Deconvolution of overlapping peaks in ion mobility spectrometry based on a multiobjective dynamic teaching-learning-based optimization.
Because of its powerful analytical ability, ion mobility spectrometry (IMS) plays an important role in the field of mass spectrometry. However, one of the main defects of IMS is its low structural resolution, which leads to the phenomenon of peak overlap in the analysis of compounds with similar mass charge ratio. A multiobjective dynamic teaching-learning-based optimization (MDTLBO) method was proposed to separate IMS overlapping peaks. This method prevents local optimization and identifies peak model coefficients efficiently. In addition, the position information of particles largely reflects the half-peak width of IMS, which makes single peaks difficult to appear and coefficient identification easier. The performance comparison of MDTLBO with other deconvolution methods (genetic algorithm, improved particle swarm optimization algorithm, and dynamic inertia weight particle swarm optimization algorithm) shows that the maximum deconvolution error of MDTLBO is only 0.7%, which is much lower than that for the other three methods. In addition, robustness is a performance index that reflects the advantages and disadvantages of the algorithm. MBTLBO is more robust than other algorithms for separating overlapping peaks. The algorithm can separate the heavily overlapped mobility peaks, produce better analysis results, and improve the resolution of IMS.


Primary percutaneous thrombus aspiration alone as definitive intervention for left main coronary artery occlusion presenting as acute anterior wall ST elevation myocardial infarction.
Primary angioplasty and stenting remains the standard of care for patients presenting with acute ST-segment elevation myocardial infarction. Recently, thrombus aspiration has been shown to improve the myocardial perfusion and outcomes in STEMI. In a subset of patients thrombus aspiration may result in optimal perfusion and minimal residual stenosis. These patients may be managed without additional stenting. Three patients with anterior wall STEMI were successfully managed with thrombus aspiration alone without additional stenting. All three are doing well at 30 day follow up with significant improvement in left ventricular ejection fraction.


Multiple forms of rat liver cysteinesulfinate decarboxylase.
Cysteinesulfinate decarboxylase, purified from male rat livers and homogeneous by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, is resolved into five distinct enzyme species (isoforms) by gel isoelectric focusing. Since the isoforms are present in fresh liver homogenates and do not arise by proteolysis, the enzyme is apparently heterogeneous in vivo. Although female rat livers contain only 5% of the cysteinesulfinate decarboxylase activity of male livers, immunological and enzymatic studies indicate that the distribution of isoforms is similar in both sexes. Rat brain and kidney also contain multiple isoforms which are cross-reactive with polyclonal antibodies prepared to the liver enzyme. The enzyme exhibits a protomer Mr of 53,000, and the native enzyme is shown by cross-linking studies to be dimeric. Purified enzyme contains no carbohydrate or phosphate and does not bind excess pyridoxal 5'-phosphate. Two pools of enzyme activity are resolved preparatively by chromatofocusing chromatography and have been examined with respect to substrate and inhibitor specificity. Both pools are most active toward L-cysteinesulfinate and L-cysteinesulfonate. Aspartate, homocysteinesulfinate, homocysteinesulfonate, 2-amino-3-phosphonopropionate, and glutamate are decarboxylated at rates less than 1% of that observed with L-cysteinesulfinate; D-cysteinesulfinate is not decarboxylated but is an effective inhibitor. The enzyme isoforms cannot be distinguished on the basis of substrate affinity or specificity. The enzyme is irreversibly inactivated by the mechanism-based inhibitors beta-methylene-DL-aspartate and beta-ethylidene-DL-aspartate. beta-Ethylideneaspartate, in contrast to the beta-methylene derivative, does not inhibit aspartate aminotransferase, an enzyme also important in cysteinesulfinate metabolism. beta-Ethylidene aspartate or related beta-ethylidene compounds may be useful in selectively altering cysteinesulfinate metabolism in vivo.


Simultaneous decontamination of cross-polluted soils with heavy metals and PCBs using a nano-metallic Ca/CaO dispersion mixture.
In the present work, we investigated the use of nano-metallic calcium (Ca) and calcium oxide (CaO) dispersion mixture for the simultaneous remediation of contaminated soils with both heavy metals (As, Cd, Cr, and Pb) and polychlorinated biphenyls (PCBs). Regardless of soil moisture content, nano-metallic Ca/CaO dispersion mixture achieved about 95-99% of heavy metal immobilization by a simple grinding process. During the same treatment, reasonable PCB hydrodechlorination efficiencies were obtained (up to 97%), though higher hydrodechlorination efficiency by preliminary drying of soil was observed.


Indirect resolution of beta-blocker agents by reversed-phase capillary electrochromatography.
The indirect resolution of five beta-adrenoreceptor blocking agents (propranolol, oxprenolol, pindolol, metoprolol, and atenolol) using precolumn derivatization with (+)-1-(9-fluorenyl)ethyl chloroformate (FLEC), and capillary electrochromatography (CEC) is reported. Three octadecylsilanized (ODS) silica gel-based stationary phases, differing in particle diameter and carbon surface density for suitability of determination of the enantiomeric composition of these substances in drugs and biological fluids, were studied. Under optimum separation conditions, all the investigated compounds were baseline-resolved within acceptable analysis times (i.e., between 10-16 min). The resolution values ranged between 1.80 and 1.14, and the separation factors were in no case less than 1.07. The possible use of the developed CEC method for the determination of enantiomeric composition of beta-adrenoreceptor blocking agents in drug substances was investigated. A study, in which the enantiomers of metoprolol were examined regarding specificity, reproducibility, limit of detection, and ruggedness, was developed in accordance with some analytical procedures for method validation.


The attractive lip: A photomorphometric analysis.
Throughout literature, there are different parameters defining the ideal shape of the lip and lower third of the face. This study was conducted to clarify what it is that makes lips attractive - and whether there are gender-related differences of an attractive lip and lower third of the face. Pictures of the lip and chin region of 176 patients were photographed in a standardised way and evaluated by 250 voluntary judges through an internet presentation by means of an analogue Likert scaling system. We found a significant higher ratio of upper vermillion height/mouth-nose distance in frontal-view images of attractive compared to unattractive female (p < 0.001) and male (p < 0.05) perioral regions. Furthermore, the ratio of upper vermillion height/chin-nose distance was significantly higher in attractive than in unattractive female (p < 0.005) and male (p < 0.05) lip and chin regions. The nasolabial angle was significantly sharper in attractive compared to unattractive female perioral regions (p < 0.001). Moreover, attractive female lip and chin regions showed a wider mentolabial angle compared to unattractive female lip and chin regions (p < 0.05). Comparing men and women, we found that attractive female perioral regions showed a higher ratio of lower vermillion height/chin-mouth distance (p < 0.05) and lower vermillion height/chin-nose distance than attractive male perioral regions (p < 0.05). We were able to define certain parameters of the lip and lower third of the face that seem to add to the attractivity of female and male individuals and prove that there are gender-related differences in form and shape of an attractive lower third of the face.


[The way to routine data from 16 emergency departments for cross-sectoral health services research : Experiences, challenges and solution approaches from the extraction of pseudonymous data for the INDEED project].
In Germany there is currently no health reporting on cross-sectoral care patterns in the context of an emergency department care treatment. The INDEED project (Utilization and trans-sectoral patterns of care for patients admitted to emergency departments in Germany) collects routine data from 16 emergency departments, which are later merged with outpatient billing data from 2014 to 2017 on an individual level. The methodological challenges in planning of the internal merging of routine clinical and administrative data from emergency departments in Germany up to the final data extraction are presented together with possible solution approaches. Data were selected in an iterative process according to the research questions, medical relevance, and assumed data availability. After a preparatory phase to clarify formalities (including data protection, ethics), review test data and correct if necessary, the encrypted and pseudonymous data extraction was performed. Data from the 16 cooperating emergency departments came mostly from the emergency department and hospital information systems. There was considerable heterogeneity in the data. Not all variables were available in every emergency department because, for example, they were not standardized and digitally available or the extraction effort was judged to be too high. Relevant data from emergency departments are stored in different structures and in several IT systems. Thus, the creation of a harmonized data set requires considerable resources on the part of the hospital as well as the data processing unit. This needs to be generously calculated for future projects.


[Effect of dendritic cells co-cultured with cytokine induced killer cells on cytotoxicity against drug resistant K562 cells].
To study the effect of dendritic cells (DC) co-cultured with cytokine induced killer (CIK) cells on cytotoxicity against K562 and K562 drug-resistant (K562/ADM) cells. Peripheral blood mononuclear cells (MNC) isolated from healthy adult donors were induced to obtain CIK cells and DC respectively and then these two kinds of cells were co-cultured. The cytotoxicity of the co-cultured cells against K562 and K562/ADM cells was measured with MTT assay. The cytotoxicity CIK cells alone to K562 and K562/ADM cells was (20.0 +/- 1.2)% - (61.1 +/- 2.2)% and (17.5 +/- 2.1)% - (45.2 +/- 3.3)% respectively at low effector to target ratios (2.5 - 20.0). This effect was significantly enhanced by co-culturing with DCs being (25.2 +/- 2.3)% - (70.9 +/- 4.1)% and (22.4 +/- 2.7)% - (62.3 +/- 5.0)%. CIK cells showed high cytotoxicity against K562 and K562/ADM cells and the activity could be enhanced by co-culturing with DC.


Reverse shoulder arthroplasty yields similar results to anatomic total shoulder arthroplasty for the treatment of humeral head avascular necrosis.
Avascular necrosis (AVN) of the humeral head frequently results in humeral head collapse and end-stage arthritic changes of the glenohumeral joint. Despite the recent proliferation of reverse total shoulder arthroplasty (RTSA), reports on the use of RTSA for AVN remain limited. The purpose of this study was to document the outcomes of shoulders indicated for RTSA in the setting of humeral head AVN and compare these with AVN shoulders indicated for the gold standard, anatomic total shoulder arthroplasty (aTSA). A retrospective review of a multinational shoulder arthroplasty database was performed between August 2005 and August 2017. All shoulders with a preoperative diagnosis of AVN (aTSA in 52 and RTSA in 67) were reviewed. The shoulders in the RTSA cohort were matched (1:1) to shoulders with cuff tear arthropathy, whereas the shoulders in the aTSA cohort were matched (1:1) to shoulders with primary osteoarthritis. The mean follow-up period was 47 months (range, 24-130 months) for RTSA and 54 months (range, 24-124 months) for aTSA. Shoulders were evaluated for active range of motion (ROM) and patient-reported outcome measures (PROMs) prior to surgery and at latest follow-up. Patients treated with RTSA were compared with both the aTSA study cohort and the control group using the Student t test or χ2 test as indicated. RTSAs performed for AVN demonstrated significant improvements in all ROMs and PROMs. Patients undergoing aTSA for AVN were significantly younger than those undergoing RTSA (59 years vs. 73 years, P < .001). At similar follow-up points, the RTSA cohort demonstrated significantly greater improvement in abduction (+51° vs. +32°, P = .03) whereas the aTSA cohort demonstrated significantly greater improvement in internal rotation. Postoperative University of California, Los Angeles scores (30 vs. 27, P = .014) and visual analog scale scores (1.4 vs. 2.4, P = .025) were better after RTSA; however, these differences between prosthesis types did not exceed the minimal clinically important difference. When compared with the control patients, the patients undergoing RTSA for AVN showed similar improvements in all ROMs and PROMs. Similarly, aTSA performed for AVN resulted in comparable improvements in pain, ROMs, and PROMs compared with aTSA performed for primary osteoarthritis. RTSA results in similar PROMs to aTSA in the treatment of AVN. Therefore, surgeons should continue to consider other patient factors such as glenoid bone loss and rotator cuff status when selecting implant polarity in patients with AVN.


T-Cell Proliferation Assay: Determination of Immunodominant T-Cell Epitopes of Food Allergens.
Characterization of allergen-specific T cells is critical to understand their contribution to disease pathogenesis. The identification of immunodominant T-cell epitopes is crucial for development of T-cell-based vaccines. Peptide-specific T-cell proliferation studies are usually performed in a library of short synthetic peptides (15mer or 20mer) with 3 or 5 offset spanning the entire length of the allergen. T-cell peptide epitopes lack the primary and tertiary structure of the native protein to cross-link IgE, but retain the ability to stimulate T cells. The peptides sequences can also be obtained either by in silico approaches and in vitro binding assays. The efficacy of T-cell epitope-based peptide immunotherapy has been proven in certain allergies. The present methodology describes T-cell proliferation assays using whole blood sample from allergic subjects.


VISUAL AND ANATOMICAL CHANGES AFTER DRUG CESSATION IN PENTOSAN POLYSULFATE SODIUM-ASSOCIATED MACULOPATHY.
The purpose of this study was to describe a case of development of pentosan polysulfate sodium (PPS)-related maculopathy that exhibited potential improvement in imaging findings after drug cessation. This study is a case report. A 66-year-old woman presented with progressive pigmentary maculopathy associated with long-term PPS usage, including development of a choroidal neovascular membrane in her right eye. After discontinuation of PPS, her clinical course was notable for partial subjective and objective improvement in visual acuity, as well as partial improvement in outer retinal architecture on ocular coherence tomography, but persistence of retinal pigment epithelium atrophy and autofluorescence changes. The course of retinopathy after discontinuation of PPS has yet to be fully determined and has so far been suggested to be progressive. Anatomical improvements seen in our case suggest that further investigations are warranted to determine whether there is potential for partial reversal of some changes in PPS maculopathy.


Icephobic/anti-icing properties of superhydrophobic surfaces.
In the winter, icing on solid surfaces is a typical occurrence that may create a slew of hassles and even tragedies. Anti-icing surfaces are one of the effective solutions for this kind of problem. The roughness of a superhydrophobic surface traps air and weakens the contact between the solid surface and liquid water, allowing water droplets to be removed before freezing. At present, the conventional anti-icing methods including mechanical or thermal technology are not only surface structure unfriendly but also have the obsessions of low efficiency, high energy consumption and high manufacturing costs. Hence, developing a way to remove ice by just modifying the surface shape or chemical composition with a low surface energy is extremely desirable. Numerous attempts have been made to investigate the evolution of ice nucleation and icing on superhydrophobic surfaces under the direction of the ice nucleation hypothesis. In this paper, the research progress of ice nucleation in recent years is reviewed from theoretical and application. The icephobic surfaces are described using the wettability and classical nucleation theories. The benefits and drawbacks of anti-icing superhydrophobic surface are summarized, as well as deicing methods. Finally, several applications of ice phobic materials are illustrated, and some problems and challenges in the research field are discussed. We believed that this review will be useful in guiding future water freezing initiatives.


Osteoarthritis.
Osteoarthritis (OA, osteoarthrosis, degenerative joint disease) represents failure of the diarthrodial joint. It has numerous causes. As the heart may fail due to disease of the myocardium, endocardium, or epicardium, the joint may fail due to an abnormality in the articular cartilage, underlying bone, synovial membrane, supporting ligaments, or neuromuscular system. Primary (idiopathic) OA represents the most common form of the disease. It is usually monoarticular and tends to progress slowly. It most commonly involves the small joints of the hands, the hips, knees, spine, and the metatarsophalangeal joint of the great toe.


Treatment of cognitive dysfunction in schizophrenia.
Cognitive impairment has always been regarded as an important characteristic of schizophrenia. Many domains of cognition are disrupted with varying degrees of deficit: attention, executive functions, verbal and visuospatial working memory, learning, and memory. However, it is only recently that cognitive dysfunction has been recognized as a primary and enduring core deficit in schizophrenia (rather than the previous focus on positive and negative symptoms). This article discusses cognitive impairment and the therapeutic effects of newer antipsychotic agents on cognitive functioning in patients with schizophrenia. Cognitive dysfunction occurs before the first psychotic episode and persists throughout the course of the illness. It involves every aspect of cognitive functioning and has an important impact on long-term social and occupational outcomes. Improvement of cognitive functioning by antipsychotic treatment can be due indirectly to the improvement of therapeutic profiles of the newer antipsychotic agents (eg, higher efficacy on positive and negative symptoms, fewer side effects, less anticholinergic effects) or directly to effects on cerebral functioning (eg, by restoring dopamine prefrontal activity). However, further research is needed regarding the therapeutic effects of the newer antipsychotic drugs on cognitive functioning and their impact on psychosocial outcome. Although newer medications may improve cognitive functioning, they do not normalize neurocognitive deficits in schizophrenia. In addition, various nonpharmacologic, psychological interventions have been used in the rehabilitation of patients with cognitive deficits.


Protease inhibitors and avascular necrosis: a systematic review and meta-analysis.
Avascular necrosis (AVN) is a pathological process associated with many medical conditions, including human immunodeficiency virus (HIV) infection. Whether or not the use of protease inhibitors (PIs) confers additional risk for AVN to HIV-infected patients is controversial. Previous epidemiological studies showed an increased risk of AVN among PI users, but these studies did not have enough power to achieve statistical significance. A meta-analysis of case-control studies reporting the odds ratios (ORs) of AVN among HIV-infected patients who were exposed to PIs compared with non-exposed patients was conducted. Pooled ORs and 95% confidence intervals (CIs) were calculated using a fixed-effect Mantel-Haenszel analysis. Four case-control studies were identified and included for data analysis. The meta-analysis demonstrated an increased odds of AVN in participants exposed to PIs, with an OR of 2.09 (95% CI 1.01-4.31; P=0.05). The statistical heterogeneity of this meta-analysis was determined not to be important, with an I(2) of 0%. The meta-analysis revealed a statistically significant increased odds of AVN among PI-exposed, HIV-infected patients. Physician should be aware of this association as it may help guide potential therapeutic options, particularly for patients with other classic risk factors for AVN.


Neuroprotection by cord blood stem cells against glutamate-induced apoptosis is mediated by Akt pathway.
The neurotransmitter glutamate mediates excitatory synaptic transmission in the brain and spinal cord. In pathological conditions massive glutamate release reaches near millimolar concentrations in the extracellular space and contributes to neuron degeneration and death. In the present study, we demonstrate a neuroprotective role for human umbilical cord blood stem cells (hUCB) against glutamate-induced apoptosis in cultured rat cortical neurons. Microarray analysis shows the upregulation of stress pathway genes after glutamate toxicity of neurons, while in cocultures with hUCB, survival pathway genes were upregulated. Real time-PCR analysis shows the expression of genes for NMDA receptors after glutamate toxicity in neurons. The neuroprotection of hUCB against glutamate toxicity is similar to the application of the glutamate receptor antagonist MK-801. Cocultures of hUCB protected neurons against glutamate-induced apoptosis as revealed by APO-BrdU TUNEL and FACS analyses. Immunoblot analysis shows that apoptosis is mediated by the cleavage of caspase-3 and caspase-7 in glutamate treated neurons. Cocultures with hUCB indicate the upregulation of Akt signaling pathway to protect neurons. Blocking of the Akt pathway by a dominant-negative Akt and using Akt-inhibitor IV, we confirm that the mechanism underlying hUCB neuroprotection involves activation of Akt signaling pathway. These results suggest the neuroprotective potential of hUCB against glutamate-induced apoptosis of cultured cortical neurons.


The effect of 5-hydroxytryptamine on the chick biventer cervicis muscle.
The actions of 5-hydroxytryptamine have been studied in the chick biventer cervicis nerve--muscle preparation. At concentrations between 2.5 X 10(-3) and 3.7 X 10(-3) M, 5HT produced a transient increase in responses to indirect stimulation, but not to direct stimulation. At higher concentrations, 5HT produced a reversible depression of twitches, which was much more marked in indirectly than in directly stimulated preparations. In a concentration range of 2.5-3.7 X 10(-3) M, 5HT increased the response to exogenous acetylcholine but reduced the response to carbachol. After pretreatment with neostigmine, 5HT inhibited responses to both acetylcholine and carbachol. It is suggested that the facilitatory effects of 5HT are due to its anticholinesterase activity. The blocking actions of 5HT are thought to be curare-like. In addition, irreversible toxic effects on the muscle preparations were found after repeated exposures to high concentrations of 5HT.


Early non-invasive detection of fetal Y chromosome sequences in maternal plasma using multiplex PCR.
Clinical indications for fetal sex determination include risk of X-linked disorders, a family history of conditions associated with ambiguous development of the external genitalia, and some fetal ultrasound findings. It is usually performed in the first trimester from fetal material obtained through CVS and is associated with an approximately 1% risk of miscarriage. Ultrasound fetal sex determination is often performed after 11 weeks of gestation. This study aims to validate a reliable method for non-invasive prenatal diagnosis of fetal gender using maternal plasma cell-free fetal DNA (cffDNA) for fetal sex assessment in the first trimester of pregnancy and test its clinical utility in the diagnosis of potentially affected pregnancies in carriers of X-linked disorders. In the validation study, blood samples from 100 pregnant women at 6-11 weeks of gestation were analysed. In the clinical study, 17 pregnancies at risk of having an affected fetus were tested. 7 ml of maternal blood in EDTA were obtained and cffDNA was extracted using a commercially available kit. DNA was enzymatically digested using a methylation sensitive endonuclease (AciI) to remove maternal unmethylated sequences of the RASSF1A gene. A multiplex PCR was performed for the simultaneous amplification of target sequences of SRY and DYS14 from chromosome Y, along with RASSF1A and ACTB sequences. Amplification of these loci indicates fetal gender, confirms the presence of cffDNA and allows assessment of digestion efficiency. After establishing the appropriate experimental conditions, validation studies were successful in all 100 cases tested with no false negative or false positive results. Y chromosome-specific sequences were detected in 68 samples, and 32 cases were diagnosed as female based on the amplification of RASFF1A sequences only, in the absence of ACTB. In the clinical studies, fetal sex was correctly diagnosed in 16 pregnancies, and one case was reported as inconclusive. Fetal sex assessment by detecting Y chromosome sequences in maternal blood can be routinely used from the 6th week of gestation. Reliable fetal sex determination from maternal blood in the 1st trimester of gestation can avoid conventional invasive methods of prenatal diagnosis.


Synthesis and biological evaluation of helioxanthin analogues.
Helioxanthin and analogues have been demonstrated to suppress gene expression of human hepatitis B virus. In the continuous attempt to optimize antiviral activity, various structural motifs were grafted on the helioxanthin scaffold. Many such analogues were synthesized and evaluated for their anti-hepatitis B virus activity. Structure-activity relationships of these helioxanthin derivatives are also discussed. Among these new compounds, 15 exhibits the highest activity against HBV (EC50=0.06 μM). This compound can suppress viral surface antigen and DNA expression. Furthermore, viral RNA is also diminished while the core promoter is deactivated upon treatment by 15. A plausible working mechanism is postulated. Our results establish helioxanthin lignans as potent anti-HBV agents with unique mode of action. Since their antiviral mechanism is distinct from current nucleoside/nucleotide drugs, helioxanthin lignans constitute a potentially new class of anti-HBV agents for combination therapy.


Genetically predicted telomere length and Alzheimer's disease endophenotypes: a Mendelian randomization study.
Telomere length (TL) is associated with biological aging, consequently influencing the risk of age-related diseases such as Alzheimer's disease (AD). We aimed to evaluate the potential causal role of TL in AD endophenotypes (i.e., cognitive performance, N = 2233; brain age and AD-related signatures, N = 1134; and cerebrospinal fluid biomarkers (CSF) of AD and neurodegeneration, N = 304) through a Mendelian randomization (MR) analysis. Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study, a population of cognitively healthy individuals at risk of AD. A total of 20 single nucleotide polymorphisms associated with TL were used to determine the effect of TL on AD endophenotypes. Analyses were adjusted by age, sex, and years of education. Stratified analyses by APOE-ɛ4 status and polygenic risk score of AD were conducted. MR analysis revealed significant associations between genetically predicted longer TL and lower levels of CSF Aβ and higher levels of CSF NfL only in APOE-ɛ4 non-carriers. Moreover, inheriting longer TL was associated with greater cortical thickness in age and AD-related brain signatures and lower levels of CSF p-tau among individuals at a high genetic predisposition to AD. Further observational analyses are warranted to better understand these associations.


Gastrointestinal Diseases in Pregnancy: Nausea, Vomiting, Hyperemesis Gravidarum, Gastroesophageal Reflux Disease, Constipation, and Diarrhea.
Many disorders of the gastrointestinal tract are common in pregnancy. Elevated levels of progesterone may lead to alterations in gastrointestinal motility which could contribute to nausea, vomiting, and/or GERD. Pregnancy-induced diarrhea may be due to elevated levels prostaglandins. This article reviews the normal physiologic and structural changes associated with pregnancy that could contribute to many of the common gastrointestinal complaints in pregnant patients. Additionally, the appropriate clinical and laboratory evaluations, other pathologic conditions that should be included in the differential, as well as the nonpharmacologic and pharmacologic therapies for each of these conditions is discussed.


Chronic hepatitis B and D: prognosis according to Child-Pugh score.
compare chronic hepatitis B patients to those superinfected with hepatitis D virus, according to Child-Pugh score regarding disease severity. retrospective descriptive study, performed with 59 patients followed in the ambulatory, of which 22 (37.3%) were chronically infected with hepatitis B virus (Group HBV) and 37 (62.7%) superinfected with Delta virus (Group HBV+HDV); variables of sex, age and items of Child-Pugh score were collected by consulting medical records. out of the patients, 57.6% were male, with a mean age of 30.5 years. Score A, which indicates lesser severity, was found in 100% of group HBV and 78.4% of group HBV+HDV. Score B, which indicates greater severity, was found only in group HBV+HDV in 21.6% of the patients. by means of the Child-Pugh score, it was observed that patients with superinfection by HDV tended to present a worse prognosis. comparar os pacientes com hepatite B crônica com superinfectados pelo vírus D segundo escore de Child-Pugh quanto à gravidade da doença. estudo descritivo retrospectivo, realizado com 59 pacientes acompanhados em ambulatório, sendo 22 (37,3%) cronicamente infectados pelo vírus da hepatite B (Grupo VHB) e 37 (62,7%) com superinfecção por vírus Delta (Grupo VHB+VHD); foram coletadas variáveis quanto ao sexo, idade e referentes ao escore de Child-Pugh por meio de consulta a prontuários. entre os pacientes 57,6% era do sexo masculino, com idade média de 30,5 anos. O escore A, que indica menor gravidade, foi encontrado em 100% do grupo VHB e 78,4% do grupo VHB+VHD. O escore B, que indica maior gravidade, foi encontrado apenas no grupo VHB+VHD em 21,6% dos pacientes. por meio do escore de Child-Pugh, observou-se que os pacientes com superinfecção por VHD tendem a apresentar pior prognóstico.


Four drug combination cytotoxic chemotherapy following surgery for breast cancer.
A prospective randomized clinical trial of treatment with vincristine, cyclophosphamide, methotrexate and 5-fluorouracil after conventional curative treatment for stage II breast cancer is described. The results at 2 years are recorded together with details of toxicity. Future plans are discussed briefly.


Senior students' experience as tutors of their junior peers in the hospital setting.
Student-led teaching has long been regarded as a useful ancillary educational method. It is also a valuable tool in the development of aspects of professionalism in student tutors and contributes to a sense of community within the student body. In 2014, a peer-assisted learning (PAL) program, organised by students at Sydney Medical School (Central), explored students' experience of tutoring their junior peers. Year 3 and 4 students within Central Clinical School (CCS) were invited to be tutors for Year 1 and 2 students respectively. Tutorials centered on the application of clinical skills. All tutors were asked to complete an end of year questionnaire. A total of 40% of senior students participated as tutors and 65% of junior students as tutees. The end of year questionnaire response rate was 48% (20/42). Most tutors (19/20, 95%) felt confident to teach tutorials although one-third (6/20, 30%) would have preferred more training in teaching. Tutors felt that the program better prepared them for their exams. Almost all tutors (19/20, 95%) enjoyed teaching and felt it fostered a sense of community at CCS (17/20, 85%). Tutors stated they were likely to be involved in teaching in the future (17/20, 85%). This student initiated PAL program provided tutors with the opportunity for content and clinical skills revision and assisted in the development of professional competencies required on entering the medical workforce. The resultant sense of community at CCS will aid the expansion of the program in 2015 with an aim to review quality assurance measures.


Addiction and "Generation Me:" Narcissistic and Prosocial Behaviors of Adolescents with Substance Dependency Disorder in Comparison to Normative Adolescents.
The purpose of this study is to explore narcissistic and prosocial behaviors as reported by adolescents with and without substance dependency disorder (SDD). This study employs a quasi-experimental design using SDD adolescents compared with two normative samples of adolescents. In comparison to normative adolescents, adolescents with SDD were strongly distinguished by overt narcissistic behaviors and less monetary giving. Levels of narcissistic and prosocial behaviors among adolescents with SDD suggest a connection between self-centeredness and addiction. Results also suggest volunteerism as a potential option to counter narcissism in substance dependent adolescents.


Therapeutic potential of targeting LSD1/ KDM1A in cancers.
LSD1 was the first histone demethylase identified by Professor Shi Yang and his team members in 2004. LSD1 employs FAD as its cofactor, which catalyzes the demethylation of H3K4 and H3K9. It is aberrantly overexpressed in different types of cancers and is associated with the growth, invasion, and metastasis of cancer cells. The knockout or inhibition of LSD1 could effectively suppress tumor development, and thus, it has become an attractive molecular target for cancer therapy. Moreover, many LSD1 inhibitors have been developed in preclinical and clinical trials to treat solid tumors and hematological malignancy. This study made an extensive review of the research obtained from the literature retrieval of electronic databases, such as PubMed, Web of Science, RCSB PDB, ClinicalTrials.gov, and EU clinical trials register. This review summarizes recent studies on the advances of LSD1 inhibitors in the literature, covering January 2015 to June 2021. It focuses on the function of LSD1 in tumor cells, summarizes the crystal structures of Homo sapiens LSD1, reviews the structural characteristics of LSD1 inhibitors, compares the screening methods of LSD1 inhibitors, and proposes guidelines for the future exploitation of LSD1 inhibitors.


Evaluation of the lacrimal drainage system.
Methods of testing for lacrimal drainage insufficiency and a modification of the Jones fluorescein dye tests are presented. Despite their excellence, Jones tests have never been widely employed because of difficulty in dye retrieval. The modification consists of instilling one drop of the dye three times at 15 second intervals, and after a one minute period, placing the head down at a 45 degree angle for ten minutes. Anatomic and roentgenogram studies show that the dye can be easily lost posteriorly unless this is done. No nasal vasoconstrictors are used to avoid false negatives.


Rationale and design of a large registry on renal denervation: the Global SYMPLICITY registry.
Hypertension is a global healthcare concern associated with a wide range of comorbidities. The recognition that elevated sympathetic drive plays an important role in the pathogenesis of hypertension led to the use of renal artery denervation to interrupt the efferent and afferent sympathetic nerves between the brain and kidneys to lower blood pressure. Clinical trials of the Symplicity™ renal denervation system have demonstrated that radiofrequency ablation of renal artery nerves is safe and significantly lowers blood pressure in patients with severe resistant (systolic BP >160 mmHg) hypertension. Smaller ancillary studies in hypertensive patients suggest a benefit from renal denervation in a variety of conditions such as chronic kidney disease, glucose intolerance, sleep apnoea and heart failure. The Global SYMPLICITY registry, which incorporates the GREAT SYMPLICITY registry initiated in Germany, is being conducted worldwide to evaluate the safety and efficacy of treatment with the Symplicity renal denervation system in real-world uncontrolled hypertensive patients, looking first at subjects with severe resistant hypertension to confirm the results of prior clinical trials, but then also subjects with a wider range of baseline blood pressure and coexisting comorbidities. The rationale, design and first baseline data from the Global SYMPLICITY registry are presented.


Association between dietary scores and 13-year weight change and obesity risk in a French prospective cohort.
The relationship between diet quality and development of obesity is complex and unresolved. The aim of this study was to assess and compare the predictive value of six different dietary scores on both relative weight change and the risk of obesity after 13 years of follow-up in adults aged 45 years and older. Six scores reflecting adherence to different nutritional recommendations (the French Programme National Nutrition Santé-Guideline Score (PNNS-GS), the Dietary Guidelines for Americans Index (DGAI), the Diet Quality Index-International (DQI-I), the Mediterranean Diet Scale (MDS), the relative Mediterranean Diet Score (rMED) and the Mediterranean Style Dietary Pattern Score (MSDPS)) were estimated in 3151 participants in the French SU.VI.MAX (SUpplémentation en VItamines et Minéraux AntioXydants) study. Associations of dietary scores with 13-year weight change were assessed through multivariate linear regression models, and obesity risk was analyzed with logistic regression, providing odds ratios (OR) and 95% confidence intervals (CI). Except for the MSDPS, higher scores, that is, better adherence to nutritional guidelines or to a Mediterranean diet, were associated with lower weight gain in men (all P-value for trend <0.05). In addition, among men, ORs for becoming obese after 13 years associated with a 1 s.d. increase in dietary scores ranged from 0.63, 95% CI: 0.51, 0.78 for DGAI to 0.72, 95% CI: 0.59, 0.88 for MDS. These associations were weaker or not statistically significant in women. Overall, the six dietary scores predicted obesity risk equally well. Among French adults, strong adherence to dietary guidelines appears to be protective with regard to weight gain and obesity, especially in men.


Diffusion tensor-based fiber tracking and intraoperative neuronavigation for the resection of a brainstem cavernous angioma.
Surgical treatment of brainstem cavernous angioma involving eloquent fiber tracts is one of the most challenging areas of contemporary neurosurgery. Diffusion tensor imaging-based fiber tracking adds essential information for preoperative planning in neurosurgical practice. Integration of the tractography into neuronavigation system makes it possible for the intraoperative visualization of the major fiber tracts. It may help increase the likelihood of the total resection of tumors adjacent to the eloquent fiber tracts and avoid new neurologic deficits after surgery. We report our valuable experience of such integration for the resection of a deeply located brainstem cavernous angioma. Inclusion of tractography in standard imaging protocols for neuronavigation systems can provide important information regarding neural tracts for the planning of brainstem surgery. It can also increase the safety of neurosurgical intervention near white matter tracts in the brainstem.


In Silico Analysis and In Vitro Characterization of the Bioactive Profile of Three Novel Peptides Identified from 19 kDa α-Zein Sequences of Maize.
In this study, we characterized three novel peptides derived from the 19 kDa α-zein, and determined their bioactive profile in vitro and developed a structural model in silico. The peptides, 19ZP1, 19ZP2 and 19ZP3, formed α-helical structures and had positive and negative electrostatic potential surfaces (range of -1 to +1). According to the in silico algorithms, the peptides displayed low probabilities for cytotoxicity (≤0.05%), cell penetration (10-33%) and antioxidant activities (9-12.5%). Instead, they displayed a 40% probability for angiotensin-converting enzyme (ACE) inhibitory activity. For in vitro characterization, peptides were synthesized by solid phase synthesis and tested accordingly. We assumed α-helical structures for 19ZP1 and 19ZP2 under hydrophobic conditions. The peptides displayed antioxidant activity and ACE-inhibitory activity, with 19ZP1 being the most active. Our results highlight that the 19 kDa α-zein sequences could be explored as a source of bioactive peptides, and indicate that in silico approaches are useful to predict peptide bioactivities, but more structural analysis is necessary to obtain more accurate data.


Contact based intervention reduces stigma among pharmacy students.
Interventions to reduce the stigma of substance use disorders by health professionals often include didactic instruction combined with an interactive component that includes a guest speaker in recovery. Few interactive studies have focused on pharmacy students. Community pharmacists are moving to the front lines to battle the opioid epidemic; therefore, pharmacy students should be included in interventions aimed at reducing stigma by health professionals. This study examined the effects of a contact-based interactive intervention delivered by a peer recovery support specialist on perceived stigma of opioid use disorder among third-year pharmacy students (N = 115) enrolled in an integrative psychiatry course. Stigma was measured using the Brief Opioid Stigma Scale. Our study found significant differences in students' perceived stigma, both with their personal beliefs and their beliefs regarding the public, supporting the use of interactive presentations by peer recovery support specialists to decrease perceived stigma of opioid use disorder by health professionals. This type of intervention for pharmacy students shows promise in reducing substance use disorder stigma and should be further explored.


Cardiovascular magnetic resonance characterization of rheumatic mitral stenosis: findings from three worldwide endemic zones.
Cardiac remodeling in rheumatic mitral stenosis (MS) is complex and incompletely understood. The objective of this study was to evaluate cardiac structural and functional changes in a cohort of patients with rheumatic MS using cardiovascular magnetic resonance (CMR). This retrospective study included 40 patients with rheumatic MS, consisting of 19 patients from India, 15 patients from China, and 6 patients from Mexico (median (interquartile range (IQR)) age: 45 years (34-55); 75% women). Twenty patients were included in the control group. CMR variables pertaining to morphology and function were collected. Late gadolinium enhancement (LGE) sequences were acquired for tissue characterization. Statistical analyses were performed using the Kruskal-Wallis test and the chi-square test. Compared to the control group, patients with MS had lower left ventricular (LV) ejection fraction (51% (42%-55%) vs 60% (57%-65%), p < 0.001), lower right ventricular (RV) ejection fraction (44% (40%-52%) vs 64% (59%-67%), p < 0.001), higher RV end-diastolic volume (72 (58-87) mL/m2 vs 59 (49-69) mL/m2, p = 0.003), larger left atrial volume (87 (67-108) mL/m2 vs 29 (22-34) mL/m2, p < 0.001), and right atrial areas (20 (16-23) cm2 vs 13 (12-16) cm2, p < 0.001). LGE was prevalent in patients with rheumatic MS (82%), and was commonly located at the RV insertion sites. Furthermore, the patient cohorts from India, China, and Mexico were heterogeneous in terms of baseline characteristics and cardiac remodeling. Our findings demonstrated that biventricular dysfunction, right and left atrial remodeling, and LGE at the RV insertion sites are underappreciated in contemporary rheumatic MS. Further studies are needed to elucidate the prognostic implications of these findings.


Radioimmunoassay of human epidermal growth factor in human breast cyst fluid.
Epidermal growth factor (EGF) was assayed radioimmunologically in three secretions of the human mammary gland: milk (n = 16), colostrum (n = 8) and breast cyst fluid (n = 139). The immunoreactivity (immunoreactive EGF) detected in these three fluids corresponds directly to monomeric EGF, as can be shown by the complete cross-reaction with the standard and the identical behaviour in chromatography on Sephadex G50. The mean concentration of EGF is significantly greater in breast cyst fluid (241 +/- 143 ng/ml) and in colostrum (197 +/- 56 ng/ml) than in milk (107 +/- 22 ng/ml). The range of individual values in cyst fluid is large, 5-945 ng/ml. A possible role of EGF as a paracrine or autocrine factor in the pathology of cystic dysplasia of the mammary gland and in the increased risk of malignant transformation is hypothesised.


Respiratory viruses in rural Zambia during the second year of the COVID-19 pandemic.
Limited data on respiratory infections are available from sub-Saharan Africa during the COVID-19 pandemic. The objective of this study was to evaluate the burden of respiratory viruses in rural Zambia from 2019-2021. Surveillance was initiated at Macha Hospital in Zambia in December 2018. Each week, patients with respiratory symptoms were enrolled from the outpatient clinic. Nasopharyngeal samples were collected and tested for respiratory pathogens. The prevalence of respiratory symptoms and viruses in 2021 was compared to results from 2019 and 2020. After seeing few cases of influenza virus and respiratory syncytial virus in 2020, a return to prepandemic levels was observed in 2021. Rhinovirus/enterovirus, parainfluenza virus 1-4, and adenovirus circulated from 2019 to 2021, while human metapneumovirus and human coronaviruses (HKU1, 229E, OC43, and NL63 subtypes) were observed sporadically. SARS-CoV-2 was observed consistently in 2021 after being first identified in December 2020. The proportion of participants with co-infections in 2021 (11.6%) was significantly higher than in 2019 (6.9%) or 2020 (7.7%). Declines in influenza virus and respiratory syncytial virus were reversed once public health measures were lifted. Respiratory viruses contributed to a significant burden of respiratory infections in 2021. This study provides important information about respiratory viruses in this changing context and underrepresented region.


Recent advancements, challenges, and practical considerations in the mass spectrometry-based analytics of protein biotherapeutics: A viewpoint from the biosimilar industry.
The extensive analytical characterization of protein biotherapeutics, especially of biosimilars, is a critical part of the product development and registration. High-resolution mass spectrometry became the primary analytical tool used for the structural characterization of biotherapeutics. Its high instrumental sensitivity and methodological versatility made it possible to use this technique to characterize both the primary and higher-order structure of these proteins. However, even by using high-end instrumentation, analysts face several challenges with regard to how to cope with industrial and regulatory requirements, that is, how to obtain accurate and reliable analytical data in a time- and cost-efficient way. New sample preparation approaches, measurement techniques and data evaluation strategies are available to meet those requirements. The practical considerations of these methods are discussed in the present review article focusing on hot topics, such as reliable and efficient sequencing strategies, minimization of artefact formation during sample preparation, quantitative peptide mapping, the potential of multi-attribute methodology, the increasing role of mass spectrometry in higher-order structure characterization and the challenges of MS-based identification of host cell proteins. On the basis of the opportunities in new instrumental techniques, methodological advancements and software-driven data evaluation approaches, for the future one can envision an even wider application area for mass spectrometry in the biopharmaceutical industry.


Maternal Intimate Partner Violence Victimization Before and During Pregnancy and Postbirth Child Welfare Contact: A Population-Based Assessment.
We conducted a population-based prospective cohort study to help elucidate the predictive relationship between a maternal prebirth self-reported history of intimate partner violence (IPV) and any postbirth reported allegation to Child Protective Services (CPS) by age 2. We linked data from the 2009-2010 Alaska Pregnancy Risk Assessment Monitoring System with CPS data through 2012. Among this cohort, we found that 8.0%w self-reported experiencing IPV 12 months prior or during pregnancy, and 8.0%w of the offspring experienced at least one CPS report of alleged maltreatment during the study period. The predictive relationship varied by maternal educational attainment. Among mothers with 12+ years education completed, the odds of a CPS report were 3.9 times compared to those with no IPV, while among mothers with <12 years education completed, no association was noted. These results suggest that for a subset of Alaskan families, maternal history of IPV is a strong independent predictor of future CPS contact.


Cytogenetic studies of Sézary cells.
Cytogenetic studies of two patients with Sézary's syndrome and of one patient with mycosis fungoides are reported. One chromosome #14 at band 14q11 was involved in chromosomal rearrangements in one patient. A review of previously reported cases shows that some chromosome abnormalities appeared nonrandomly, involving chromosomes #1, #4, #6, #7, #9, #13, #14, and #17. Abnormalities on 2p and monosomy 10 were emphasized.


Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin-malin complex.
Protein phosphatase type 1 (PP1) plays a major role in the regulation of glycogen biosynthesis. PP1 is recruited to sites of glycogen formation by its binding to specific targeting subunits. There, it dephosphorylates different enzymes involved in glycogen homeostasis leading to an activation of glycogen biosynthesis. Regulation of these targeting subunits is crucial, as excess of them leads to an enhancement of the action of PP1, which results in glycogen accumulation. In this work we present evidence that PPP1R3D (R6), one of the PP1 glycogenic targeting subunits, interacts physically with laforin, a glucan phosphatase involved in Lafora disease, a fatal type of progressive myoclonus epilepsy. Binding of R6 to laforin allows the ubiquitination of R6 by the E3-ubiquitin ligase malin, what targets R6 for autophagic degradation. As a result of the action of the laforin-malin complex on R6, its glycogenic activity is downregulated. Since R6 is expressed in brain, our results suggest that the laforin-malin complex downregulates the glycogenic activity of R6 present in neuron cells to prevent glycogen accumulation.


[Malaria vaccine].
With about 2.2 billion of the world' s population at risk, malaria remains as one of the most infectious disease globally. The failure of existing control strategies necessitates the need for vaccine development. Our efforts have been geared on the development of an effective vaccine using SE36 protein based from the N-terminal domain of Serine Repeat Antigen (SERA5) of Plasmodium falciparum. Immunoepidemiological data underscores the uniqueness of SERA vs. other vaccine candidate, showing a semi-perfect correlation of the naturally induced antibody response to SE36 protein with increased protective immunity in adults and children. GMP-grade SE36 was formulated adsorbed to aluminum hydroxide gel as BK-SE36. Immunological test using squirrel monkeys provided significant protection after P. falciparum challenge infection. No significant safety issues have been identified in healthy, malaria-unexposed adults in a Phase Ia clinical trial in Japan. Cumulative data confirms that the vaccine is safe and highly immunogenic.


Local Complications of Breast Surgery during Pregnancy and Lactation.
During pregnancy and lactation, breast vascularity increases and edema occurs in the breast . As a consequence, rate of complications of breast biopsy and surgery like bleeding, infection, delayed healing and wound dehiscence is expected to be higher. Milk fistula is a rare event that may complicate surgery or needle biopsy of the breast in a breastfeeding woman, or in late stages of pregnancy . Suppression of lactation has been proposed in the literature as both a preventive and a therapeutic step. However, the advantages of nursing for both mother and child are numerous, and the author do not propose it as a preventive measure nor as a must in treatment of milk fistula. Prevention and management of milk fistula are discussed in this chapter.


[Allergic reactions to patent blue violet: mechanisms, frequency and treatment].
The authors report their observation of a serious allergic incident involving the blue patent, hospitalisation in their intensive care unit, and extremely major therapy. They describe the three mechanisms of allergic reaction: real anaphylaxia, and anaphylactoid reaction, either by direct histamino-release, or by alternate activation of the complementary system. It would seem that, after doses of the differing fractions of complement in this patient, there was an activation of the complementary system. The authors emphasize the importance of preventive treatment: hypo-histamine, antihistamine, corticoid, and curative relative to the gravity of the disorders observed: cutaneous, cardiac, and respiratory. Finally, they recall that this test must be carried out in a hospital establishment with a reanimation unit.


Requiem for the STAT Test: Automation and Point of Care Testing.
Quick turnaround of laboratory test results is needed for medical and administrative reasons. Historically, laboratory tests have been requested as routine or STAT. With a few exceptions, a total turnaround time of 90 minutes has been the usually acceptable turnaround time for STAT tests. We implemented front-end automation and autoverification and eliminated batch testing for routine tests. We instituted on-site intraoperative testing for selected analytes and employed point of care (POC) testing judiciously. The pneumatic tube system for specimen transport was expanded. The in-laboratory turnaround time was reduced to 45 minutes for more than 90% of tests that could reasonably be ordered STAT. With rare exceptions, the laboratory no longer differentiates between routine and STAT testing. Having a single queue for all tests has improved the efficiency of the laboratory. It has been recognized in manufacturing that batch processing and having multiple queues for products are inefficient. The same principles were applied to laboratory testing, which resulted in improvement in operational efficiency and elimination of STAT tests. We propose that the target for in-laboratory turnaround time for STAT tests, if not all tests, be 45 minutes or less for more than 90% of specimens.


Effect of gamma radiation on the protective efficacy of Thuja orientalis essential oil on stored cowpea against Callosobruchus maculatus and Callosobruchus chinensis.
Cowpea is an essential pulse food in several regions throughout the world. Essential oil isolated from Thuja orientalis unripe fruits exposed to gamma radiation at dose levels of 0, 1, 3 and 5 kGy was evaluated as cowpea seed protectant against Callosobruchus maculatus and Callosobruchus chinensis. Cowpea seeds were treated with three rates of the oils from non-irradiated and irradiated fruits, 0.5, 1.5 and 3.0 g kg-1. Mortality of C. maculatus and C. chinensis adults after 3 and 7 days, progeny reduction and weight loss of cowpea seeds after 45 days were recorded for all treatments. The pronounced mortality of C. maculatus adults was achieved at the highest rate 3.0 g kg-1 of the irradiated oil with 5 kGy (98.3%). While in the case C. chinensis, all tested application rates induced marked adult mortality and a complete mortality (100%) resulted at two application rates (0.5 and 1.5 g kg-1) of irradiated oil with 5 kGy and 3.0 g kg-1 after 7 days. Strong progeny suppression of C. maculatus and C. chinensis was resulted at the highest rate of 3.0 g kg-1 of irradiated oil with 5 kGy (11.3 ± 0.3) and (8.5 ± 3.8) after 45 days of treatment, respectively. High protection of cowpea seeds with weight loss 0.5 and 1.4% for C. maculatus and C. chinensis was achieved at 3.0 g kg-1 of irradiated oil dose of 5 kGy, respectively after 45 days. Our results indicate that gamma irradiation of T. orientalis fruits improve the protective activity of their essential oil against C. maculatus and C. chinensis on stored cowpea seeds and the irradiated oil could be successfully used for management of these bruchid insects.


A bone remodelling model including the directional activity of BMUs.
Bone is able to adapt itself to the mechanical and biological environment by changing its porosity and/or orientation of its internal microstructure in a process known as bone remodelling. As a consequence, a change of bone mechanical properties is produced leading to an optimum structure, able to bear the external loads with the minimum weight. This adaptation is carried out by a temporal association of cells known as BMUs (basic multicellular units) that resorb old bone and sometimes produce new organic extracellular matrix (osteoid) that is later mineralized. This involves changes in porosity, damage level (density of microcracks accumulated by cyclic loads) and mineral content. All of these features were taken into account in a previous model, but the whole process and therefore the resulting bone constitutive behaviour was considered isotropic. The model proposed herein, recognizing that bone is actually anisotropic, tries to explain how BMUs modify the anisotropy by changing their progressing direction. We check the potential of the model to predict the alignment of the bone microstructure with the external loads in different situations. Then, the model is also applied to obtain the anisotropy and mechanical properties of the human proximal femur under physiological loads with initial conditions corresponding to a heterogeneous, but otherwise isotropic bone.


Neuronal activity in primary motor cortex differs when monkeys perform somatosensory and visually guided wrist movements.
This study was designed to investigate how activity patterns of primary motor cortical (MI) neurons change when monkeys perform the same movements guided by somatosensory and/or visual cues. Two adult male rhesus monkeys were trained to make wrist extensions and flexions after holding a steady position during an instructed delay period lasting 0.5-2.0 s. Monkeys held against a 0.07 Nm load that opposed flexion movements. Wrist movements were guided by vibratory cues (VIB-trials), visual cues (VIS-trials), or both in combination (COM-trials). Extracellular recordings of 188 MI neurons were made during all three paradigms. Individual neurons were counted twice, once for each movement direction, yielding 376 cases. All neurons had significant task-related activity (TRA) changes relative to delay period activity during at least one of the three paradigms. TRA was analyzed to determine if it was different as a function of the sensory cue(s) that initiated movement and that specified movement endpoints. Cases were grouped by whether the TRA changes were greater in VIB- or VIS-trials; this defined their "bias". One hundred and eighteen cases (31.4%) had greater TRA changes in VIB-trials (Vb-neurons), whereas 185 (49.2%) showed greater TRA changes in VIS-trials (Vs-neurons). The remaining 73 cases (19.4%) had similar TRA changes in VIB- and VIS-trials (Nb-neurons). For Vb- and Vs-neurons, earlier TRA onsets and greater TRA changes were observed in the trials for which these neurons were biased. During the COM-trials, the TRA was intermediate. During the trials for which the activity was not biased, the TRA was the least. For Nb-neurons, no significant TRA differences were observed across paradigms. TRA changes of MI neurons may represent movement planning-related inputs from other central, presumably cortical, sources as well as contribute to motor outflow from the cortex. These data suggest that Vb- and Vs-neurons are affected differently by somatosensory- and visually related central inputs, resulting in different TRAs, even for essentially identical movements. Such differences may depend not only on the type of sensory information that initiates movement but also whether that information specifies movement endpoints or might interfere with movement monitoring.


EZH2 is a sensitive marker of malignancy in salivary gland tumors.
The immunohistochemical detection of Enhancer of zeste homologue 2 (EZH2) proved to be a useful tool to recognize the malignant nature of tumors in a wide variety of neoplasms. The histological diagnostics of salivary gland tumors is a challenging task, and a reliable marker of malignancy would be extremely helpful. EZH2 expression was investigated in 54 malignant and 40 benign salivary gland tumors of various histological types by standard immunohistochemistry. The majority (n = 52) of the malignant tumors stained positively, while all the investigated benign tumors were negative for EZH2. EZH2 expression in salivary gland tumors, similarly to the tumors of other organs is not characteristic for any tumor type, but is a solid marker of the malignant nature of the tumors.


Long-term follow-up in 12 children with pulmonary arteriovenous malformations: confirmation of hereditary hemorrhagic telangiectasia in all cases.
To assess whether pulmonary arteriovenous malformation (PAVM) is associated with hereditary hemorrhagic telangiectasia (HHT). This study was a review of 12 children (sex ratio = 1) including family history, mutation analysis, and long-term follow-up. Five children were under age 3 years when PAVM was diagnosed. Presentations included pulmonary symptoms (n = 8), cerebral abscess (n = 2), and transient ischemic attack (TIA) (n = 1); 1 patient was asymptomatic. Nine of the 12 children (75%) had a family history of PAVM. The diagnosis of HHT was confirmed in all cases. A mutation in ENG was found in 9 of the 10 children available for testing. No mutation in ACVRL1 was found. During long-term follow-up (mean, 16 years), the following complications occurred: TIA (n = 2), hemoptysis (n = 2), and cerebral abscess (n = 2). Nine children experienced recurrence of PAVM. The children with no recurrence were those without a family history of PAVM. The diagnosis of HHT should be considered in a child with an apparently isolated PAVM. Because serious complications may occur at any age, we recommend screening for PAVM and long-term follow-up in children from families with HHT, especially those with an ENG mutation.


Pharmacokinetics of butorphanol tartrate in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus).
To determine the pharmacokinetics of butorphanol tartrate after IV and IM single-dose administration in red-tailed hawks (RTHs) and great horned owls (GHOs). 6 adult RTHs and 6 adult GHOs. Each bird received an injection of butorphanol (0.5 mg/kg) into either the right jugular vein (IVj) or the pectoral muscles in a crossover study (1-week interval between treatments). The GHOs also later received butorphanol (0.5 mg/kg) via injection into a medial metatarsal vein (IVm). During each 24-hour postinjection period, blood samples were collected from each bird; plasma butorphanol concentrations were determined via liquid chromatography-mass spectrometry. 2- and 1-compartment models best fit the IV and IM pharmacokinetic data, respectively, in both species. Terminal half-lives of butorphanol were 0.94 +/- 0.30 hours (IVj) and 0.94 +/- 0.26 hours (IM) for RTHs and 1.79 +/- 1.36 hours (IVj), 1.84 +/- 1.56 hours (IM), and 1.19 +/- 0.34 hours (IVm) for GHOs. In GHOs, area under the curve (0 to infinity) for butorphanol after IVj or IM administration exceeded values in RTHs; GHO values after IM and IVm administration were less than those after IVj administration. Plasma butorphanol clearance was significantly more rapid in the RTHs. Bioavailability of butorphanol administered IM was 97.6 +/- 33.2% (RTHs) and 88.8 +/- 4.8% (GHOs). In RTHs and GHOs, butorphanol was rapidly absorbed and distributed via all routes of administration; the drug's rapid terminal half-life indicated that published dosing intervals for birds may be inadequate in RTHs and GHOs.


Molecular analysis of cell-free circulating DNA for the diagnosis of somatic mutations associated with resistance to tyrosine kinase inhibitors in non-small-cell lung cancer.
In non-small-cell lung cancer, the molecular diagnosis of somatic mutations is instrumental for the choice of the most appropriate treatment. However, despite an initial response, resistance to tyrosine kinase inhibitors occurs and thereafter tumors progress. For this reason, next generation inhibitors able to overcome acquired resistances are currently in development. Therefore, the identification of the molecular determinants of resistance is needed to adapt treatment accordingly. The analysis of circulating cell-free tumor DNA represents a powerful tool to monitor the somatic changes induced by treatment. This review focuses on the most recent advantages in the diagnosis of acquired resistance in circulating cell-free tumor DNA and underlines the strategies ready to be translated in the clinical practice.


Spike train statistics and Gibbs distributions.
This paper is based on a lecture given in the LACONEU summer school, Valparaiso, January 2012. We introduce Gibbs distribution in a general setting, including non stationary dynamics, and present then three examples of such Gibbs distributions, in the context of neural networks spike train statistics: (i) maximum entropy model with spatio-temporal constraints; (ii) generalized linear models; and (iii) conductance based integrate and fire model with chemical synapses and gap junctions.


Identification of IKZF1 genetic mutations as new molecular subtypes in acute myeloid leukaemia.
Genetic mutations of IKZF1 have been frequently delineated in B-lineage acute leukaemia (B-ALL) but rarely elucidated in acute myeloid leukaemia (AML). IKZF1 mutations confer a poor prognosis in AML, and hotspot mutations of IKZF1, N159Y and N159S tend to occur in B-ALL and AML respectively. However, the pathogenesis of IKZF1 N159S in AML and IKZF1 lineage susceptibility are largely unknown. The genetic and clinical characteristics of IKZF1-mutated AML patients were evaluated. Multi-omics analysis and functional assays were performed in vitro using IKZF1 mutations knock-in AML cell lines. 23 (4.84%) small sequence variants of IKZF1 were identified in 475 newly diagnosed AML (non-M3) patients. Based on RNA sequencing, three classes of IKZF1-related AML were defined, including 9 patients (39.13%) with IKZF1 N159S mutations, 10 (43.47%) with CEBPA mutations and 4 others (17.39%). IKZF1 N159S may define a unique subgroup with higher HOXA/B expression and native B-cell immune fractions. Gene expression data of multiple knock-in cell lines indicate that the lymphocyte differentiation-related MME and CD44 kept high expression in IKZF1 N159Y but were downregulated in N159S. CUT&TAG sequencing showed that IKZF1 N159S reshaped the binding profiles of IKZF1. Integration analysis suggested that the pathogenesis of IKZF1 N159S may depend on the deregulation of several cofactors, such as oncogenic MYC and CPNE7 targets. Collectively, we dissected the molecular spectrum and clinical features of IKZF1-related AML, which may promote an in-depth understanding of the pathogenesis, lineage susceptibility and clinical research of AML.


Possible subdivision of postsynaptic alpha-adrenoceptors mediating pressor responses in the pithed rat.
Additional evidence has been obtained indicating a possible subclassification of postsynaptic alpha-adrenoceptors into alpha 1 - and alpha 2 -subtypes. The pressor responses to the alpha-adrenoceptor agonists L-phenylephrine and guanfacine were quantified after i.v. administration to pithed rats. The alpha-sympatholytic drug yohimbine (1 mg/kg) displaced both dose-response curves to the right, but the effect was greatest for guanfacine. After prazosin (0.1 mg/kg) a 53-fold shift to the right was noticed for the dose-response characteristic of L-phenylephrine. Prazosin antagonized the effect of only the higher doses of guanfacine. The findings indicate that L-phenylephrine and prazosin preferentially interact with alpha 1 -adrenoceptors as agonist and antagonist, respectively. Yohimbine proved less selective than prazosin, but preferentially blocks postjunctional alpha 2 -adrenoceptors in the vascular wall. The results obtained with guanfacine may be interpreted to indicate that this drug acts on alpha 2 -adrenoceptors at lower doses and additionally stimulates alpha 1 -adrenoceptors at higher ones. Preliminary findings with corynanthine and rauwolscine support this interpretation.


Rapid rise in prevalence of knee replacements and decrease in revision burden over past 3 decades in Finland: a register-based analysis.
The prevalence of knee joint replacements (KJR) has been less investigated in situations where the increase in incidence is known. This study investigated the annual and population-based prevalence of KJR and the relationship between the prevalence of KJRs and the incidence of revision surgery. All KJRs performed between 1980 and 2020 were identified from the Finnish Arthroplasty Register (FAR). KJR revisions and removals were extracted from the FAR and hospital discharge registers and patient deaths from Finnish Digital and Population Data Services Agency. We analyzed the annual prevalence by dividing the number of KJR survivors by the population aged 40 or older. The revision burden factor (RBF) was determined by dividing the annual number of revisions by the number of primary and revision KJRs in the population. Proportions of bilateral implants and patients with older KJRs performed 10 or more years earlier were identified. KJR prevalence in Finland increased by 298% between 2000 and 2020, reaching 4.0% in 2020. The proportion of patients with bilateral KJRs and those with older KJRs had increased to 37% and 34%, respectively, by 2020. The annual RBF decreased statistically significantly from 1.9% to 0.7% between 1996 and 2020 (proportion ratio, PR 0.37 [95% CI 0.33-0.42]) and was higher among males (PR 1.23 [CI 1.20-1.26]). Although the recent rapid increase in KJRs is abating and the RBF is diminishing, it is important to take the continuing increase in the prevalence of KJRs into account when assessing hospitals' future resources.


Structure of a human Clara cell phospholipid-binding protein-ligand complex at 1.9 A resolution.
The Clara cell phospholipid-binding protein, previously referred to as CC10, is a homodimeric protein of M(r) 15,800. It is secreted into the bronchioalveolar lining layer in mammalian lung. A combination of X-ray crystallography and chemical analysis was used to determine that phosphatidylcholine and phosphatidylinositol are bound to the protein as isolated from human lung lavage. We now report the crystal structure of the protein-phospholipid complex at 1.9 A resolution. The phospholipid is bound inside the protein's large hydrophobic cavity. A model is proposed for the manner in which a channel may open to provide access to the cavity, allowing the binding or potential release of phospholipid.


Aphid-ant interaction reduces chrysomelid herbivory in a cottonwood hybrid zone.
In a cottonwood (Populus) hybrid zone, Chaitophorus aphids attract aphid-tending ants which subsequently reduce herbivory by the leaf-feeding beetle, Chrysomela confluens. Observations and experimental manipulations of aphids and beetle larvae on immature cottonwood trees demonstrated that: 1) via their recruitment of ants, aphids reduced numbers of beetle eggs and larvae on the host; 2) these interactions occurred within a few days of the host being colonized by aphids; and 3) although aphid colonies were ephemeral, their presence resulted in a 2-fold reduction in beetle herbivory. The aphid-ant interaction is most important in the hybrid zone where 93% of the beetle population is concentrated (for reasons unrelated to aphids and ants). Because beetle defoliation of immature trees is high (ca. 25%), the indirect effect of aphids in reducing herbivory is likely more beneficial to trees in the hybrid zone than in adjacent pure zones where beetle herbivory is virtually absent. Tree genotype likely affects the impact of the aphid-ant interaction on trees within the hybrid zone, since levels of herbivory differ between sympatric Fremont and hybrid cottonwoods.


Characterization and primary structures of bovine and porcine thyroxine-binding globulin.
Thyroxine-binding globulin (TBG) is the major serum transport protein for iodothyronines in most of the large, omni- or herbivorous mammals. Characterization of human TBG (hTBG), including its 20 known natural variants, allowed the identification of the ligand-binding site and a correlation of diminished synthesis or loss of function with mutations in the TBG gene. Further refinement of the structure-function correlation, especially the high binding affinity and heat stability, requires characterization of other mammalian TBGs, of which only rat and sheep TBG were available. We now present some of the chemical and physical properties of bovine TBG (bTBG) and porcine TBG (pTBG) and their primary structures deduced from their cDNA sequences. The serum concentrations of bTBG and pTBG estimated by Scatchard analysis of T(4)-binding were similar to hTBG. The T(4)-binding affinity of human, bovine and porcine TBGs were all similar, at 1.2x10(10) M(-1). However, heat stability of the animal TBGs was reduced, with a half life of denaturation of 7 min (bTBG) and 5 min (pTBG) at 55 degreeC, compared with 21 min for hTBG. Nucleotide alignment revealed identity with hTBG of 85.5% (bTBG) and 83.7% (pTBG) and amino acid identity of 82.8% (bTBG) and 82.6% (pTBG). As expected, the relevant parts of the ligand-binding domain (amino acids 215-291, and 363-395) were highly conserved at more than 95% similarity. Comparison of the five known mammalian TBGs allows focusing of future mutagenesis experiments to further characterize the properties of the molecule.


[Evaluation of the "Jiangsu/WHO 100% condom use programme in China"].
To evaluate the effect and to explore the feasible model of 100% condom use programme (100%CUP) under existing policy and law milieu, so as to provide information for the adjustment of HIV/AIDS policy and intervention strategies. Information on knowledge, attitude and behavior of female sex workers (FSWs) in entertainment establishments were collected and followed by qualitative and quantitative analysis including: samples tested for Chlamydia; a repeated cross-investigation and the final evaluation on the effect of the programme. The reported rate of condom use at the last sex activity with clients increased from 74.9% to 92.2% while the rate of sexually transmitted disease (STD) prevalence droped from 25.1% to 14.1% after three year's intervention program. The number of condoms distributed increased from 50,000 per quarter of a year in 2001 to over 100,000 in 2003. The rates of awareness on the knowledge of STD/AIDS prevention increased obviously. The 100%CUP was proved to be feasible and effective in the pilot site, and should be expanded in entertainment establishments.


Experience with ifosfamide in paediatric tumours.
Ifosfamide, alone or in combination, is used in a variety of childhood tumours. Soft-tissue sarcomas are especially sensitive, with a 78% actuarial survival. Hyperaminoaciduria and a brief transient decrease in the plasma level of certain amino acids are the earliest signs of tubular toxicity.


The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients.
B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents. However, approximately 40% to 50% of rituximab (RTX) treated RA patients have a poor response. We investigated whether baseline gene expression levels can discriminate between clinical non-responders and responders to RTX. In 14 consecutive RA patients starting on RTX (test cohort), gene expression profiling on whole peripheral blood RNA was performed by Illumina® HumanHT beadchip microarrays. Supervised cluster analysis was used to identify genes expressed differentially at baseline between responders and non-responders based on both a difference in 28 joints disease activity score (ΔDAS28 < 1.2) and European League against Rheumatism (EULAR) response criteria after six months RTX. Genes of interest were measured by quantitative real-time PCR and tested for their predictive value using receiver operating characteristics (ROC) curves in an independent validation cohort (n = 26). Genome-wide microarray analysis revealed a marked variation in the peripheral blood cells between RA patients before the start of RTX treatment. Here, we demonstrated that only a cluster consisting of interferon (IFN) type I network genes, represented by a set of IFN type I response genes (IRGs), that is, LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2, was associated with ΔDAS28 and EULAR response outcome (P = 0.0074 and P = 0.0599, respectively). Based on the eight IRGs an IFN-score was calculated that reached an area under the curve (AUC) of 0.82 to separate non-responders from responders in an independent validation cohort of 26 patients using Receiver Operator Characteristics (ROC) curves analysis according to ΔDAS28 < 1.2 criteria. Advanced classifier analysis yielded a three IRG-set that reached an AUC of 87%. Comparable findings applied to EULAR non-response criteria. This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.


First detection of Leishmania infantum kinetoplast DNA in hair of wild mammals: application of qPCR method to determine potential parasite reservoirs.
The data presented in this paper describe the application of a method for a reliable and non-invasive diagnosis of leishmaniosis in wild reservoirs, based on the detection of Leishmania infantum kinetoplast DNA (kDNA) in hair samples by Real Time PCR (qPCR). The study has been performed on 68 ear/leg hair samples from 5 different wild species (Vulpes vulpes, Canis lupus, Martes foina, Rattus norvegicus and Erinaceus europaeus) from several geographic areas of West and North Spain. The presence of Leishmania kDNA was detected in 14 of the 68 analyzed samples, being the highest quantity of DNA observed in foxes. This is the first report of the presence of Leishmania in a hedgehog. The kDNA remained stable under the exposure of hair to different environmental conditions (freezing or high temperature, ultraviolet rays or treatment with tanning salts). This detection method could constitute a suitable alternative for the search of the parasite in wild hosts, due to the numerous advantages that hair samples present for collection, transport and storage processes.


Vitamin D (25-0H D3) status and pathological response to neoadjuvant chemotherapy in stage II/III breast cancer: Data from the NEOZOTAC trial (BOOG 10-01).
Serum levels of 25-OH vitamin D3 (vitamin D) have been shown to be prognostic for disease-free survival in patients with breast cancer. We investigated the predictive value of these levels for pathological response after neoadjuvant chemotherapy in patients with breast cancer taking part in the NEOZOTAC phase-III trial. Additionally, the effect of chemotherapy on vitamin D levels was studied. Serum vitamin D was measured at baseline and before the last cycle of chemotherapy. The relationship between these measurements and clinical outcome, as defined by pathological complete response in breast and lymph nodes (pCR) was examined. Baseline and end of treatment vitamin D data were available in 169 and 91 patients, respectively. Median baseline vitamin D values were 58.0 nmol/L. In patients treated with chemotherapy only, serum vitamin D levels decreased during neoadjuvant chemotherapy (median decrease of 16 nmol/L, P = 0.003). The prevalence of vitamin D levels < 50 nmol/L increased from 38.3% at baseline to 55.9% after chemotherapy. In the total population, baseline and end of therapy vitamin D levels were not related to pathological response. No associations were found between pCR and vitamin D level changes. The significant decrease in vitamin D post-neoadjuvant chemotherapy suggests that vitamin D levels should be monitored and in case of decrease of vitamin D levels, correction may be beneficial for skeletal health and possibly breast cancer outcome.


ADIPOQ gene polymorphisms and susceptibility to polycystic ovary syndrome: a HuGE survey and meta-analysis.
Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders. The aim of this study was to investigate possible associations between 45T/G and 276G/T variants of the ADIPOQ gene and susceptibility to PCOS. A meta-analysis of 11 published case-control studies on the 45T/G variant of the ADIPOQ gene (involving a total of 1176 patients with PCOS and 1759 controls) and eight published case-control studies on the 276G/T variant of the ADIPOQ gene (involving a total of 895 patients with PCOS and 1024 controls) was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. The comparison of G vs. T in ADIPOQ 45T/G showed significant differential susceptibility to PCOS (OR=1.397, 95% CI 1.156-1.689). A significant association was also found between PCOS susceptibility and the comparison of G vs. T in ADIPOQ 276G/T (OR 0.812, 95% CI 0.704-0.937). However, protective effects were found in both sites under the co-dominant model for Caucasians. Further studies are warranted to assess these associations in greater detail, especially in Asian populations.


Contact force and impedance decrease during ablation depends on catheter location and orientation: insights from pulmonary vein isolation using a contact force-sensing catheter.
Contact force (CF) sensing during radiofrequency (RF) ablation allows controlling lesion size. The aim of this study was to analyze the impact of catheter tip location and orientation on the association of CF and impedance decrease. We retrospectively analyzed RF applications from 32 patients undergoing catheter ablation for paroxysmal atrial fibrillation using a force-sensing catheter and 3D mapping system. CF, catheter location and orientation relative to the tissue during ablation as well as the absolute impedance decrease during the first 20 s of ablation as a surrogate for lesion effectiveness were analyzed for 791 RF applications. While a higher CF was achieved around the right pulmonary veins (12.5 vs. 11.4 g, p = 0.045), a lower median absolute impedance decrease within the first 20 s was seen around the right veins compared to the left veins (9.3 vs. 10.2 Ω, p = 0.02). With different catheter orientations relative to the tissue, higher CF and impedance decrease was seen when the catheter was orientated parallel or oblique to the tissue (30°-145°) as compared perpendicularly (0-30°) with a median CF of 13.2 vs. 8.0 g (p < 0.001) and a median impedance decrease during the first 20 s of 11 vs. 7 Ω (p < 0.001). Importantly, achieved CF, baseline impedance, catheter orientation and location all independently predicted the initial absolute and relative impedance decrease in a multivariable linear regression model (p < 0.05). The effectiveness of RF ablation lesions, as assessed by the initial impedance decrease, is not only dependent on the achieved catheter CF but also on catheter orientation and location.


Characterizing the burden of premature ejaculation from a patient and partner perspective: a multi-country qualitative analysis.
Premature ejaculation (PE) is a common sexual dysfunction among men which affects men and their partners. Little qualitative data are available to characterize the impact of PE on men and their partners about ejaculatory control, sexual satisfaction, emotional distress and relationships. The objective of this study was to assess the impact of PE from the perspective of men with PE and the female partners of men with PE on their sexual experience, distress and relationships. Qualitative data were collected through 14 focus groups in the US and through one-on-one interviews in the US, UK, Italy, France, Germany, and Poland. Study participants included heterosexual men with PE and female partners of males with PE. All participants were asked about how PE affects their daily life, including emotional impacts. One-on-one interviews also included obtaining feedback on the male and female versions of 4-single item measures of PE focusing on ejaculatory control, satisfaction with intercourse, interpersonal distress, and relationship difficulty. Participants included 172 males with PE and 67 female partners of men with PE. Lack of control over ejaculation and dissatisfaction with intercourse emerged as central themes of PE. Lack of ejaculatory control resulted in greater dissatisfaction and greater emotional distress, including feelings of inadequacy, disappointment, and anxiety. Continued PE ultimately leads to greater problems with partners and often disrupts partner relationships. Participants indicated that PE was keeping them from attaining complete intimacy in their relationships even when their partners were generally satisfied with sexual intercourse. Impacts of PE on sexual satisfaction, emotional distress and partner relationships were consistent across countries. Feedback on the single-item PE measures confirmed relevance of the item content and further confirmed major themes identified from the qualitative data. This qualitative study provides valuable insights on the substantial psychosocial burden of PE in the US and the Europe. Lack of control over ejaculation resulted in dissatisfaction with intercourse and increased emotional distress, and wide-ranging impact for both men with PE and their partners of men with PE. Data collected in this study may help inform the content of new patient reported measures for use in PE research.


An international comparative study of active living environments and hospitalization for Wales and Canada.
Rationale: Previous studies indicate active living environments (ALEs) are associated with higher physical activity levels across different geographic contexts, and could lead to reductions in hospital burden. Both Wales UK and Canada have advanced data infrastructure that allows record linkage between survey data and administrative health information. To assess the relationship between ALEs and hospitalization in Wales and Canada. We performed a population-based comparison using individual-level survey data from the Welsh Health Survey (N = 9968) linked to the Patient Episode Database for Wales, and the Canadian Community Health Survey (N = 40,335) linked to the Discharge Abstract Database. Using equivalent protocols and open-source data for street networks, destinations, and residential density, we derived 5-class measures of the ALE for Wales and Canada (classed 1 through 5, considered least favourable to most favourable for active living, respectively). We evaluated relationships of ALEs to health, behaviours and hospitalization using multivariate regression (reference group was the lowest ALE class 1, considered least favourable for active living). For Canada, those living in the highest ALE class 5 had lower odds of all-cause hospitalization (OR 0.66, 95% CI 0.54 to 0.81; as compared to the lowest ALE class 1). In contrast, those living in the highest ALE class 5 in Wales had higher odds of all-cause hospitalization (OR 1.37, 95% CI 1.04 to 1.80). The relationship between ALEs and cardiometabolic hospitalization was inconclusive for Canada (OR 0.75, 95% CI 0.50 to 1.12), but we observed higher odds of cardiometabolic hospitalization for respondents living in higher ALE classes for Wales (OR 1.46, 95% CI 1.10 to 1.78; comparing ALE class 4 to ALE class 1). Canadian respondents living in high ALE neighbourhoods that are understood to be favourable for active living had lower odds of all-cause hospitalization, whereas Welsh respondents living in high ALEs that were deemed favourable for active living exhibited higher odds of all-cause hospitalization. Environments which promote physical activity in one geographic context may not do so in another. There remains a need to identify relevant context-specific factors that encourage active living.


Spontaneous remission of acute adult T-cell leukaemia with chromosomal abnormality infiltrating to skin and liver.
Acute type of adult T-cell leukaemia (ATL) has been recognized as highly-progressive T-cell malignancy with a median survival of 7 months. We present a case who had a spontaneous remission from acute type ATL with organ involvement and chromosomal abnormality implying very poor prognosis. Although the mechanism of spontaneous remission remains uncertain, our case was unique with regard to the progression and regression of leukaemia.


A new bubble oxygenator (OCVC oxygenator): development and clinical application.
A new bubble oxygenator, designed for simple operation and clinical efficacy in intracardiac surgery, has been developed and clinically evaluated. This device is characterized by an oxygenating chamber with controllable blood-volume, integral heat exchanger and two-stage microfilter of gravity drainage system, an apparatus for creating and uniformly distributing oxygen bubbles, and construction materials of the device known to be minimally traumatic to the blood. Clinical experience in 132 infantile and pediatric open heart procedures has demonstrated its effectiveness as measured by embolic complications and simplicity in maintaining physiologic blood gas levels.


Targeted drug delivery to the retinal pigment epithelium: Untapped therapeutic potential for retinal diseases.
The retinal pigment epithelium (RPE) plays a crucial part in sight-threatening diseases. In this review, we shed light on the pivotal implication of the RPE in age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity; and explain why a paradigm shift toward targeted RPE therapy is needed to efficiently fight these retinal diseases. We provide guidance for the development of RPE-specific nanotherapeutics by giving a comprehensive overview of the possibilities and challenges of drug delivery to the RPE and highlight successful nanotherapeutic approaches targeting the RPE.


Toxicology then and now.
A review of the history of the evolution of the science of toxicology from the original concepts of Paracelsus through the early development of analytical chemistry and its contributions to the detection of toxic substances in foods and drugs as these have led to modern regulatory rules for public protection is presented. The legal actions taken to protect against adulteration of food prior to the early steps by the U.S. Department of Agriculture that concluded with the passage of the 1906 Food and Drug Act are systematically documented. The history is reviewed of the Food and Drug Administration's role in the use of animal toxicity studies to develop reasonable criteria for safety of foods and drugs for man. Modern concepts of molecular distribution, metabolism, and excretion of substances in the animal body are discussed as these impinge on the so-called "protection index." The legal and often litigious controversies over the claimed carcinogenicity of chemical substances is documented with comments on the Delaney dilemma and the role of in vitro tests in toxicology. The review concludes with a discussion of the hazards of use of stochastic mathematical models to assess carcinogenicity and suggests that the criteria employed in the report of the Scientific Committee of the Food Safety Council are properly structured to give a contemporary evaluation of all the currently available data. References give documentation of events over the past 200 years that explain the present state of toxicology as a discipline.


Long-term follow-up of internal threaded Kirschner-wire fixation of the scarf bunionectomy.
The authors discuss the scarf ("Z") bunionectomy and report on results of their review of 230 procedures fixated with internal threaded Kirschner (K)-wires, at least 1 year in duration.


Sagittal abdominal diameter and waist circumference appear to be equally good as identifiers of cardiometabolic risk.
Body mass index (BMI) and waist circumference (WC) are commonly used markers of cardiometabolic risk. However, sagittal abdominal diameter (SAD) has been proposed as a possibly more sensitive marker of intra-abdominal obesity. We investigated differences in how SAD, WC, and BMI were correlated with cardiometabolic risk markers. This cross-sectional study investigated anthropometric and metabolic baseline measurements of individuals from six trials. Multiple linear regression and (partial) correlation coefficients were used to investigate associations between SAD, WC, and BMI and cardiometabolic risk markers, including components of the metabolic syndrome as well as insulin resistance, blood lipids, and lowgrade inflammation. In total 1516 mostly overweight or obese individuals were included in the study. SAD was significantly more correlated with TG than WC for all studies, and overall increase in correlation was 0.05 (95% CI (0.02; 0.08). SAD was significantly more correlated with the markers TG and DBP 0.11 (95% CI (0.08, 0.14)) and 0.04 (95% CI (0.006, 0.07), respectively compared to BMI across all or most studies. This study showed that no single anthropometric indicator was consistently more strongly correlated across all markers of cardiometabolic risk. However, SAD was significantly more strongly correlated with TG than WC and significantly more strongly correlated with DBP and TG than BMI.


Association Between Preoperative Angioembolization and Bleeding Complications in Patients With Benign Liver Tumors: Analysis of a National Database.
The role of angioembolization (AE) in patients with benign liver diseases is an area of active research. This study aims to assess any difference in liver resection outcomes in patients with benign tumors dependent on utilization of preoperative AE. A retrospective cohort study of patients undergoing elective liver resections for benign liver tumors was performed using the National Surgical Quality Improvement Program database (2014-2019). Only tumors of 5 cm in size or more were included in the analysis. We categorized the patients based on preoperative AE (AE + versus AE -). The primary outcome measured included bleeding complications within 72 h. The secondary outcomes were to determine predictors of bleeding. After propensity score matching, there were 103 patients in both groups. There was no difference in intraoperative or postoperative blood transfusions within 72 h of surgery (14.6% versus 12.6%; P = 0.68), reoperation (1.9% versus 1.9%; P = 1), or mortality (1.0% versus 0.0%; P = 1) between the two groups. Multivariate regression analysis revealed an open surgical approach (odds ratio [OR]: 4.59 confidence interval [CI]: 2.94-7.16), use of Pringle maneuver (OR: 1.7, CI: 1.26-2.310), preoperative anemia (OR: 2.79, CI: 2.05-3.80), and preoperative hypoalbuminemia (OR: 1.53 [1.14-2.05]) were associated with the need for intraoperative or postoperative blood transfusions within 72 h of surgery. Preoperative AE was not associated with reducing intraoperative or postoperative bleeding complications or blood transfusions within 72 h after surgery.


Incidence and predictive factors of depressive symptoms in Alzheimer's disease: the REAL.FR study.
Many patients develop psychiatric and behavioral disturbances in the course of Alzheimer's disease (AD). Among these disturbances, depressive symptoms are frequent and affect nearly 40% of patients. The natural history and course of such symptoms in AD, and in particular the predictive factors, are little known. We studied the incidence and risk factors for the development of the first depressive symptoms in AD. Multicenter prospective study. Three hundred twelve AD patients from the French Network on AD (REAL.FR) without depression and without antidepressant treatment at baseline were followed up and assessed every 6 months for 4 years. During follow-up, all events occurring between two visits were carefully recorded. We used the Neuropsychiatric Inventory (NPI) for comprehensive evaluation of behavioral and psychological symptoms and depressive symptoms in particular. A multivariate analysis was performed using a backward stepwise Cox proportional hazards model. The incidence of depressive symptoms was 17.45% person/years, 95%CI (13.88-21.02). Among non-time dependent variables, duration of disease (RR=0.51; 95%CI: 0.30-0.85, p=0.0102) and the number of comorbid conditions (RR=0.45; 95%CI: 0.24-0.83, p=0.0115) were protective factors against the development of depressive symptoms. Agitation/aggression (RR=1.96; 95%CI: 1.19-3.23, p=0.0078) and sleep disturbances (RR=2.65; 95%CI: 1.40-5.00, p=0.0026) were time-dependent variables predictive of depressive symptoms. Better knowledge of predictive factors of mood disturbances in AD will enable clinicians to set up appropriate management of their patients. As published longitudinal studies are few, further works should be carried out to improve knowledge of the pattern and course of depression and depressive symptoms in AD.