor discrepancy rates were not higher for acute community-setting examinations outside of interpreting radiologists' fellowship training. Discrepancy rates increased for advanced examinations. CLINICAL IMPACT. The findings support multispecialty radiologist practice in acute community settings. Efforts to match examination and interpreting radiologist sub-specialty may not reduce diagnostic discrepancies.


Peptide inhibitors of N-succinyl diaminopimelic acid aminotransferase (DAP-AT): a novel class of antimicrobial compounds.
Dipeptide substrates of N-Succinyl Diaminopimelic Acid Aminotransferase (DAP-AT) were converted to hydrazines by treatment with hydrazine and cyanoborohydride. These compounds were tested in vitro as inhibitors of DAP-AT from E. coli and in vivo as antibiotics. The hydrazino-dipeptides showed potent slow binding slow binding inhibition of DAP-AT as well as antimicrobial activity.


Pediatric Benign Soft Tissue Oral and Maxillofacial Pathology.
Despite the many types of oral pathologic lesions found in infants and children, the most commonly encountered are benign soft tissue lesions. The clinical features, diagnostic criteria, and treatment algorithms of pathologies in the age group from birth to 18 years of age are summarized based on their prevalence in each given age distribution. Treatment modalities include both medical and surgical management.


Feasibility of fast MR imaging of the liver at 1.5 T.
A phantom with T1 and T2 relaxation times encompassing normal liver and liver lesions was constructed to evaluate fast magnetic resonance pulse sequences using TR from 21-100 milliseconds, TE 12-60 milliseconds and flip angles from 5 degrees-90 degrees. Ten of these fast MR sequences were then selected and compared with conventional spin-echo sequences in normal volunteers (n = 3) and in patients with liver lesions (n = 6). Subjectively, the fast MR sequences eliminated motion artefacts. Objectively, 8 of 10 fast sequences had signal-to-noise ratios comparable to spin-echo imaging whereas only 2 of 10 had contrast-to-noise ratios that were similar to spin-echo imaging. This preliminary study, performed at 1.5 Tesla, does not show any clear-cut advantage of fast imaging over spin-echo imaging in the detection of liver lesions. The use of a liver tissue equivalent phantom provides a rapid, practical approach in evaluation of fast scans.


Pipeline for transferring annotations between proteins beyond globular domains.
DisProt is the primary repository of Intrinsically Disordered Proteins (IDPs). This database is manually curated and the annotations there have strong experimental support. Currently, DisProt contains a relatively small number of proteins highlighting the importance of transferring annotations regarding verified disorder state and corresponding functions to homologous proteins in other species. In such a way, providing them with highly valuable information to better understand their biological roles. While the principles and practicalities of homology transfer are well-established for globular proteins, these are largely lacking for disordered proteins. We used DisProt to evaluate the transferability of the annotation terms to orthologous proteins. For each protein, we looked for their orthologs, with the assumption that they will have a similar function. Then, for each protein and their orthologs, we made multiple sequence alignments (MSAs). Disordered sequences are fast evolving and can be hard to align, therefore, we implemented alignment quality control steps ensuring robust alignments before mapping the annotations. We have designed a pipeline to obtain good-quality MSAs and to transfer annotations from any protein to their orthologs. Applying the pipeline to DisProt proteins, from the 1731 entries with 5623 annotations, we can reach 97,555 orthologs and transfer a total of 301,190 terms by homology. We also provide a web server for consulting the results of DisProt proteins and execute the pipeline for any other protein. The server Homology Transfer IDP (HoTIDP) is accessible at http://hotidp.leloir.org.ar.


S-allyl cysteine attenuates free fatty acid-induced lipogenesis in human HepG2 cells through activation of the AMP-activated protein kinase-dependent pathway.
S-Allyl cysteine (SAC), a nontoxic garlic compound, has a variety of pharmacological properties, including antioxidant and hepatoprotective properties. In this report, we provide evidence that SAC prevented free fatty acid (FFA)-induced lipid accumulation and lipotoxicity in hepatocytes. SAC significantly reduced FFA-induced generation of reactive oxygen species, caspase activation and subsequent cell death. Also, SAC mitigated total cellular lipid and triglyceride accumulation in steatotic HepG2 cells. SAC significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in HepG2 cells. Additionally, SAC down-regulated the levels of sterol regulatory element binding protein-1 (SREBP-1) and its target genes, including ACC and fatty acid synthase. Use of a specific inhibitor showed that SAC activated AMPK via calcium/calmodulin-dependent kinase kinase (CaMKK) and silent information regulator T1. Our results demonstrate that SAC activates AMPK through CaMKK and inhibits SREBP-1-mediated hepatic lipogenesis. Therefore, SAC has therapeutic potential for preventing nonalcoholic fatty liver disease.


TIRAP-mediated activation of p38 MAPK in inflammatory signaling.
The role of TIRAP (toll/interleukin-1 receptor (TIR) domain-containing adapter protein) in macrophage inflammatory signalling has been significantly evolved since its discovery in 2001 due to its dynamic nature and subcellular localization to regulate multiple signaling through several protein-protein interactions (PPIs). Structural analysis of these interactions can reveal a better understanding of their conformational dynamics and the nature of their binding. Tyrosine phosphorylation in the TIR domain of TIRAP is very critical for its function. In toll-like receptor (TLR) 4/2 signalling, Bruton's tyrosine kinase (BTK) and Protein kinase C delta (PKCδ) are known to phosphorylate the Y86, Y106, Y159, and Y187 of TIRAP which is crucial for the downstream function of MAPKs (mitogen-activated protein kinases) activation. The objective of this study is to understand the interaction of TIRAP with p38 MAPK through molecular docking and identify the importance of TIRAP tyrosine phosphorylation in p38 MAPK interaction. In this structural study, we performed an in-silico molecular docking using HADDOCK 2.4, pyDockWEB, ClusPro 2.0, and ZDOCK 3.0.2 tools to unravel the interaction between TIRAP and p38 MAPK. Further, manual in-silico phosphorylations of TIRAP tyrosines; Y86, Y106, Y159, and Y187 was created in the Discovery Studio tool to study the conformational changes in protein docking and their binding affinities with p38 MAPK in comparison to non-phosphorylated state. Our molecular docking and 500 ns of molecular dynamic (MD) simulation study demonstrates that the Y86 phosphorylation (pY86) in TIRAP is crucial in promoting the higher binding affinity (∆Gbind) with p38 MAPK. The conformational changes due to the tyrosine phosphorylation mainly at the Y86 site pull the TIRAP closer to the active site in the kinase domain of p38 MAPK and plays a significant role at the interface site which is reversed in its dephosphorylated state. The heatmap of interactions between the TIRAP and p38 MAPK after the MD simulation shows that the TIRAP pY86 structure makes the highest number of stable hydrogen bonds with p38 MAPK residues. Our findings may further be validated in an in-vitro system and would be crucial for targeting the TIRAP and p38 MAPK interaction for therapeutic purposes against the chronic inflammatory response and associated diseases.


Excessive intimal hyperplasia in human coronary arteries before intimal lipid depositions is the initiation of coronary atherosclerosis and constitutes a therapeutic target.
The consensus hypothesis on coronary atherosclerosis suggests high LDL-C levels as the major cause and pursues it as the therapeutic target, explicitly assuming: (i) tunica intima of human coronaries consists of only one cell layer - endothelium, situated on a thin layer of scarcely cellular matrix; and (ii) subendothelial lipoprotein retention initiates the disease. Facts showed: (i) normal tunica intima invariably consists of multiple cellular layers; and (ii) initial lipid depositions occurred in the deepest layers of tunica intima. This review suggests that coronary atherosclerosis starts with pathological intimal expansion, resulting in intimal hypoxia and neovascularization from adventitial vasa vasorum, facilitating lipoprotein extraction by previously avascular deep intimal tissues. Until the hypothesis incorporates real knowledge, our efforts will probably be off-target.


High prevalence of obesity and diabetes mellitus in Konya, a central Anatolian city in Turkey.
The objective of this study was to determine the prevalence of overweight, obesity, impaired fasting glucose, diabetes and the relationship between adiposity and carbohydrate metabolism, by age and gender in Konya, a city in central Anatolia. A cross-sectional population based survey was performed. One month before the field survey a media campaign was started in each district by local municipalities. Ten percent of the target population age 20 and over were invited to participate and the participation rate was 82.1%. Twelve thousand eight hundred and sixty-six inhabitants (7000 women and 5866 men, mean age 46.7+/-15.9 years) were evaluated for height and body weight between May and September of 2001. Two thousand eight hundred and thirty consecutive subjects (1788 women and 1042 men, mean age 48.2+/-15.7 years) were tested for fasting blood glucose in addition to an anthropometric evaluation. The crude IFG rate was 24% (27.1% in women and 18.5% in men) and the diabetes rate 8.4% (8% in women and 9.1% in men). The survey identified previously undiagnosed diabetes in 3.7% (4.3% of women and 2.9% of men). The prevalence of diabetes (p=0.0005) and obesity (p=0.0005) increased with age. Obese men and women had a higher risk of being diabetic than their normal weight counterparts (OR, 2.05; CI 95%, 1.13-3.71; p=0.0186 and OR, 2.53; CI 95%, 1.57-4.07; p=0.0001, respectively). Overall, the overweight rate was 34.2% (33.5% of women and 36.3% of men) and the obesity rate was 23.7% (32.4% of women and 14.1% of men) (n=12,866). Women had a significantly higher risk of being obese than men (OR, 2.84; CI 95%, 2.62-3.08; p=0.0005). The diabesity rate was 3.4% (4.1% in women and 2.1% in men). Carbohydrate intolerance and adiposity are highly prevalent in Konya, and the two conditions are positively correlated with each other, by age and gender.


Expression of immunohistochemical markers in patients with AIDS-related lymphoma.
AIDS-related lymphomas (ARL) present high biological heterogeneity. For better characterization of this type of lymphoma, the objectives of the present study were to evaluate the expression of immunohistochemical markers of cell differentiation (CD10, Bcl-6, MUM-1) and determine cell origin profile according to Hans' classification of diffuse large B-cell lymphoma in AIDS patients. This study included 72 consecutive patients with ARL diagnosed at the University Hospital, Universidade Federal do Rio de Janeiro (UFRJ) and at the Brazilian Instituto Nacional de Câncer (INCA) from 2000 to 2006. The morphologic distribution of the lymphomas was the following: 61% were diffuse large B-cell lymphomas (DLBCLs), 15% were Burkitt's lymphomas, 13% were plasmablastic lymphomas, 10% were high-grade lymphomas and 1% was follicular lymphoma. The positivity for each immunohistochemical marker in DLBCLs, Burkitt's lymphoma and plasmablastic lymphoma was respectively: CD20, 84%, 100%, and 0; CD10, 55%, 100%, and 0; Bcl-6, 45%, 80%, and 0; MUM-1, 41%, 20%, and 88%. A higher positivity of CD20 (84% x 56%, p = 0.01) was found in DLBCL compared to non-DLBCL; in Burkitt's lymphomas a higher positivity of CD10 (100% x 49%, p = 0.04) and Bcl-6 (80% x 39%, p = 0.035) were found compared to non-Burkitt's lymphomas. Germinal center (GC) profile was detected in 60% of DLBCLs. Our study suggests particular findings in ARL, as the most frequent phenotype was GC, different from HIV-negative patients.


Identification and quantification of N-methylepinephrine in human urine.
N-Methylepinephrine was analysed in human urine using a high-performance liquid chromatographic catecholamine assay. The identity of the compound was confirmed by gas chromatography-mass spectrometry. The excretion of N-methylepinephrine is slightly less than that of epinephrine: excretion values were in the range 2-65 nmol per 24 h (0.4-13 micrograms per 24 h) in 150 hypertensive patients. In addition to increased epinephrine excretion, increased urinary excretion of N-methylepinephrine was found in three out of five patients with histologically proven pheochromocytoma.


Effectiveness of a home-based, family caregiver-administered manual massage intervention in managing dementia symptoms and reducing caregiver stress: A randomized, controlled clinical trial.
To investigate the effectiveness of family caregiver-administered home-based manual massages in managing dementia symptoms and reducing caregiver stress. Thirty-eight pairs of participants-patients with dementia and their family caregivers-were randomly allocated to the experimental or the control group. The caregivers underwent 3-h-long massage training. Subsequently, the patients received a 30-min-long, home-based massage from their caregivers thrice a week for 8 consecutive weeks. The Cornell Scale for Depression in Dementia (CSDD), Cohen-Mansfield Agitation Inventory (CMAI), and Perceived Stress Scale (PSS) were assessed before and after the interventions. After intervention, the experimental group exhibited significant improvements in CSDD and CMAI scores compared with the scores of the control group (all p < .001). Furthermore, the experimental group obtained more favorable PSS scores than did the control group (p = .013). Family caregiver-administered home-based massage therapy is recommended for managing dementia symptoms and reducing caregiver stress.


USMLE Step 1 scores and PGY-5 ABSITE performance are predictive of American Board of Surgery examination first-time pass rates.
Standardized exams are utilized throughout a resident's career. With USMLE Step 1 score reports changing to pass/fail only, we sought to evaluate the relationships among USMLE Step 1 and 2, PGY-5 ABSITE, and ABS performance. Retrospective analyses of PGY-5 USMLE Step 1 and Step 2 scores, ABSITE percentile ranks, and ABS QE and CE first-time pass rates of graduates from 2010 to 2019 were performed. PGY-5 residents scoring ≤ 20th percentile on ABSITE during their PGY-5 year were more likely to have lower USMLE Step 1 scores, but not Step 2 scores, and have a lower ABS first pass rate. Lower Step and ABSITE scores together were associated with lower ABS first pass rate. As USMLE Step 1 is now a pass/fail examination, programs may need to utilize other information to select residency candidates and structure educational activities differently within their programs.


Spectrum and epidemiology of intestinal failure.
Although there is common agreement about the corecases in which there is no alternative to HPN, cultural and economic differences lead to major variations in the types of disease treated, the ages of patients treated, the duration of and prevalence of treatment. It is unlikely that there will be agreement between countries on the extent to which artificial nutritional support will be used.


The roles of alcohol dehydrogenase in patients with atrial fibrillation.
Alcohol consumption is known to increase the risk of atrial fibrillation (AF). Whether the genotypes of alcohol-metabolizing genes (alcohol dehydrogenase [ADH1B]) are associated with the risk of AF recurrence after catheter ablation remains unclear. The ADH1B genotypes of 281 patients who received catheter ablation for AF were examined. We followed this group of patients to monitor their AF recurrence. Alcohol consumption levels of this cohort were evaluated before and after catheter ablation. There was no difference in the underlying diseases presented by the patients with different ADH1B genotypes. Regardless of the ADH1B genotypes, the amount of alcohol consumption was the only factor associated with left atrial dilatation. The ADH1B*2 alleles (hazard ratio: ADH1B*1/*2 vs *1/*1: 2.64; ADH1B*2/*2 vs *1/*1: 1.80, P = 0.02) and the levels of alcohol consumption were independently associated with AF recurrence in the patients with paroxysmal AF after catheter ablation. ADH1B polymorphisms were not associated with AF recurrence in the patients with nonparoxysmal AF. We also found that the association of increased AF recurrence with alcohol consumption and the ADH1B genotypes cannot be explained by mechanisms of systemic inflammation. ADH1B*2/*2 genotype and amount of alcohol consumption increase the risk of AF recurrence after catheter ablation.


Enhanced magnetic ordering by impurity Fe substitution on electron-doped superconductors Eu2-x+y Ce x-y Cu1-y Fe y O4+α-δ.
Crystal structure and magnetic properties are two important properties of superconducting materials that need to be studied. We partially substituted the Cu with a magnetic impurity Fe in the electron-doped superconducting cuprate of Eu2-x+y Ce x-y Cu1-y Fe y O4+α-δ (ECCFO) to investigate the effect of Fe impurity substitution on crystal structure and magnetic properties. In this study, we have chosen concentrations of x = 0.12 and 0.15, and concentrations of y = 0.01, 0.02, and 0.05. The crystal structure was studied by analyzing XRD patterns, and magnetic properties were analyzed using data obtained from susceptibility measurements. For y = 0, the lattice parameter a and Cu-O(2) bond length increased with increasing x from 0.12 to 0.15. It is confirmed by magnetic susceptibility measurement that the T c of x = 0.15 (14 K) is larger than that of x = 0.12 (12 K). For the effect of the addition of Fe on the structural parameters, the lattice parameter c increased with the addition of Fe, which means the distance between the charge reservoir and the conducting layer is getting farther. The addition of Fe to the ECCFO sample increased the C and μ e f f values. This is because Fe impurity causes an increase in the magnetic ordering of the ECCFO material and reduces its superconductivity.


Linear IgA disease of adults: association with lymphoproliferative malignancy and possible role of other triggering factors.
Seventy patients with linear IgA disease of adults were followed up for a mean of 8.5 years and all malignant diseases in this group were ascertained. There were three cases of lymphoproliferative malignancy, which constituted a significant excess over the 0.2 cases that would be expected by comparison with an age- and sex-matched population using National Cancer Registry statistics. In contrast, the non-lymphoid malignancy rate of 13% is almost identical to the expected 14%. A subgroup of 35 of the adult linear IgA disease patients were assessed with respect to the possible precipitating illnesses or drugs, as well as co-existing medical conditions. Almost one-third of patients described an event that was felt could possibly have triggered the linear IgA disease, the most frequent being non-steroidal anti-inflammatory or antibiotic drug therapy, trauma/burns and upper respiratory tract infections. However, it is difficult to determine how often the preceding event is coincidental, and how often, if at all, it is causal.


The role of thymectomy in red cell aplasia.
Red cell aplasia is an unusual cause of anemia. Fifty percent of all patients with red cell aplasia will have a thymoma. Twenty-five to 30% of those who undergo thymectomy will be cured. Data are presented that suggest that any patient with red cell aplasia should have thymectomy through a median sternotomy. One of 3 such patients who underwent the operation has had complete remission for two years.


Phantabulation: a case of visual imagery interference on visual perception.
We report the case of a 52-year old man who, following rupture of an anterior communicating artery aneurysm, presented with a phenomenon not previously described, which we have labelled "Phantabulation." Phantabulation is characterized by frequent and purposeful interactions with contextually appropriate imagined objects. We suggest that this phenomenon results from confusion between real and imagined objects, caused by failure to inhibit florid visual imagery, facilitated by cortical release mechanisms.


Maintenance of permanently implanted cardiac pressure catheters in experimental animals.
Two techniques for maintaining permanently implanted cardiac catheters in experimental animals are described. Polyvinylchloride catheters are coated with TDMAC-Heparin, a polymer complex currently used clinically to prevent thrombogenesis in vascular shunts. Long-term catheter obstruction and thrombus formation have been obviated by using this method. Also, to assure multiple, painless studies in awake animals, a somewhat different technique for pressure catheter access has been developed and is detailed in this report.


Chromoendoscopy, Narrow-Band Imaging or White Light Endoscopy for Neoplasia Detection in Inflammatory Bowel Diseases.
Studies have confirmed an increased risk of colorectal cancer in patients with ulcerative colitis; hence, surveillance is recommended. Optional modalities include white light endoscopy (WLE) or dye-spray chromoendoscopy. However, narrow-band imaging (NBI) is still not considered comparable to chromoendoscopy. The aim of this study was to compare the diagnostic yield (DY) of WLE, chromoendoscopy, NBI for detection of neoplasia in patients with inflammatory bowel disease (IBD) by performing a meta-analysis of the existing literature. We searched databases for prospective studies. For each modality, we performed comparative per-lesion analysis (any neoplasia detection) and per-patient analysis (patient with neoplastic lesions). Meta-analysis was performed using fixed-effect model unless heterogeneity was high. Odds ratios (ORs) with 95% CIs were calculated and pooled. Five studies compared chromoendoscopy to WLE. Chromoendoscopy (n = 361) was superior to WLE (n = 358) with per-patient analysis OR 2.05 (95% CI 1.26, 3.35) and per-lesion analysis OR 2.79 (95% CI 2.08, 3.73). High-definition (HD) chromoendoscopy was superior to HD-WLE with per-lesion analysis OR 2.48 (95% CI 1.55, 3.97). In four studies comparing NBI to WLE (n = 305), no difference was found in per-patient analysis OR 0.97 (95% CI 0.62, 1.53) and per-lesion analysis OR 0.94 (95% CI 0.63, 1.4). In two studies comparing CE to NBI (n = 104), no difference was found in per-patient analysis OR 1.0 (95% CI 0.51, 1.95) and per-lesion analysis OR 1.29 (95% CI 0.69, 2.41). Chromoendoscopy is superior to WLE for detection of dysplasia in IBD, even with HD endoscopy. No difference in DY could be demonstrated for NBI in comparison with other modalities.


Hemagglutination inhibiton in capillary tubes--a simple and reliable test for HBsAg.
A technique is described which allows testing for HBsAg by hemagglutination inhibition in capillary tubes. The test is rapid, and compares favorably in sensitivity to radioimmunoassay. The equipment is simple, and its design eliminates the risk of infection from the HBsAg reagents.


Immediate coma and poor outcome in subarachnoid haemorrhage are independently associated with an aneurysmal origin.
Subarachnoid haemorrhage (SAH) may present with coma and this is known to be associated with aneurysmal origin and blood load. Aneurysmal origin is associated with increased blood load and existing data do not allow us to determine if the association between coma and aneurysmal SAH is wholly due to blood load or if aneurysmal origin has an additional independent effect. The objective of our study is to find if an aneurysmal origin is a predictor of acute onset of coma independent of blood load. A series of consecutive patients with spontaneous SAH were divided into two groups: aneurysmal (aSAH) and non-aneurysmal--angiographically negative SAH (naSAH). Blood load was quantified so that the effect of aneurysmal origin could be resolved from the effect of the amount of blood spilled. Non-parametric regression was used to relate blood load to coma and poor outcome rates for aneurysmal bleeds. We analysed a total of 421 patients presenting during the period 2009-2011. Ninety aneurysmal cases presented with coma, seventy immediately in the early phase and seven shortly after rebleeding. None of the naSAH cases presented with immediate coma and 1 developed delayed coma. Delayed coma was associated with acute hydrocephalus in both groups. Aneurysmal origin was found to be an independent determinant of immediate coma (p=0.02) and poor outcome (p<0.001). Immediate coma and poor outcome in SAH are associated with an aneurysmal origin and do not characterize naSAH.


A mathematical high bar-human body model for analysing and interpreting mechanical-energetic processes on the high bar.
The aims of this study were: 1. To study the transfer of energy between the high bar and the gymnast. 2. To develop criteria from the utilisation of high bar elasticity and the utilisation of muscle capacity to assess the effectiveness of a movement solution. 3. To study the influence of varying segment movement upon release parameters. For these purposes a model of the human body attached to the high bar (high bar-human body model) was developed. The human body was modelled using a 15-segment body system. The joint-beam element method (superelement) was employed for modelling the high bar. A superelement consists of four rigid segments connected by joints (two Cardan joints and one rotational-translational joint) and springs (seven rotation springs and one tension-compression spring). The high bar was modelled using three superelements. The input data required for the high bar human body model were collected with video-kinematographic (50 Hz) and dynamometric (500 Hz) techniques. Masses and moments of inertia of the 15 segments were calculated using the data from the Zatsiorsky et al. (1984) model. There are two major phases characteristic of the giant swing prior to dismounts from the high bar. In the first phase the gymnast attempts to supply energy to the high bar-humanbody system through muscle activity and to store this energy in the high bar. The difference between the energy transferred to the high bar and the reduction in the total energy of the body could be adopted as a criterion for the utilisation of high bar elasticity. The energy previously transferred into the high bar is returned to the body during the second phase. An advantageous increase in total body energy at the end of the exercise could only be obtained through muscle energy supply. An index characterising the utilisation of muscle capacity was developed out of the difference between the increase in total body energy and the energy returned from the high bar. A delayed and initially slow but even reduction of hip and shoulder angles provided more advantageous release conditions. The total body energy could be improved by up to 15%, the vertical CM release velocity by up to 10% and the angular momentum by up to 35%.


Layered-Double-Hydroxide Nanosheets as Efficient Visible-Light-Driven Photocatalysts for Dinitrogen Fixation.
Semiconductor photocatalysis attracts widespread interest in water splitting, CO2 reduction, and N2 fixation. N2 reduction to NH3 is essential to the chemical industry and to the Earth's nitrogen cycle. Industrially, NH3 is synthesized by the Haber-Bosch process under extreme conditions (400-500 °C, 200-250 bar), stimulating research into the development of sustainable technologies for NH3 production. Herein, this study demonstrates that ultrathin layered-double-hydroxide (LDH) photocatalysts, in particular CuCr-LDH nanosheets, possess remarkable photocatalytic activity for the photoreduction of N2 to NH3 in water at 25 °C under visible-light irradiation. The excellent activity can be attributed to the severely distorted structure and compressive strain in the LDH nanosheets, which significantly enhances N2 chemisorption and thereby promotes NH3 formation.


Environmental and anthropogenic factors affecting the probability of occurrence of Oncomegas wageneri (Cestoda: Trypanorhyncha) in the southern Gulf of Mexico.
Understanding the environmental and anthropogenic factors influencing the probability of occurrence of the marine parasitic species is fundamental for determining the circumstances under which they can act as bioindicators of environmental impact. The aim of this study was to determine whether physicochemical variables, polyaromatic hydrocarbons or sewage discharge affect the probability of occurrence of the larval cestode Oncomegas wageneri, which infects the shoal flounder, Syacium gunteri, in the southern Gulf of Mexico. The study area included 162 sampling sites in the southern Gulf of Mexico and covered 288,205 km(2), where the benthic sediments, water and the shoal flounder individuals were collected. We used the boosted generalised additive models (boosted GAM) and the MaxEnt to examine the potential statistical relationships between the environmental variables (nutrients, contaminants and physicochemical variables from the water and sediments) and the probability of the occurrence of this parasite. The models were calibrated using all of the sampling sites (full area) with and without parasite occurrences (n = 162) and a polygon area that included sampling sites with a depth of 1500 m or less (n = 134). Oncomegas wageneri occurred at 29/162 sampling sites. The boosted GAM for the full area and the polygon area accurately predicted the probability of the occurrence of O. wageneri in the study area. By contrast, poor probabilities of occurrence were obtained with the MaxEnt models for the same areas. The variables with the highest frequencies of appearance in the models (proxies for the explained variability) were the polyaromatic hydrocarbons of high molecular weight (PAHH, 95 %), followed by a combination of nutrients, spatial variables and polyaromatic hydrocarbons of low molecular weight (PAHL, 5 %). The contribution of the PAHH to the variability was explained by the fact that these compounds, together with N and P, are carried by rivers that discharge into the ocean, which enhances the growth of hydrocarbonoclastic bacteria and the productivity and number of the intermediate hosts. Our results suggest that sites with PAHL/PAHH ratio values up to 1.89 promote transmission based on the high values of the prevalence of O. wageneri in the study area. In contrast, PAHL/PAHH ratio values ≥ 1.90 can be considered harmful for the transmission stages of O. wageneri and its hosts (copepods, shrimps and shoal flounders). Overall, the results indicate that the PAHHs affect the probability of occurrence of this helminth parasite in the southern Gulf of Mexico.


Reproducibility of cerebral and peripheral haemodynamic responses to active, passive and motor imagery paradigms in older healthy volunteers: a fTCD study.
Cerebral blood flow velocity (CBFv) changes to sensorimotor and cognitive paradigms have been used to assess the integrity of haemodynamic responses, though the reproducibility of these responses has not been properly assessed. Continuous recordings of blood pressure, end-tidal CO(2), heart rate and bilateral CBFv were obtained during 60s of active, passive and mental imagined paradigms on two different occasions over a 1-week period in 13 healthy subjects. The correlation coefficient, standard error of measurement (SEM), intra-class correlation (ICC) and its 95% CI (confidence intervals) for each variable were calculated at the beginning and end of each paradigm. The temporal patterns of haemodynamic responses revealed substantial reproducibility. For the CBFv response, the SEM ranged from 2.4 to 5.5% for the different manoeuvres, whilst the ICC ranged from 0.5 to 0.8 with better reproducibility occurring at the beginning of the paradigm. These findings have important implications for the design of studies of the natural history of haemodynamic changes following ageing and disease.


Distinct glycoforms of human alpha1-acid glycoprotein have comparable synthesis rates: a [13C]valine-labelling study in healthy humans.
Various alpha1-acid glycoprotein (AGP) glycoforms are present in plasma differing in extent of branching and/or fucosylation of their 5 N-linked glycans, as well as in concentration. It is assumed that hepatic synthesis determines the relative occurrence of the AGP-glycoforms in plasma, but experimental evidence is lacking. In this study, we have investigated the contribution of fractional synthesis rates to the plasma concentration of AGP-glycoforms that differed in relative occurrence in healthy human plasma. During a [13C]valine infusion, AGP was isolated from the plasma of healthy volunteers. Four AGP-glycoforms, differing strongly in plasma concentration were obtained by sequential affinity chromatography over concanavalin-A- and Aleuria aurantia -agarose columns. The incorporation of the [13C]valine tracer into the AGP-glycoforms was measured by gas chromatography combustion isotope ratio mass spectrometry. The mean fractional synthesis rates of the four AGP-glycoforms did not differ significantly between each other as well between individuals. The results indicated a renewal of about 15%/day of the plasma pools of each of the AGP-glycoforms. This is in support to the assumption that the differences in plasma concentration of the AGP-glycoforms are a reflection of the state of the hepatic glycosylation process.


Blockade of chloride ion transport enhances the cytocidal effect of hypotonic solution in gastric cancer cells.
Cancer cells that are exfoliated into the peritoneal cavity during surgery are viable and have the potential to produce peritoneal recurrence. Although peritoneal lavage with distilled water is applied in some cancer surgeries to kill tumor cells, there is no consensus regarding the optimal methodology and its effects. Three human gastric cancer cell lines, MKN28, MKN45, and Kato-III, were exposed to distilled water, and the resultant morphologic changes were observed using a microscope. Analysis of cell volume changes was performed using a flow cytometer. To investigate the cytocidal effects of the water, re-incubation of the cells was performed after exposing them to hypotonic solution. Additionally, the effects of 5-nitro-2-3-phenylpropylamino)-benzoic acid (NPPB), a Cl(-) channel blocker, and R(+)-[(dihydroindenyl)oxy] alkanoic acid (DIOA), a blocker of the K(+)/Cl(-) co-transporter, on the cells during their exposure to hypotonic solution were analyzed. After the cells had been exposed to the distilled water, a rapid increase in cell volume occurred followed by cell rupture. In the MKN45 and Kato-III cells, treatment with NPPB increased cell volume by inhibiting regulatory volume decrease and enhanced the cytocidal effects of the hypotonic solution, whereas no such effects were observed in the MKN28 cells. On the other hand, treatment of the MKN28 cells with DIOA inhibited RVD and enhanced the cytocidal effects of hypotonic shock. These findings support the efficacy of peritoneal lavage with distilled water during surgery for gastric cancer and suggest that the regulation of Cl(-) transport enhances the cytocidal effects of hypotonic shock.


Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol.
Short QT syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenesis in KCNH2 T618I-associated SQTS using a multi-scale human ventricle model. A Markov chain model of IKr was developed firstly to reproduce the experimental observations. It was then incorporated into cell, tissue, and organ models to explore how the mutation provided substrates for ventricular arrhythmias. Using this T618I Markov model, we explicitly revealed the subcellular level functional alterations by T618I mutation, particularly the changes of ion channel states that are difficult to demonstrate in wet experiments. The following tissue and organ models also successfully reproduced the changed dynamics of reentrant spiral waves and impaired rate adaptions in hearts of T618I mutation. In terms of pharmacotherapy, we replicated the different effects of a drug under various conditions using identical mathematical descriptions for drugs. This study not only simulated the actions of an effective drug (quinidine) at various physiological levels, but also elucidated why the IKr inhibitor sotalol failed in SQT1 patients through profoundly analyzing its mutation-dependent actions.


Interleukin-4 Restores Insulin Sensitivity in Insulin-Resistant Osteoblasts by Increasing the Expression of Insulin Receptor Substrate 1.
Obesity and latent inflammation can give rise to insulin resistance and type 2 diabetes. Here we established an insulin resistance model of osteoblasts to explore the restoration effect of anti-inflammatory interleukin-4 (IL-4) on insulin sensitivity and its mechanism. We found that IL-4 inhibited cell proliferation in a concentration- and time-dependent manner. Insulation resistance significantly reduced the phosphorylation levels of the insulin receptor substrate 1 (IRS1; Tyr612), Akt (Ser473), and AS160 (Ser318) proteins. The addition of IL-4 to the insulin resistance model led to a dose-dependent stimulation of the phosphorylation of IRS1, Akt, and AS160. IL-4 fully restored the activation of the insulin cascade in insulin-resistant cells at the concentration of 50 ng/ml. Additionally, IL-4 promoted the expression of IRS1 in a time-dependent manner. We conjecture that IL-4 restores insulin sensitivity in osteoblasts by upregulating the expression of IRS1. It was also found that IL-4 promoted the expression of osteoprotegerin depending on the time of exposure. This effect may play an important role in the regulation of the energy metabolism in the whole body.


Transcatheter closure of very large (>or= 25 mm) atrial septal defects using the Amplatzer septal occluder.
Between June 1999 and September 2002, 45 patients (age, 34 +/- 13 years; mean shunt ratio, 2.6 +/- 0.6) underwent transcatheter atrial septal defect (ASD) closure at our institution with the Amplatzer septal occluder (mean device size, 31.4 +/- 3 mm). Patients were selected by transesophageal echocardiography. The mean ASD dimension was 25.3 +/- 3.7 mm and 33 (73%) patients had deficient anterior rim. Specific procedural details included the use of 13 or 14 Fr introducer sheaths and the right upper pulmonary vein approach if the conventional approach failed. There were two procedural failures, with device embolization in both (surgical retrieval in one, catheter retrieval in one). During follow-up (3-30 months; median, 16 months), one patient (59 years) with previous atrial flutter had pulmonary embolism and was managed with anticoagulation. Two patients developed symptomatic atrial flutter. Fluoroscopy time was 31.6 +/- 19.5 min for the first 22 cases and 19.6 +/- 11.4 min for the rest (P = 0.04). Transcatheter closure of large ASDs is technically feasible but careful long-term follow-up is needed to document its safety.


First clinical manifestation of Brugada syndrome during pregnancy.
The role of hormonal changes during pregnancy in Brugada syndrome is unknown. Only rare case reports of Brugada syndrome during pregnancy have been published. In this article, we describe a patient with first clinical manifestation of Brugada syndrome during pregnancy. The definitive diagnosis could only be achieved by drug challenge with ajmaline after childbirth because the spontaneous typical Brugada-like pattern was absent. Elevated hormone levels during pregnancy may increase the risk for arrhythmias in particular cases.


Prospective Studies Comparing Structured vs Nonstructured Diagnostic Protocol Evaluations Among Patients With Fever of Unknown Origin: A Systematic Review and Meta-analysis.
Patients meeting the criteria for fever of unknown origin (FUO) can be evaluated with structured or nonstructured approaches, but the optimal diagnostic method is unresolved. To analyze differences in diagnostic outcomes among patients undergoing structured or nonstructured diagnostic methods applied to prospective clinical studies. PubMed, Embase, Scopus, and Web of Science databases with librarian-generated query strings for FUO, PUO, fever or pyrexia of unknown origin, clinical trial, and prospective studies identified from January 1, 1997, to March 31, 2021. Prospective studies meeting any adult FUO definition were included. Articles were excluded if patients did not precisely fit any existing adult FUO definition or studies were not classified as prospective. Abstracted data included years of publication and study period, country, setting (eg, university vs community hospital), defining criteria and category outcome, structured or nonstructured diagnostic protocol evaluation, sex, temperature threshold and measurement, duration of fever and hospitalization before final diagnoses, and contribution of potential diagnostic clues, biochemical and immunological serologic studies, microbiology cultures, histologic analysis, and imaging studies. Structured protocols compared with nonstructured diagnostic methods were analyzed using regression models. Overall diagnostic yield was the primary outcome. Among the 19 prospective trials with 2627 unique patients included in the analysis (range of patient ages, 10-94 years; 21.0%-55.3% female), diagnoses among FUO series varied across and within World Health Organization (WHO) geographic regions. Use of a structured diagnostic protocol was not significantly associated with higher odds of yielding a diagnosis compared with nonstructured protocols in aggregate (odds ratio [OR], 0.98; 95% CI, 0.65-1.49) or between Western Europe (Belgium, France, the Netherlands, and Spain) (OR, 0.95; 95% CI, 0.49-1.86) and Eastern Europe (Turkey and Romania) (OR, 0.83; 95% CI, 0.41-1.69). Despite the limited number of studies in some regions, analyses based on the 6 WHO geographic areas found differences in the diagnostic yield. Western European studies had the lowest percentage of achieving a diagnosis. Southeast Asia led with infections at 49.0%. Noninfectious inflammatory conditions were most prevalent in the Western Pacific region (34.0%), whereas the Eastern Mediterranean region had the highest proportion of oncologic explanations (24.0%). In this systematic review and meta-analysis, diagnostic yield varied among WHO regions. Available evidence from prospective studies did not support that structured diagnostic protocols had a significantly better rate of achieving a diagnosis than nonstructured protocols. Clinicians worldwide should incorporate geographical disease prevalence in their evaluation of patients with FUO.


Spontaneous double-barrelled esophagus. Report of two cases and review of the literature.
We report two patients who suffered spontaneous dissection of the esophagus, the so-called double-barrelled esophagus. We review the literature about this unusual lesion to define its clinical picture, its possible causes, and several treatment approaches.


Enhanced port-wine stain lightening achieved with combined treatment of selective photothermolysis and imiquimod.
Pulsed dye laser (PDL) is the gold standard for treatment of port-wine stain (PWS) birthmarks but multiple treatments are required and complete resolution is often not achieved. Posttreatment vessel recurrence is thought to be a factor that limits efficacy of PDL treatment of PWS. Imiquimod 5% cream is an immunomodulator with antiangiogenic effects. We sought to determine if application of imiquimod 5% cream after PDL improves treatment outcome. Healthy individuals with PWS (n = 24) were treated with PDL and then randomized to apply posttreatment placebo or imiquimod 5% cream for 8 weeks. Chromameter measurements (Commission Internationale de l'Eclairage L∗a∗b∗ colorspace) for 57 PWS sites (multiple sites per patient) were taken at baseline and compared with measurements taken 8 weeks posttreatment. The Δa∗ (change in erythema) and ΔE (difference in color between normal-appearing skin and PWS skin) were measured to quantify treatment outcome. Two patients developed minor skin irritation. Other adverse effects were not noted. Average ∆a∗ was 0.43 for PDL + placebo sites (n = 25) and 1.27 for PDL + imiquimod sites (n = 32) (P value = .0294) indicating a greater reduction in erythema with imiquimod. Average ∆E was 2.59 for PDL + placebo and 4.08 for PDL + imiquimod (P value = .0363), again indicating a greater color improvement with imiquimod. Effects were evaluated after a single treatment and duration of effect is unknown. Combined selective photothermolysis and antiangiogenic therapy may enhance PWS treatment efficacy.


Lymphedema of the penis and scrotum.
The problem of genital lymphedema is commonly secondary to filariasis in most regions of the world. In the Western Hemisphere surgical manipulations usually exacerbate this significant problem. Lower leg edema may also result from these interventional procedures.


Release evaluation of drugs from ordered three-dimensional silica structures.
Cubic mesoporous structures with Ia3d symmetry, such as MCM-48 and large pore Ia3d material (LP-Ia3d), which present different pore size (3.6 and 5.7nm, respectively), have been prepared, characterized and used as drug delivery systems. Ibuprofen and erythromycin have been chosen as drug models for delivery studies. The influence of the pore size at these structures has been studied and the results show that the delivery rate of drugs decreases with the pore size of the matrix. The influence of chemical nature of the pore surface on the delivery process has been also studied. In this case, the hydrophilic pore surface has been modified with hydrocarbon chains (C8 and C18 moieties) and the effect upon drug delivery of hydrophobic drugs like erythromycin has been studied. The results show a noticeable decrease of the delivery rate when the surface of the matrices is modified.


The role of post-trauma stress symptoms in the development of chronic musculoskeletal pain and disability: A systematic review.
Traumatic injuries are amongst the leading causes of death and disability in the world across all age groups. This systematic review aimed to (1) describe the role of post-traumatic stress symptoms (PTSS) on the development of chronic pain and/or pain-related disability following musculoskeletal trauma and (2) report pain and or pain-related disability by injury severity/type. Electronic databases were searched, from inception to 31 November 2021 and updated on 10 May 2022, to identify studies in which: participants were adults aged ≥16 years sustaining any traumatic event that resulted in one or more musculoskeletal injuries; an outcome measure of PTSS was used within 3 months of a traumatic event; the presence of pain and/or pain-related disability was recorded at a follow-up of 3 months or more. Two reviewers independently screened papers and assessed the quality of included studies. Eight studies were included. Owing to between-study heterogeneity, the results were synthesized using a narrative approach. Five studies investigated the relationship between PTSS and pain. Participants with PTSS were more likely to develop persistent pain for at least 12 months post-injury. Six studies assessed the relationship between PTSS and pain-related disability. The results suggest that patients with PTSS had significantly higher disability levels for at least 12 months post-injury. Findings from this comprehensive systematic review support a clear relationship between PTSS post-injury and future pain/disability, with the potential importance of certain PTSS clusters (hyper-arousal and numbing). The findings of this systematic review indicate an association between PTSS reported within 3 months of a traumatic musculoskeletal injury and the development of longer-term pain and disability. The PTSS clusters of 'hyper-arousal' and 'numbing' appear to be of particular importance in this relationship. CRD42021285243.


Relationship between gene mutations and clinicopathological features in nonampullary duodenal epithelial tumors.
Molecular features of nonampullary duodenal epithelial tumors (NADETs) remain unclear. The aim of this study is to determine the association between the genetic features and clinicopathological findings of NADETs. In total, 75 NADETs were enrolled in this study, and was performed targeted DNA sequencing of the GNAS, KRAS, TP53, and APC genes. Histological grade was classified as category 3 or category 4/5 according to the Vienna classification, and the immunophenotype was categorized as the gastric phenotype (G type), gastrointestinal phenotype (GI type), or the intestinal phenotype (I type). The prevalence of GNAS and KRAS mutations was significantly higher in the G type than in the GI/I type (GNAS, P = 0.027; KRAS, P = 0.005). In contrast, the frequency of TP53 mutations was significantly higher in the GI/I type than in the G type (P = 0.049). Notably, APC mutations, excluding c.4479 G>A which was synonymous mutation, were more frequently identified in category 4/5 tumors than in category 3 tumors (50% vs. 24.5%; P = 0.039). G-type NADETs harbored frequent GNAS and KRAS mutations, whereas TP53 mutations are common in NADETs with intestinal features. APC mutations were significantly associated with high-grade neoplasia and invasive carcinoma.


P-REALITY X: A Real-World Analysis of Palbociclib Plus an Aromatase Inhibitor in HR+/HER2- Metastatic Breast Cancer-A Podcast.
Stringent enrollment criteria can limit the diversity of patient populations in clinical trials and, consequently, the generalizability of clinical trial data to real-world clinical practice. In this podcast, we discuss how real-world data in heterogeneous patient populations can complement clinical trial data in informing treatment decision making for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer. Specifically, our focus is on P-REALITY X, an observational retrospective analysis that was recently published in npj Breast Cancer. P-REALITY X used real-world data from the Flatiron database to compare the effectiveness of palbociclib plus an aromatase inhibitor versus an aromatase inhibitor alone as first-line treatment for patients with HR+/HER2- metastatic breast cancer. After stabilized inverse probability treatment weighting to control for observed confounders, both overall survival and real-world progression-free survival were significantly prolonged with palbociclib plus an aromatase inhibitor versus an aromatase inhibitor alone. Furthermore, overall survival and real-world progression-free survival benefits were observed across most subgroups examined. We discuss the clinical implications of P-REALITY X data, including how these results add to data from prior randomized clinical trials and real-world studies in supporting the use of first-line palbociclib plus an aromatase inhibitor as a standard-of-care treatment for patients with HR+/HER2- metastatic breast cancer. We also provide an example of how to integrate and describe key information about the P-REALITY X study in plain language when discussing palbociclib as a therapeutic option with patients.


Intracranial involvement of posttransplant lymphoproliferative disorder multiple myeloma.
We report a 61-year-old man with intracranial multiple myeloma (MM) presenting as a posttransplant lymphoproliferative disorder (PTLD) following a kidney transplant. Two months after his transplant, the man developed acute rejection with Epstein-Barr virus (EBV) viremia, requiring aggressive immunosuppression. Twenty months following transplantation, the patient presented with multiple neurologic deficits. Imaging revealed numerous lytic lesions in the skull, most conspicuously a 4.1cm right frontal skull mass with prominent intracranial extension. Histologic sections of the frontal bone lesion showed sheets of atypical plasma cells that were positive for CD138 and kappa immunoglobulin light chains. Chromogenic in situ hybridization for EBV-encoded small RNA was also positive. Plasma cell neoplasms, either as MM or a plasmacytoma, are one of the least common forms of PTLD, and their rarity limits the possibility of major studies to detail their behavior. Most often seen after renal transplantation, the majority are EBV-driven, similarly to other PTLD. While studies have demonstrated several risk factors, behavior and optimal management of PTLD plasma cell neoplasms are unknown. Plasma cell neoplasms affect the nervous system in a variety of ways but rarely via intracranial disease. MM usually presents initially with several classic signs and symptoms, but our patient's presentation was typical of a localized brain tumor with generalized and focal gross neurologic defects.


[Continuous monitoring of polycyclic hydrocarbons in an industrial urban zone: preliminary data].
Polynuclear hydrocarbon pollution is controlled sistematically in an industrial area in Genoa town. Quantitative and qualitative evaluation was carried out by gas chromatographic technique. First results show a remarkable intake of such pollutants in the air. The used sample collection allowed also the evaluation of polynuclear hydrocarbon levels according to the day hours.


Long-term complications in uniformly treated paediatric Langerhans histiocytosis patients disclosed by 12 years of follow-up of the JLSG-96/02 studies.
Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia derived from immature myeloid dendritic cells with the mitogen-activated protein kinase (MAPK) pathway gene mutation. LCH is rarely fatal, but patients develop various permanent consequences (PCs). We report the frequencies of LCH-related PCs in paediatric patients (n = 317) treated by the JLSG-96/02 AraC-containing regimens. One-third of LCH patients had at least one PC at a median follow-up of 12 years. Central nervous system (CNS)-related PCs (neurological and endocrinological) accounted for 21·5%, non-CNS-related 16·7%. We require novel therapeutic measures to further reduce the frequency of LCH-related PCs.


Experience with vascular control before excision of giant, highly vascular sacrococcygeal teratomas in neonates.
Sacrococcygeal teratomas (SCT) are the most common neoplasms in newborns with a reported occurrence of 1 in 35,000 live births. Highly vascularized tumors in which the ratio of tumor weight to patient weight approaches 1:1 are frequently associated with hyperdynamic states, prenatal hydrops, placentamegaly, postnatal high-output cardiac failure, and carry a high perinatal mortality rate. Operative management of giant, highly-vascular sacrococcygeal teratomas in neonates can be complicated by life-threatening hemorrhage. Laparotomy, control of the aorta, and the arterial blood supply to these tumors before resection has been advocated as a safer alternative. The authors report their experience with three infants successfully treated using this approach. Hemodynamic stability was maintained during the operations. All tumors were resected successfully. The patients are alive without evidence of recurrence, 8.5 months to 18 months (average, 14.3 months) after the operation. Alpha-fetoprotein levels dropped to normal range after the removal of SCT and have remained normal in follow-up. Vascular control before excision of giant, highly-vascular SCT in neonates is safe, decreases intraoperative blood loss, and postoperative morbidity.


Establishing a physical criterion for assigning personnel to U.S. Air Force jobs.
The Air Force has had problems with personnel being physically unable to perform the tasks within their assigned Air Force Specialty Code (AFSC). An assignment criterion was developed based on a single isoinertial strength score (X1): the incremental 1.83 m lift. The job assignment criterion was developed through three phases of work: Phase I analyzed AFSC tasks; Phase II developed strength/stamina tests; and Phase III established the assignment criteria.


Determination of magnesium binding to macromolecules.
An equilibrium dialysis technique for examining magnesium binding to macromolecules is described. The technique is used to determine the binding constants of magnesium to human prothrombin. This procedure should be of great utility for many biochemical systems which exhibit magnesium affinity.


Structural analysis of HmtT and HmtN involved in the tailoring steps of himastatin biosynthesis.
Himastatin is a novel antibiotic featuring a bicyclohexadepsipeptide structure. On the himastatin biosynthesis pathway, three cytochrome P450s (HmtT, HmtN, HmtS) are responsible for the post-tailoring of the cyclohexadepsipeptide backbone. Here we report the crystal structures of HmtT and HmtN. The overall structures of these two proteins are homologous to other cytochrome P450s. However, the exceptionally long F-G loop in HmtT has a highly unusual conformation and extends deep into the active site. As a result, the F/G helices of HmtT are both kinked. In contrast, the F/G helices of HmtN are straight. Also, the F/G helices in HmtT and HmtN take distinctive orientations, which may be a contributing factor for the substrate specificity of these two enzymes.


Modification of UV-induced mutation frequencies in Chinese hamster cells by dose fractionation, cycloheximide and caffeine treatments.
Chinese hamster (V79) cells were irradiated with a fractionated regime of ultraviolet light (UV1 + UV2). The fractionation of a UV dose always increased the colony-forming ability but reduced (or it did not change) the mutation frequencies. Treatment with cycloheximide between the two UV irradiations resulted in two types of effects, depending on the protocols used. Long exposures to cycloheximide (i.e., greater than 6 h) for the entire period between UV1 and UV2 or partial treatment of cycloheximide (i.e., 3 h) long before UV2 always resulted in reduced colony-forming ability and enhanced or unchanged mutation frequencies. Exposure to cycloheximide for the entire period in the short fractionated regime (i.e., 4 h) between UV1 and UV2 or partial treatment of cycloheximide just prior to UV2 tended to give the opposite effects. Caffeine treatment before UV2, with or without UV1, significantly increased the mutation frequencies. These results suggest that an error-free postreplication repair system exists in Chinese hamster cells which is inhibitable by particular cycloheximide or caffeine treatments.


The distribution of HBV, HCV and HGV among livers with fulminant hepatic failure of different aetiology.
The aim of the study was to assess the impact factor of HCV and HGV in fulminant hepatic failure. The 5'-untranslated regions of HCV RNA and HGV RNA and a segment of the core antigen sequence of HBV were amplified after extracting the nucleic acids from snap-frozen tissue aliquots from explanted livers of 26 consecutive patients undergoing orthotopic liver transplantation for fulminant hepatic failure preoperatively diagnosed as either autoimmune (n=2), HAV/HBV (n=8), toxic (n=4) or aetiologically unknown (n=12). HCV RNA was detected in five of 26 (19.2%) livers with fulminant hepatic failure. All five HCV RNA-positive livers belonged to the group of non-toxic, non-autoimmune liver failure (n=20), three of them were found in the group of liver failure with unknown aetiology (n=12) and two in the group of HBV-associated liver failure (n=7), making an HCV incidence of 25%, 25% and 28.6%, in the different groups, respectively. HGV RNA was detected in 10 of 17 (58.8%) explants and in all four groups of fulminant hepatic failure as defined preoperatively. HBV DNA was identified in six livers of 26 patients (23.1%) with fulminant hepatic failure. Neither HCV RNA nor HBV DNA was detected in the livers of patients with toxic or autoimmune fulminant hepatic failure. These results indicate that HBV and HCV, but not HGV, play an aetiologic role in fulminant hepatic failure. HCV-positive cases were concentrated either in the group of otherwise unexplained fulminant hepatic failure or in the group of HBV fulminant hepatic failure. HGV-positive cases, on the other hand, were found within all four preoperatively defined groups, indicating a role as cofactor rather than as single aetiologic agent.


In vitro uptake of apoptotic body mimicking phosphatidylserine-quantum dot micelles by monocytic cell line.
A new quantum dot (QD) PEGylated micelle laced with phosphatidylserine (PS) for specific scavenger receptor-mediated uptake by macrophages is reported. The size and surface chemistry of PS-QD micelles were characterized by standard methods and the effects of their physicochemical properties on specific targeting and uptake were comprehensively studied in a monocytic cell line (J774A.1).


Polymer-cysteamine conjugates: new mucoadhesive excipients for drug delivery?
In the present study, the features of two new thiolated polymers--the so-called thiomers--were investigated. Mediated by a carbodiimide cysteamine was covalently attached to sodium carboxymethylcellulose (Na-CMC) and neutralised polycarbophil (Na-PCP). Depending on the weight-ratio polymer to cysteamine during the coupling reaction, the resulting CMC-cysteamine conjugate and PCP-cysteamine conjugate showed in maximum 43 +/- 15 and 138 +/- 22 micromole thiol groups per g polymer (mean +/- S.D.; n=3), respectively, which were used for further characterisation. Tensile studies carried out with the CMC-cysteamine conjugate on freshly excised porcine intestinal mucosa displayed no significantly (P<0.01) improved mucoadhesion, whereas, the mucoadhesive properties of the PCP-cysteamine conjugate were increased 2.5-fold compared with the unmodified polymer. The swelling behaviour of the CMC-cysteamine conjugate was uninfluenced by the covalent attachment of the sulfhydryl compound. In contrast the swelling behaviour of the PCP-cysteamine conjugate was improved significantly (P<0.01) versus unmodified PCP. Furthermore, in aqueous solutions the disintegration time of tablets based on the CMC- and PCP-cysteamine conjugates was prolonged 1.5 and 3.2-fold, respectively, in comparison to tablets containing the corresponding unmodified polymers. According to these results, especially the PCP-cysteamine conjugate represents a promising new pharmaceutical excipient for various drug delivery systems.


Monoclonal antibodies inhibiting RNA polymerase from Escherichia coli.
Monoclonal hybridoma antibodies directed against RNA polymerase from E. coli have been obtained. Only a few have been found to inhibit the enzyme activity. Antibodies produced by two clones, PYN-1 and PYN-2, inhibit RNA polymerase at the stage of RNA chain elongation. The PYN-1 antibodies react with the beta'-subunit of the enzyme. The PYN-2 antibodies react with the beta-subunit and with its 130 kDa amber fragment.


Quality of life in nonpharmacologic treatment of atrial fibrillation.
The mainstay of treatment for atrial fibrillation, AF, remains pharmacologic control, either by maintaining sinus rhythm or by controlling the ventricular rate and allowing AF to continue. In patients where pharmacologic therapy i not effective, not tolerated or contraindicated, nonpharmacologic treatment may be beneficial. In the last two decades the number of nonpharmacologic treatment options (catheter ablation, cardiac pacing, internal defibrillation, and dysrhythmia surgery) for AF have markedly increased and the number of patients undergoing such treatment is steadily increasing. The most important reason for these treatment strategies is the hope of reducing symptoms, preventing complications and improving quality of life, QoL. However, the impact of nonpharmacologic therapy on QoL is far from established. Following a short presentation of the basic definitions and instruments used in QoL research the present paper reviews clinical studies that have assessed QoL in patients undergoing nonpharmacologic treatment of AF. Major limitations and methodological problems are emphasized. Among these are highly selected often-heterogeneous patients groups, small size, lack of control group and the use of non-validated QoL instruments. Furthermore, in most studies antiarrhythmic medication have been discontinued at the time of the intervention and it is not clear to which degree the improvement in QoL is related solely to the nonpharmacologic treatment or to the removal of drug related adverse effects. Although the currently available data from adequately designed studies are sparse and further investigations are needed, it is noteworthy that the majority of patients undergoing nonpharmacologic treatment report enhanced QoL.


Metagenomic profile of the fecal microbiome of preterm infants consuming mother's own milk with bovine milk-based fortifier or infant formula: a cross-sectional study.
Preterm (PT) infants harbor a different gut microbiome than full-term infants. Multiple factors affect gut microbial colonization of PT infants, including low gestational age, high rates of Cesarean section, exposure to antibiotics, and diet. Human milk, whether it's mother's own milk (MOM) or donor human milk, is the preferred feeding mode for PT infants but needs to be fortified to achieve adequate nutrient content. Infant formulas are introduced at later stages if human milk is insufficient or unavailable. How these dietary exposures affect the gut microbiome of PT infants is poorly understood. The goal of this study was to evaluate the metagenomic potential of the fecal microbiome of PT infants consuming MOM with bovine milk-based fortifier compared with PT formula alone. Forty-two stool samples, from 27 infants consuming MOM or formula (21 samples in each group) were included. Twelve infants had repeated sampling (2-3 samples). Shotgun genomic DNA sequencing was performed and analyzed using MetaPhlAn and HUMAnN2. Multivariate regression analysis, adjusting by the repeated sampling, was used to identify the features that differed between PT infants consuming MOM compared with formula. The primary function of the fecal microbiome of PT infants was characterized by a high abundance of biosynthesis pathways. A set of core features was identified; these belonged to pathways for amino acid metabolism and vitamin K-2 biosynthesis. Five pathways significantly differed between the MOM and formula group. Pathways for fatty acid and carbohydrate degradation were significantly higher in the MOM group. Taxonomically, members of the phylum Actinobacteria and the genus Bifidobacterium were higher in PT infants exposed to MOM. This study provides insight into the influence of feeding MOM compared with infant formula on the structure and function of the fecal microbiome of PT infants.


Evaluation of anti-factor VIII antibody levels in patients with haemophilia A receiving immune tolerance induction therapy or bypassing agents.
Bleeding episodes in patients who have haemophilia A (HA), a hereditary bleeding disorder caused by a deficiency in factor VIII (FVIII), are treated or prophylactically prevented with infusions of exogenous FVIII. Neutralizing antibodies, referred to as inhibitors, against infusion products are a major complication experienced by up to 30% of patients who have severe HA. Bypassing agents (BPA), a class of therapeutics given to patients who have inhibitors, bypass the need for FVIII in the coagulation cascade, and long-term inhibitor eradication is accomplished using immune tolerance induction therapy (ITI). Data examining the antibody levels in patients receiving BPA and ITI are limited. Measure anti-FVIII antibody levels in specimens from patients receiving ITI or BPA in order to evaluate the anti-FVIII antibody response in those patients. Specimens were tested using the CDC-modified Nijmegen-Bethesda assay (NBA) and the CDC fluorescence immunoassay (FLI) for anti-FVIII IgG1 and IgG4 . NBA-negative specimens from patients undergoing ITI or receiving BPAs have a higher frequency of anti-FVIII IgG4 positivity compared with the previously published level for NBA-negative HA patients. Analysis of anti-FVIII antibody levels in serial samples from patients undergoing ITI reveals that antibodies can persist even after the patient's NBA result falls into the negative range. Measurement of anti-FVIII antibodies may be a useful means to better contextualize NBA results in specimens from patients receiving BPA or ITI. In addition, assessment of anti-FVIII antibody levels has the potential to improve inhibitor surveillance and clinical decision-making related to the progress of ITI.


Bullous Pemphigoid Arising in Lower Leg Vein Graft Incision Site.
Bullous pemphigoid is a blistering disorder which can be idiopathic or arise secondary to drugs or trauma; however, blistering arising within surgical scars is rare. We present a patient with no prior skin history who developed blistering in his left calf vein harvesting scar soon after coronary artery bypass surgery.


Vinflunine: a new microtubule inhibitor agent.
Vinflunine (Javlor) is the first fluorinated microtubule inhibitor belonging to the Vinca alkaloids family. Vinflunine is obtained by semisynthesis using superacidic chemistry to selectively introduce two fluorine atoms at the 20' position of the catharanthine moiety. This compound has been selected for clinical development on the basis of encouraging preclinical activity that warrants study in patients with a wide spectrum of solid tumors. Clinically significant activity has been seen in phase II studies, mainly in the treatment of transitional cell carcinoma of the urothelial tract, non-small cell lung cancer, and carcinoma of the breast. Vinflunine is currently in phase III trial assessment in patients with (second line) transitional cell carcinoma of the urothelium and first-line advanced breast cancer. The efficacy of vinflunine in patients with advanced non-small cell lung cancer previously treated with a platinum-containing regimen was confirmed by a large phase III trial.


Primary synovial osteochondromatosis of the hip: extracapsular patterns of spread.
To identify patterns of extracapsular extension of synovial osteochondromatosis of the hip. Seven cases of synovial osteochondromatosis of the hip were retrospectively reviewed. Imaging performed included conventional radiography ( n=7), arthrography ( n=1), CT ( n=3) and MR imaging ( n=3). Disease extent on imaging was assessed for each patient and the presence of intra-articular effusion, capsular abnormality and osteochondral bodies recorded. The presence and distribution of extra-articular spread was also assessed and correlated with the surgical findings. In all cases diagnosis was confirmed by biopsy, with all patients undergoing tumor resection with or without synovectomy. In five cases (5/7) disease extended beyond the hip capsule, while the remaining two cases (2/7) were confined to the hip joint. These findings were confirmed at surgery. Two distinct patterns of extracapsular spread were identified. The first pattern, noted in three cases, involved tumor extension along iliopsoas. The second pattern, noted in five cases, involved tumor extension along the obturator externus fat plane. In three cases both patterns were present. Extra-articular spread of synovial osteochondromatosis is common. Patterns of extra-articular spread may be predictable based on involvement of recognized periarticular bursae of the hip joint. Bursal patterns of extra-articular spread include extension into the iliopsoas bursa as well as communication along the obturator externus bursa of the hip.


Perinatal Obsessive-Compulsive Disorder: Epidemiology, Phenomenology, Etiology, and Treatment.
We review recent evidence concerning the epidemiology, etiology, and treatment of obsessive-compulsive disorder (OCD) in the perinatal period. We examine studies reporting on rates of both new-onset OCD and exacerbation in both pregnancy and postpartum; explore both biological and psychosocial risk factors for the disorder; and review the latest evidence concerning treatment. Evidence is limited in all areas, with rates of both OCD and subthreshold obsessive-compulsive symptoms varying widely across studies. Prevalence is likely higher in the perinatal period than in the general population. Clinical features in the perinatal period are more likely than at other times to concern harm to the child, with contamination and aggressive obsessions and cleaning and checking compulsions especially common. Research into the biological etiology is too limited at this time to be definitive. Both observational and randomized controlled trials support cognitive behavioral therapy with exposure and response prevention (CBT with ERP) as a first-line treatment, with limited evidence also supporting the use of selective serotonin reuptake inhibitors (SSRIs). Treatment considerations in the perinatal period must weigh the risks of treatment vs. the risks of untreated illness. Perinatal OCD is common and can be impairing. Clinical features differ somewhat compared to non-perinatal periods. Treatment does not differ from that used in the general population, though evidence pertaining specifically to the perinatal period is sparse.


Gene Targeted Mice with Conditional Knock-In (-Out) of NMDAR Mutations.
For the genetic alterations of NMDA receptor (NMDAR) properties like Ca2+-permeability or voltage-dependent gating in mice and for the experimental analysis of nonsense or missense mutations that were identified in human patients, single nucleotide mutations have to be introduced into the germ line of mice (Burnashev and Szepetowski, Curr Opin Pharmacol 20:73-82, 2015; Endele et al., Nat Genet 42:1021-1026, 2010). This can be done with very high precision by the well-established method of gene replacement, which makes use of homologous recombination in pluripotent embryonic stem (ES) cells of mice. The homologous recombination at NMDAR subunit genes (Grin; for glutamate receptor ionotropic NMDAR subtype) has to be performed by targeting vectors, also called replacement vectors. The targeting vector should encode part of the gene for the NMDAR subunit, the NMDAR mutation, and a removable selection maker. In these days, the targeting vector can be precisely designed using DNA sequences from public databases. The assembly of the vector is then done from isogenic NMDAR gene fragments cloned in bacterial artificial chromosomes (BACs) using "high fidelity" long-range PCR reactions. During these PCR reactions, the NMDAR mutations are introduced into the cloned NMDAR gene fragments of the targeting vector. Finally, the targeting vector is used for homologous recombination in mouse ES cells. Positive ES cell clones which have the correct mutation have to be selected and are then used for blastocyst injection to generate chimeric mice that hopefully transmit the Grin gene targeted ES cells to their offspring. In the first offspring generation of the founder (F1), some animals will be heterozygous for the targeted NMDAR gene mutation. In order to regulate the expression of NMDAR mutations, it is important to keep the targeted NMDAR mutation under conditional control. Here, we describe a general method how those conditionally controlled NMDAR mutations can be engraved into the germ line of mice as hypomorphic Grin alleles. By breeding these hypomorphic Grin gene targeted mice with Cre recombinase expressing mice, the hypomorphic Grin allele can be activated at specific time points in specific cell types, and the function of the mutated NMDAR can be analyzed in these - so called - conditional mouse models. In this method chapter, we describe in detail the different methodical steps for successful gene targeting and generation of conditional NMDAR mutant mouse lines. Within the last 20 years, several students in our Department of Molecular Neurobiology in Heidelberg used these techniques several times to generate different mouse lines with mutated NMDARs.


Elastic aortic properties in patients with X syndrome.
Elastic properties of the aorta represent an important determinant of left ventricular function and coronary blood flow but there are few data about aortic stiffness in patients with X syndrome. To investigate the elastic aortic proprieties (aortic stiffness and distensibility) and arterial wall motion velocities as measured by tissue Doppler imaging (TDI) in patients with cardiac X syndrome. Fifteen patients with X syndrome (typical chest pain and angiographically normal coronary arteries associated with a positive exercise test) were enrolled in the study. The control group consisted of 15 healthy patients. The aortic elastic indexes, namely distensibility (cm(2) dyne(-1)) and stiffness index (β index) were calculated from M-mode echocardiographically-derived thoracic aortic diameters using accepted formulae, and TDI parameters were measured on the wall of the ascending aorta 3 cm above the aortic valve. Anterior wall aortic expansion velocity (S), early (E) and late (A) diastolic retraction velocity and peak systolic strain were determined. Aortic elastic proprieties were more impaired in the syndrome X group than in the control group. Aortic distensibility was significantly lower in the syndrome X group (3.2 ± 1.3 vs. 7.95 ± 4 cm(2) dyne(-1), p<0.001), while stiffness index was higher (7.3 ± 2.1 vs. 4.1 ± 1.6, p<0.001) than in the control group. Peak systolic (S) and diastolic waves (E and A waves) of the aortic wall TDI were similar in patients and controls (S wave: 5.7 ± 1.6 cm/s vs. 5.8 ± 1.6 cm/s, E wave: -4.8 ± 2.0 vs. -4.1 ± 2.0 cm/s; A wave: -4.32 ± 2.1 vs. -4.76 ± 1.8 cm/s) while tissue strain of the aortic wall was lower in patients with X syndrome than controls (-12.80 ± 7% vs. -22.3 ± 5.9%, p<0.00001). Deterioration in aortic elasticity properties in patients with cardiac syndrome X suggests that this disease may be a more generalised disturbance of the vasculature.


Application of supercritical fluid chromatography for separation and quantitation of 15 co-formulated binary anti-hypertensive medications using a single elution protocol.
A facile supercritical fluid chromatography method is proposed to analyse 15 co-formulated binary anti-hypertensive drug combinations using a customized elution procedure. The effect of mobile phase composition, column back pressure and temperature was suitably optimized for adequate retention, analyte response and resolution. The chromatographic separation of the different drug combinations was performed on a DCPak poly(4-vinylpyridine) column (250 × 4.6 mm, 5 μm) at 125-bar pressure and 40°C using a photodiode array detector. A linear gradient of CO2 and 0.1% formic acid in methanol provided the best elution conditions for all drug combinations. Baseline separation of the drugs was possible with resolution factor Rs ranging from 1.42 to 12.58. The method was validated for specificity, sensitivity, accuracy and precision, recovery and robustness. The limit of detection and limit of quantitation for aliskiren, amlodipine, atenolol, candesartan, hydrochlorothiazide, lisinopril, losartan, metoprolol, olmesartan, telmisartan and valsartan were in the range of 0.26-2.56 and 0.77-7.75 μg/mL, respectively. The thermodynamic study revealed that interactions of the drugs with the stationary phase were spontaneous as evident from the negative free energy values, and the separation process was enthalpy driven. The developed method was successfully employed to analyse these drugs in their co-formulated tablet formulations.


Using Sentiment Analysis to Understand What Patients Are Saying About Hand Surgeons Online.
Physician review websites have influence on a patient's selection of a provider. Written reviews are subjective and difficult to quantitatively analyze. Sentiment analysis of writing can quantitatively assess surgeon reviews to provide actionable feedback for surgeons to improve practice. The objective of this study is to quantitatively analyze large subset of written reviews of hand surgeons using sentiment analysis and report unbiased trends in words used to describe the reviewed surgeons and biases associated with surgeon demographic factors. Online written and star-rating reviews of hand surgeons were obtained from healthgrades.com and webmd.com. A sentiment analysis package was used to calculate compound scores of all reviews. Mann-Whitney U tests were performed to determine the relationship between demographic variables and average sentiment score of written reviews. Positive and negative word and word-pair frequency analysis was also performed. A total of 786 hand surgeons' reviews were analyzed. Analysis showed a significant relationship between the sentiment scores and overall average star-rated reviews (r2 = 0.604, P ≤ .01). There was no significant difference in review sentiment by provider sex; however, surgeons aged 50 years and younger had more positive reviews than older (P < .01). The most frequently used bigrams used to describe top-rated surgeons were associated with good bedside manner and efficient pain management, whereas those with the worst reviews are often characterized as rude and unable to relieve pain. This study provides insight into both demographic and behavioral factors contributing to positive reviews and reinforces the importance of pain expectation management.


Genome Sequence of Klebsiella pneumoniae YBQ, a Clinical Strain Isolated from the Sputum of a Patient with Severe Pneumonia.
We report here the genome of Klebsiella pneumoniae YBQ, a clinical strain isolated from the sputum of a patient with acute Klebsiella pneumoniae infection. The genome consists of a 5,119,471-bp circular chromosome and a 184,347-bp plasmid. Genome annotation predicted 5,028 coding DNA sequences (CDSs), 84 tRNAs, 25 rRNAs, and 47 small RNAs (sRNAs).


Production of single- and double-strand breaks in plasmid DNA by ozone.
Agarose gel electrophoresis and electron microscopy were used to determine the type of lesions produced in DNA by ozone. This strong oxidizing agent was found to relax, linearize, then degrade native plasmid (pAT153) DNA molecules in solution. Ozone, like ionizing radiation, thus produced DNA breakage. To ascertain this point, wild-type and radiosensitive strains of Escherichia coli were transfected with control or ozonated plasmid DNA, and the host cells were selected for antibiotic resistance. A significant reduction in the transforming ability of pAT153 was observed following ozonation. Mutants deficient in the repair of DNA single-strand breaks yielded less ampicillin- or tetracycline-resistant clones than repair-proficient strains. In E. coli, the same gene products are probably involved in the repair of both radiation- and ozone-induced DNA breaks.


Immunohistochemical analysis of murine mononuclear phagocytes that express class II major histocompatibility antigens.
Expression of class II major histocompatibility antigen(s) was analyzed in mouse tissue sections using an immunocytochemical technique. Parallel sections were stained for the macrophage-specific antigen F4/80. MHCII antigen(s) were absent from the majority of F4/80+ cells in liver, bone marrow, splenic red pulp, and brain (microglia) but were present on intraepithelial, periepithelial, and free (e.g. alveolar) cells in gastrointestinal, urogenital, respiratory, and endocrine tissues. The staining pattern in such tissues was not distinguishable from that of F4/80. The results suggest that a major subpopulation of mononuclear phagocytes express MHCII antigen(s) constitutively.


Total synthesis and detection of the bilirubin oxidation product (Z)-2-(3-ethenyl-4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)ethanamide (Z-BOX A).
The selective total synthesis of the pure Z-isomer of BOX A (8a), a product of oxidative heme degradation with significant physiological impact, was achieved in four to six steps starting from 3-bromo-4-methylfuran-2,5-dione (1). Z-BOX A forms a strong hydrogen bridge framework in the crystalline state. LC-MS techniques allow identification and characterization of isomeric forms of BOX A.