Open versus minimally invasive small bowel resection for Crohn's disease: a NSQIP retrospective review and analysis.
Many patients with Crohn's Disease will require surgical resection. While many studies have described outcomes following ileocecectomy, few have evaluated surgical resection of other portions of small bowel. We sought to compare open and minimally invasive surgery (MIS) approaches for small bowel resection excluding ileocecectomy of patients with Crohn's Disease using the National Surgical Quality Improvement Program (NSQIP) database. The NSQIP database was queried for patients with Crohn's disease or complications related to Crohn's disease who underwent segmental small bowel resection utilizing open or minimally invasive approaches between 2012 and 2018. Patients requiring ileocecectomy or diagnosed with ascites, disseminated cancer, pre-operative sepsis, ASA class 5, and patients requiring mechanical ventilation were excluded. The association of pre-operative variables including patient demographic information and comorbidities with surgical approach were examined using Fishers exact test. Intraoperative, and 30-day post-operative outcomes were compared between the groups using both univariate and multivariate logistical regression models. SAS was used for data analysis with p < 0.05 considered significant. After exclusions, we found 1697 patients with Crohn's disease who underwent segmental small bowel resection, 1252 of whom underwent open surgery and 445 of whom underwent MIS. After adjusting for possible confounders with multivariable analysis, patients who underwent MIS had a lower incidence of wound events (surgical site, organ space, or deep wound infection, or dehiscence), post-operative bleeding, need for return to the operating room, and shorter total hospital length of stay despite longer operative times compared with open surgery. This retrospective review of NSQIP shows that minimally invasive small bowel resection is associated with equivalent or improved morbidity over open surgery in select patients with small bowel Crohn's Disease. We show that in select patients minimally invasive small bowel resection can be safe and performed for patients with isolated small bowel Crohn's disease.


Effects of comorbidity and clustering upon referrals in primary care.
To examine the effect of patient characteristics and comorbidity on referrals in primary care. Cross-sectional analysis of patient encounters and referrals during a 1-year period for a primary care network of 9 clinics. The analysis adjusted for the clustering effect of physicians and clinics on the data. 23,720 specialty referrals were generated from 251,240 patient encounters, resulting in a total referral rate of 9.4 referrals per 100 encounters. Age, gender, and certain comorbid conditions were significant predictors of referral for any given encounter. Patient characteristics and comorbidity are predictors of referral. Studies of primary care processes need to account for clustering of physicians and clinics in their research design.


Synergies of Antiangiogenic Therapy and Immune Checkpoint Blockade in Renal Cell Carcinoma: From Theoretical Background to Clinical Reality.
The hallmarks of renal cell carcinoma (RCC) are angiogenesis and immunogenic tumor microenvironment. Over the past decades, treatment options for metastatic RCC (mRCC) have been expanding, from the inhibition of vessel formation via antiangiogenic agents (AAs) to the stimulation of immune system by immune checkpoint inhibitors (ICIs). Since 2005, the introduction of antiangiogenic agents targeting vascular endothelial growth factor (VEGF), its receptors (VEGFRs), and mammalian target of rapamycin (mTOR) pathway have experienced moderate success in the therapeutics of mRCC, but patient outcomes remain suboptimal. Recently, the development of ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed death-1/programmed death ligand 1 (PD-1/PD-L1) pathways has dramatically changed the treatment landscape of mRCC. Expressly, the combination of ipilimumab and nivolumab has been confirmed to improve clinical outcomes and approved as a standard care for intermediate- or poor-risk mRCC patients. Nevertheless, innate or adaptive drug resistance is observed within both treatment approaches, limiting overall clinical benefit. This phenomenon will underscore the urgent need for new combinational therapy strategies with different mechanisms of action, which can improve efficacy in an extended patient population without severe toxic effects. In 2019, as the results of two critical phase III trials came to light, FDA approved axitinib plus avelumab, or pembrolizumab as first-line standard management for mRCC, which cements the combination of AAs plus ICIs and advances the mRCC treatment field. This review summarizes current evidence on the interplay and synergies between AAs and immunomodulating drugs in mRCC, focusing on the theoretical background and the status of current clinical development.


Success Rate and Perinatal Outcomes of Selective Reduction by Radiofrequency Ablation in Monochorionic Multiple Pregnancies with a Hydropic Fetus; A Prospective Interventional Single-Arm Study.
Selective reduction of the fetus is one of the therapeutic methods in complicated monochorionic twins. The present study aimed to investigate the success rate and perinatal outcomes of selective reduction using radiofrequency ablation (RFA) in monochorionic multiple pregnancies with a hydropic fetus. This prospective interventional single-arm study was conducted in a referral hospital from 2017 to 2019. Totally, 27 complicated monochorionic twin and triplet pregnancies underwent RFA to occlude the umbilical vein of the hydropic fetus. The participants were followed until 2 months post-delivery. Procedure success rate, survival rate, gestational age at delivery, and neonatal outcome were evaluated. The umbilical cord in 26 (96.2%) cases was successfully occluded by RFA with no maternal complications. Live birth was within 75%. The mean±SD age at delivery was 34.4±3.83 weeks. The gestational age at delivery in TTTS (twin-to-twin transfusion syndrome)-induced hydrops was significantly lower than the non-TTTS hydrops group (P=0.003). Four cases experienced preterm premature rupture of the membranes (PPROM) before 34 weeks. Of all viable neonates, 8 cases were admitted to the neonatal intensive care unit (NICU). In 2 months follow-up post-delivery, all neonates had normal findings without any adverse outcomes. Selective reduction by RFA in complicated monochorionic pregnancies with a hydropic fetus may be a safe method with a high success rate and 100% neonatal survival. This method may be optimal for feticide in non-TTTS hydropic twins.


Nicotine increases neural response to unpleasant stimuli and anxiety in non-smokers.
Studies in smokers suggest that nicotine might exert anxiolytic, stress-dampening and mood-enhancing effects and beneficially influences neural processing of affective information. Regarding non-smokers, results are inconsistent, and no data exist on the effect of nicotine on neural emotion processing. We applied functional magnetic resonance imaging (fMRI) to assess the influence of nicotine on brain activation during processing of emotional stimuli in 31 non-smokers with a maximum lifetime cigarette consumption of 20 cigarettes. Participants were subjected to two fMRI scans with event-related presentations of images taken from the International Affective Picture System, receiving nicotine (2 mg) and placebo gums in a double-blinded, randomized cross-over design. Furthermore, subjective affect was assessed. Nicotine increased brain activity in response to unpleasant stimuli in the amygdala, anterior cingulate cortex (ACC) and basal ganglia, whereas processing of pleasant stimuli was not altered. Psychophysiological interaction (PPI) analyses revealed that nicotine increased connectivity between the amygdala and the perigenual ACC (pACC) during processing of unpleasant stimuli and decreased connectivity between those structures during processing of pleasant stimuli. Participants reported higher state anxiety under nicotine than placebo. A single dose of nicotine acted as a stressor in non-smokers, leading to increased anxiety and neural activation elicited by unpleasant stimuli as well as altered connectivity within the amygdala-pACC circuit. Besides the possibility that reactions to nicotine may differ between non-smokers and smokers due to tolerance and neuroadaptive processes that occur during prolonged nicotine use, a priori differences in smokers and non-smokers might potentially explain diverse effects of nicotine on affect and emotional reactivity.


Causal effects of cannabis legalization on parents, parenting, and children: A systematic review.
Medical and recreational cannabis legalization lead to increased cannabis use among adults. There is concern that legalization has negative implications for minors via effects on parents. We conducted a systematic review of studies examining legalization in the United States. Web of Science, PsycInfo, and PubMed were searched through May 2021, studies examining effects of legalization on maternal cannabis and other substance use during pregnancy and postpartum, perinatal outcomes, parental cannabis and other substance use and attitudes, parenting, and child outcomes were identified, and two independent reviewers extracted information on study designs, samples, and outcomes, and assessed classification of evidence and risk of bias. Forty-one studies met inclusion criteria; only 6 (15%) used the most causally informative study design (difference in differences). It is likely legalization increases maternal cannabis use during pregnancy and postpartum, parental cannabis use, and approval of adult cannabis use. Legalization may increase some adverse perinatal outcomes, though findings were inconsistent. It is likely legalization increases unintentional pediatric cannabis exposure. There is insufficient evidence for effects of legalization on child abuse and neglect, and there have been no studies examining effects of legalization on other aspects of parenting or on child adjustment. There is a critical lack of causally informative epidemiological studies examining effects of legalization on parenting and young children. Additional causally informative research is needed. Studies of parental cannabis use in a legal context are particularly needed. Commonsense guidelines must recognize the shifting national landscape around legalization while seeking to minimize potential harm to minors.


ICARE Radon Calibration Device.
An aerodynamic calibration device called ICARE is briefly described. ICARE is currently being used at the Nuclear Research Center of Saclay in France for the certification of instruments employed in measurement of artificial radioactive particulate airborne contamination. ICARE is essentially a blower. Aerosols calibrated in size and labelled with 137Cs or 239Pu are injected in the mainstream of the blower upstream of the test section. To extend ICARE's field of application to the case of instruments employed in measurement of 222Rn and of its decay products, a new line of injection has been designed and is under construction, in the frame of a contract financed by the European Community Commission. The main effort is presently oriented to-ward the development of a reliable 222Rn source, based on a solid deposit of 226Ra on organic fibers, and of a reference method for the measurement of 222Rn activity per unit volume of air. This reference is based on a modified version of standard containers being used in the French reference method for calibrated measurements of 133Xe and 85Kr by gamma spectroscopy.


Reactivity of Neutral Tantalum Sulfide Clusters Ta3Sn (n = 0-4) with N2.
Nitrogen (N2) fixation is a challenging and vital issue in chemistry. Inspired by the fact that the active sites of nitrogenases are polynuclear metal sulfide clusters, the reactivity of gas-phase metal sulfide clusters toward N2 has received considerable attention to gain fundamental insights into nitrogen fixation. Herein, neutral tantalum sulfide clusters have been prepared and their reactivity toward N2 has been investigated by mass spectrometry in conjunction with density functional theory (DFT) calculations. The experimental results showed that Ta3Sn (n = 0-3) could adsorb N2, while Ta3S4 was inert to N2. The DFT calculations revealed that the complete cleavage of the N≡N bond on the trinuclear metal center in the Ta3S0-3/N2 reaction systems was overall barrierless under thermal collision conditions. The sulfur ligands can facilitate the approaching of N2 toward the metal center but weaken the electron-donating ability of the metal center. The inertness of Ta3S4 is ascribed to the electron-deficient state of Ta3 in Ta3S4 and the least effective orbital interaction in the Ta3S4/N2 couple. This study provides new insights into the ligand effect on the interaction of the metal clusters with N2.


Automatic pulmonary ground-glass opacity nodules detection and classification based on 3D neural network.
Pulmonary ground-glass opacity (GGO) nodules are more likely to be malignant compared with solid solitary nodules. Due to indistinct boundaries of GGO nodules, the detection and diagnosis are challenging for doctors. Therefore, designing an automatic GGO nodule detection and classification scheme is significantly essential. In this paper, we proposed a two-stage 3D GGO nodule detection and classification framework. First, we used a pretrained 3D U-Net to extract lung parenchyma. Second, we adapted the architecture of Mask region-based convolutional neural networks (RCNN) to handle 3D medical images. The 3D model was then applied to detect the locations of GGO nodules and classify lesions (benign or malignant). The class-balanced loss function was also used to balance the number of benign and malignant lesions. Finally, we employed a novel false positive elimination scheme called the feature-based weighted clustering (FWC) to promote the detection accuracy further. The experiments were conducted based on fivefold cross-validation with the imbalanced data set. Experimental results showed that the mean average precision could keep a high level (0.5182) in the phase of detection. Meanwhile, the false positive rate was effectively controlled, and the competition performance metric (CPM) reached 0.817 benefited from the FWC algorithm. The comparative statistical analyses with other deep learning methods also proved the effectiveness of our proposed method. We put forward an automatic pulmonary GGO nodules detection and classification framework based on deep learning. The proposed method locate and classify nodules accurately, which could be an effective tool to help doctors in clinical diagnoses.


An Antibody to the Castor Bean Glyoxysomal Lipase (62 kD) also Binds to a 62 kD Protein in Extracts from Many Young Oilseed Plants.
An antibody raised against purified glyoxysomal lipase (triacylglycerol hydrolase EC 22.214.171.124.) from castor bean (relative molecular weight of 62,000) also binds to a protein with a relative molecular weight of 62,000 in extracts of food reserve tissues from many young oilseed plants. These plants include Brassica napus L., Zea mays L., Arachis hypogaea L., Glycine max L., Gossipium hirsutum L., Cucurbita pepo L., Helianthus annuus L., Pisum sativum L., and Cicer arietinum L. The antibody caused inhibition of triacylglycerol hydrolysis by the lipases in extracts from seedlings of corn, oilseed rape, castor bean, soybean, and peanut. The pattern of antilipase binding to the 62 kilodalton protein in subcellular fractions from these other seedlings was consistent with the patterns of lipase activity reported in the literature and it is suggested that lipases from these oil seeds all have a subunit with a molecular weight of 62,000. The protein was only found in the food reserve tissues and was not present in extracts of roots and leaves of mature plants. In addition, the immunoreactive 62 kilodalton polypeptide was not detectable in lima beans and only at very low levels in kidney beans. Both these seeds are known to contain very little storage lipid and would not be expected to contain lipase. With the exception of the acid lipase of castor bean, ungerminated seeds do not generally contain active lipases. The immunoreactive 62 kilodalton protein could not be detected in the ungerminated seeds of most plants and only at very low low levels in others.


High prevalence of anti-cardiolipin antibody, C1q-, C3d-, and mRF-IgG immune complexes, and anti-nuclear antibody in hemophiliacs irrespective of infection with human immunodeficiency virus type 1.
We investigated the prevalence of various autoantibodies [anti-cardiolipin antibody (aCL), lupus anticoagulant (LA), immune complexes (ICs), anti-nuclear antibody (ANA), and anti-deoxyribonucleic acid antibody (aDNA)] in hemophiliac individuals with (n = 50) and without (n = 42) infection by human immunodeficiency virus type 1 (HIV-1). The positivity rate for ANA was similar in both groups, and none of the patients was positive for LA and aDNA. aCL was positive in 35 of 50 (70%) HIV-1-positive hemophiliac individuals and 33 of 42 (79%) HIV-1-negative hemophiliac individuals. However, the majority of the aCL was revealed to be beta 2-glycoprotein I independent, thus corresponding to a syphilis type aCL that does not cause the so-called antiphospholipid syndrome. A total of 39 of the 45 HIV-1 positive hemophiliac individuals (87%) and 34 of 41 HIV-1-negative hemophiliac individuals (83%) had at least one type of IC [C1q-, C3d-, and/or murine monoclonal rheumatoid factor (mRF)- IgG]. The mechanism producing various autoantibodies in hemophiliac persons irrespective of their HIV-1 status is still unclear, but pathogens (e.g., HIV-1, hepatitis B, and hepatitis C) and alloantigens in the blood products that these patients require may be possible candidates. The clinical significance of the presence of these autoantibodies and the underlying mechanisms involved both need to be clarified further.


Reactivity of Anodically Generated 4-Methoxystilbene Cation Radicals: The Influence of Ortho-Substituted Hydroxymethyl, Aminomethyl, and Carboxylic Acid Groups.
The effect of ortho'-substituted side chains bearing nucleophilic groups such as CH2OH, CH2NHR, and CO2H on the reactivity of anodically generated 4-methoxy- and 3,4-dimethoxystilbene cation radicals was investigated, and results were compared with those of substrates where the nucleophilic groups such as OH and NHR are directly attached to the aromatic ring. It was found that when ortho'-substituted groups such as CH2OH or CH2NHR are present in the other ring, only direct intramolecular cation-nucleophile reactions occur to give bisbenzopyrans or bisisoquinolines. Crossover products (previously obtained when the ortho' substituents were OH and NH2) such as the fused benzoxepanes/fused benzoazepanes were not formed. When the ortho' substituent is COOH, direct intramolecular cation-nucleophile reaction occurs to give the corresponding bis-δ-lactones in high yield. The presence of an additional 3-methoxy substituent resulted in the formation of other fused polycyclic products due to competing aromatic substitution reactions. Reaction pathways leading to the different products and reasons for the difference in behavior shown by the present stilbenes are presented. The results have provided additional insight into the reactivity and behavior of anodically generated stilbene cation radicals.


Case Report: Large Granular Lymphocyte Leukemia (LGLL)-A Case Series of Challenging Presentations.
Large granular lymphocyte leukemia (LGLL) represents a rare group of diseases with considerable difficulties in their correct diagnostic workup and therapy. The major challenges lie in their distinction from reactive (including autoimmune) lymphoproliferations. Moreover, monoclonal LGL proliferative diseases are in fact a heterogeneous group of disorders, as recognized by the three subtypes in the current WHO classification. It distinguishes two chronic forms (the focus of this case series), namely T-LGLL and chronic lymphoproliferative disorders of Natural Killer cells (CLPD-NK) as well as aggressive NK-cell leukemia. In the clinical routine, the variable presentations and phenotypes of T-LGLL and CLPD-NK are underappreciated. The relevant differential diagnoses range from benign reactive T-cell expansions to other mature T-cell leukemias to highly aggressive γδ-lymphomas. T-LGLL or CLPD-NK patients suffer from a wide variety of symptoms often including, but not limited to, cytopenias or classical autoimmune phenomena. They receive treatments ranging from mere supportive measures (e.g. antibiotics, growth factors, transfusions) over strategies of immunosuppression up to anti-leukemic therapies. The diagnostic pitfalls range from recognition of the subtle T-cell proliferation, repeated establishment of monoclonality, assignment to a descript immunophenotypic pattern, and interpretations of molecular aberrancies. Here, we report a series of selected cases to represent the spectrum of LGLL. The purpose is to raise awareness among the scientifically or practically interested readers of the wide variety of clinical, immunological, and phenotypic features of the various forms of LGLL, e.g. of T-cell type, including its γδ forms or those of NK-lineage. We highlight the characteristics and courses of four unique cases from two academic centers, including those from a prospective nationwide LGLL registry. Each case of this instructive catalogue serves to transport a key message from the areas of (chronic inflammatory) contexts in which LGLL can arise as well as from the fields of differential diagnostics and of various treatment options. Implications for optimization in these areas are discussed.


Gang youth as a vulnerable population for nursing intervention.
Gang youth often come from socially and economically marginalized communities. Such youth report significantly higher rates of participation in violence, substance use, and risky sexual behaviors than their nongang peers. This manuscript argues that gang-identified youth constitute a vulnerable population. Data are drawn from the general research literature and a case example of how a nurse in Los Angeles partnered with law enforcement to provide preventive health care to gang youth and youth at-risk for joining gangs. Gang youth are a vulnerable population amenable to nursing intervention. Gang youth may have particular health care needs and may need special access to health care.


Discovery of an unconventional centromere in budding yeast redefines evolution of point centromeres.
Centromeres are the chromosomal regions promoting kinetochore assembly for chromosome segregation. In many eukaryotes, the centromere consists of up to mega base pairs of DNA. On such "regional centromeres," kinetochore assembly is mainly defined by epigenetic regulation [1]. By contrast, a clade of budding yeasts (Saccharomycetaceae) has a "point centromere" of 120-200 base pairs of DNA, on which kinetochore assembly is defined by the consensus DNA sequence [2, 3]. During evolution, budding yeasts acquired point centromeres, which replaced ancestral, regional centromeres [4]. All known point centromeres among different yeast species share common consensus DNA elements (CDEs) [5, 6], implying that they evolved only once and stayed essentially unchanged throughout evolution. Here, we identify a yeast centromere that challenges this view: that of the budding yeast Naumovozyma castellii is the first unconventional point centromere with unique CDEs. The N. castellii centromere CDEs are essential for centromere function but have different DNA sequences from CDEs in other point centromeres. Gene order analyses around N. castellii centromeres indicate their unique, and separate, evolutionary origin. Nevertheless, they are still bound by the ortholog of the CBF3 complex, which recognizes CDEs in other point centromeres. The new type of point centromere originated prior to the divergence between N. castellii and its close relative Naumovozyma dairenensis and disseminated to all N. castellii chromosomes through extensive genome rearrangement. Thus, contrary to the conventional view, point centromeres can undergo rapid evolutionary changes. These findings give new insights into the evolution of point centromeres.


Efficacy of tooth splinting and occlusal adjustment in patients with periodontitis exhibiting masticatory dysfunction: A systematic review.
To evaluate the efficacy of tooth splinting (TS) and occlusal adjustment (OA) compared to no TS or OA in patients with periodontitis exhibiting masticatory dysfunction. The primary outcome criterion was tooth loss (TL), and the secondary outcome parameters were change in probing pocket depth (PPD), change in clinical attachment level (CAL), tooth mobility (TM), and patient-reported outcome measures (PROMs). Literature search was performed on three electronic databases (from 01/1965 to 04/2021) and focused on clinical studies with at least 12 months follow-up. From a total of 1515 publications, 51 articles were identified for full-text reading, of which 2 retrospective case series on TS with low risk of bias and 1 randomized and 2 prospective studies on OA with unclear risk of bias were included. For TS, synthesis of data showed that in 72 patients, 26 out of 311 teeth (weighted mean incidence of TL 8.4%) and 156 out of 1541 teeth with no TS (weighted mean incidence of TL 10.1%) were lost over 2 years following non-surgical periodontal therapy. The randomized controlled clinical trial (RCT) indicated CAL gain for teeth with OA compared to no OA. For the effect of OA on TL, PPD, and TM, heterogeneous data were retrieved from the included studies. Within the limitations of this review and based on a low level of evidence, it is concluded that TS does not improve survival of mobile teeth in patients with advanced periodontitis. OA on teeth with mobility and/or premature contacts may lead to improved CAL, while the effect of OA on the remaining periodontal parameters remains unclear.


[Pregnancy and poly-drug use: changes in patient population and care, 1999-2008].
Changes in drug use in the general French population over the last decade have also been observed among pregnant women. There have also been significant changes in the treatment of substance users. Data relating to maternal drug use and the treatment of drug-using mothers were collected based on a retrospective cohort of 170 newborns with mothers using at least two different substances. The decrease in the proportion of heroin-users, the rise of opiate maintenance treatments and cannabis, and the development of new forms of treatment are linked to shorter maternity stays for newborns and shorter treatments for neonatal abstinence syndrome. The percentage of preterm births and of children placed in foster care is also on the decrease. Changes in drug use among mothers and new forms of treatment given to mother-infant dyads may account for the decrease in treatment for NAS, the shorter length of hospital stays, and the decreasing number of children placed in foster care.


Type IV pili: dynamics, biophysics and functional consequences.
The surfaces of many bacteria are decorated with long, exquisitely thin appendages called type IV pili (T4P), dynamic filaments that are rapidly polymerized and depolymerized from a pool of pilin subunits. Cycles of pilus extension, binding and retraction enable T4P to perform a phenomenally diverse array of functions, including twitching motility, DNA uptake and microcolony formation. On the basis of recent developments, a comprehensive understanding is emerging of the molecular architecture of the T4P machinery and the filament it builds, providing mechanistic insights into the assembly and retraction processes. Combined microbiological and biophysical approaches have revealed how T4P dynamics influence self-organization of bacteria, how bacteria respond to external stimuli to regulate T4P activity for directed movement, and the role of T4P retraction in surface sensing. In this Review, we discuss the T4P machine architecture and filament structure and present current molecular models for T4P dynamics, with a particular focus on recent insights into T4P retraction. We also discuss the functional consequences of T4P dynamics, which have important implications for bacterial lifestyle and pathogenesis.


Unique Phenotypes With Corresponding Pathology in Late-Onset Hereditary Transthyretin Amyloidosis of A97S vs. V30M.
Hereditary transthyretin amyloidosis (ATTRv) encompasses different phenotypes among various genotypes. The analysis of the natural history and risk factors of faster progression in different genotypes would refine the treatment strategy. The clinical manifestations of ATTRv from A97S (p.A117S) of Taiwanese and late-onset V30M (p.V50M) of Japanese were compared. An autopsy study of A97S was performed. There existed three unique features in the A97S cohort compared to the V30M cohort: (1) dysphagia, (2) carpal tunnel syndrome (CTS), and (3) onset age. First, dysphagia was common in A97S (53.4%) but not in V30M and served as a contributor to fast disease progression. All phases of swallowing were affected. In the autopsy pathology, there were extensive amyloid deposits in the viscera and nerves of the tongue, larynx, and esophagus. In A97S, 45 patients (43.3%) had a history of CTS before the onset of length-dependent symptoms by 3 years. The amyloid deposition was more prominent in the median nerve than that in the transverse carpal ligament. The onset age at different stages was younger in the A97S cohort than the V30M cohort by 4-5 years. These phenotypic characteristics together with autopsy pathology in A97S are distinct from V30M. Early dysphagia in A97S correlated with fast progression. In A97S, median neuropathy leading to CTS might be in a continuous spectrum of ATTRv course rather than an independent disease entity. Such observations may serve as a foundation to explore and analyze unique phenotypes among various genotypes.


Effects of hypoglycaemia on early embryogenesis in rat embryo organ culture.
As congenital malformations may be caused by perturbations of glycolytic flux on early embryogenesis [16], effects of hypoglycaemia were investigated by using rat embryo organ culture. Nine and one-half day old rat embryos were grown in vitro for 48 h (day 9 1/2 to 11 1/2) in the presence of hypoglycaemic serum for different hours during the culture period. Hypoglycaemic serum was obtained from rats given insulin intraperitoneally. On exposure to hypoglycaemic serum during the first 24 h of culture (day 9 1/2 to 10 1/2), embryos showed marked growth retardation and had increased frequencies of neural lesions (42.7% versus 0%, p less than 0.01), in contrast to hypoglycaemic exposure during the second 24 h of culture (day 10 1/2 to 11 1/2), where only minor growth retardation and low frequencies of neural lesions (2.4% versus 0%, NS) were seen. Even exposure to hypoglycaemic serum for a relatively short period (8 h) during the first 24 h of culture resulted in neural lesions at the frequency of 9.3-13.3%. The embryos exposed to hypoglycaemia demonstrated decreased glucose uptake and lactic acid formation, indicating decreased energy production via glycolysis that constitutes the principal energy pathway at this stage of embryonic development. These results suggest that hypoglycaemia during critical periods of embryogenesis has adverse effects on the development of the embryo and these effects might be mediated through metabolic interruption of embryogenesis.


Relationships between psychosocial factors and abusive parenting attitudes in low-income single mothers.
Linkages among family violence, maternal mental health, and parenting attitudes are not clearly understood. To investigate the relationships of abuse (childhood and/or partner), everyday stressors, self-esteem, depressive symptoms, and anger with abusive parenting attitudes. Cross-sectional analysis of data collected in interviews with 53 low-income, single mothers from wave two of a 3-wave study. A conceptual framework and bivariate correlations guided a series of multiple regressions to identify the best predictors for each variable. A high prevalence of abuse, depressive symptoms, and abusive parenting attitudes was found. Few women had ever received mental health treatment. Abuse (partner and childhood physical) predicted higher everyday stressors which in turn predicted lower self-esteem. Childhood abuse and lower self-esteem predicted more depressive symptoms. More depressive symptoms were related to higher levels of state anger. More everyday stressors and more depressive symptoms predicted higher levels of trait anger. Higher levels of anger expression were associated with higher everyday stressors and lower self-esteem. The presence of partner abuse best predicted higher levels of overall abusive parenting attitudes and more parent-child role reversal. Less parental empathy was associated with higher levels of state anger. This study partially explains the relationships of maternal abuse history and mental health status with parenting attitudes. Other predictors of parenting attitudes remain to be identified. The findings underscore the need for healthcare providers to consider the mental health status and abuse histories of low-income, single mothers. The potential disturbance in the parenting process of single mothers in abusive relationships warrants further investigation.


[Tumor markers--personal experience. The use of tumor markers for cancer of digestive organs].
This review is concerned mainly with our experience in the use of tumor markers for cancer of digestive organs from study of tumor markers by the author over the past 20 years. Development of a radioimmunoassay for highly sensitive detection of alpha-fetoprotein (AFP) by Ishii et al. in 1971 enhanced the usefulness of screening for early hepatocellular carcinoma (HCC) occurring in the course of liver cirrhosis. PIVKA-II, reported as a highly specific tumor marker for HCC, was thought to be less available for detection of early HCC occurring in the course of liver cirrhosis in comparison with AFP. Carcinoembryonic antigen (CEA), a most popular and useful tumor marker for cancer of digestive organs, was frequently positive in sera of colorectal cancer patients who had no subjective complaint or physical sign. This experience supported employment of CEA as a routine screening test for colorectal cancer. A survey of routine examinations of serum CA 19-9 for a period of one month in the clinical laboratory of our hospital proved that 92% of the positive cases of low-level CA 19-9 from 37 U/ml to 75 U/ml were noncancerous. This result indicated that the cut-off value of 37 U/ml employed for serum CA 19-9, which had been evaluated as a specific and highly sensitive tumor marker for pancreatic cancer and bile duct cancer, was too low. Accordingly, it was thought necessary to investigate a change of cut off value and reevaluate CA 19-9 for pancreatic cancer and bile duct cancer in comparison with other tumor markers of carbohydrate antigen such as CA 50, sialyl SSEA-1. From our experience in the use of tumor markers, the combination assays of fetal protein such as AFP, CEA, basic fetoprotein (BFP) and carbohydrate antigen, such as CA 19-9 and CA 50, for routine examination of tumor marker, are recommended for effective screening of cancer of digestive organs.


Mineral content of colostrum and mature milk of lactating Nigerian women as influenced by stage of lactation.
380 milk samples (96 colostrum and 284 mature milk samples) collected from 240 lactating Nigerian women within the first 9 months of lactation were analyzed for zinc, copper, iron, calcium, and magnesium concentrations by atomic absorption spectrophotometry. Mean levels of zinc, copper, iron, calcium, and magnesium in colostrum were 5.83, 0.52, 0.55, 400, and 33 mcg/ml, respectively; the levels for the same minerals in mature milk collected in the 8th and 12th week of lactation were 3.08, 0.29, 0.38, 300, and 31 mcg/ml, respectively. While milk levels of all minerals decreased with increase in lactation age, zinc levels showed the fastest rate of decrease. Milk zinc levels at the 9th month were only 13% of that in colostrum. Similar percentages for copper, iron, calcium, and magnesium were 49, 60, 34, and 74%, respectively. Estimates of intake by solely breastfed infants during the first 6 months showed gross inadequacies when compared with Recommended Daily Allowances. Results suggest the need for early supplementation, especially as zinc deficiencies as well as a high incicdence of iron deficiency anemia has been reported in Nigerian infants.


Integrity and full coding sequence of B19 virus DNA persisting in human synovial tissue.
Primary infection by human parvovirus B19 is often accompanied by arthropathy of varying duration, of which the most severe cases can be indistinguishable from rheumatoid arthritis (RA). While this might seem to imply a role in RA pathogenesis, recent studies have verified long-term persistence of B19 DNA in synovial tissue not only in patients with rheumatoid or juvenile arthritis, but also in immunocompetent, non-arthritic individuals with a history of prior B19 infection. However, the latter data are based on PCR amplification of short segments of DNA, with little sequence information. We determined the nucleotide sequence and examined the integrity of the protein-coding regions of B19 genomes persisting in synovial tissue and compared the results with data from synovial tissues of recently infected patients. In synovium of both previously and recently infected subjects, the viral coding regions were found to be present in an apparently continuous, intact DNA molecule. Comparison with sequences reported from blood or bone marrow showed that the synoviotropism or persistence of the B19 virus DNA was not due to exceptional mutations or particular genotype variants. The synovial retention of full-length viral genomes may represent a physiological process functioning in long-term storage of foreign macromolecules in this tissue.


Immune responses of Leishmania donovani infected BALB/c mice following treatment with free and vesicular sodium stibogluconate formulations.
The anti-parasitic efficacy of free and a non-ionic surfactant vesicular (NIV) sodium stibogluconate (SSG) formulation of the drug, and their effect on the immune responses of Leishmania donovani infected BALB/c mice, was compared. The SSG NIV formulation maintained a significant suppression of splenic, hepatic and bone marrow parasite burdens (P < 0.005) compared to control values throughout the study. Infected controls and drug treated animals had high levels of L. donovani specific antibodies by day 14 of the study and the titre of these antibodies increased throughout the study for infected controls and free SSG treated animals. Initially SSG NIV treated animals had significantly higher specific IgG2a levels (P < 0.01, day 16) compared with infected controls and free SSG treated mice, but by day 31 the levels of this isotype and other antibodies (IgG1, IgG3 and IgM) were significantly lower (P < 0.05) than values for the other two groups. There was no difference in the proliferative responses of spleen cells taken from infected controls and drug treated animals to both specific and non-specific stimulation at day 16 of the study. On day 31, only spleen cells taken from infected mice given SSG NIV displayed a significant proliferative response to parasite antigen preparations and Concanavalin A stimulation (P < 0.01). No IL4 was detected in supernatants from in vitro spleen cells cultures. Significant levels of IFN-gamma was induced by stimulation of cells from vesicular drug treated animals with a frozen parasite preparation compared with medium controls (P < 0.05) on day 49 but not day 16. Similar stimulation did not induce IFN gamma production in spleen cells from infected controls or free drug treated animals. Only SSG NIV treated animals gave a significant positive DTH response to an L. donovani parasite preparation (P < 0.05) given on day 31. The results of this study indicate that there was a formulation dependent qualitative difference in the post-treatment immune responses of L. donovani infected animals, with SSG NIV animals displaying immune responses expected for a cured phenotype.


Multigrasp myoelectric control for a transradial prosthesis.
This paper presents the design and preliminary experimental verification of a multigrasp myoelectric controller. The controller enables the direct and proportional control of a multigrasp transradial prosthesis through a set of nine postures using two surface EMG electrodes. Five healthy subjects utilized the multigrasp controller to manipulate a virtual prosthesis to experimentally quantify the performance of the controller in terms of real time performance metrics. For comparison, the performance of the native hand was also characterized using a dataglove. The average overall transition times for the multigrasp myoelectric controller and the native hand with the dataglove were found to be 1.49 and 0.81 seconds, respectively. The transition rates for both were found to be the same (99.2%).


Accurate theoretical and experimental characterization of optical grating coupler.
Periodic structures, acting as reflectors, filters, and couplers, are a fundamental building block section in many optical devices. In this paper, a three-dimensional simulation of a grating coupler, a well-known periodic structure, is conducted. Guided waves and leakage characteristics of an out-of-plane grating coupler are studied in detail, and its coupling efficiency is examined. Furthermore, a numerical calibration analysis is applied through a commercial software package on the basis of a full-wave finite-element method to calculate the complex propagation constant of the structure and to evaluate the radiation pattern. For experimental evaluation, an optimized grating coupler is fabricated using electron-beam lithography technique and plasma etching. An excellent agreement between simulations and measurements is observed, thereby validating the demonstrated method.


Reversing the amyloid trend: Mechanism of fibril assembly and dissolution of the repeat domain from a human functional amyloid.
Amyloids are traditionally observed in the context of disease. However, there is growing momentum that these structures can serve a beneficial role where the amyloid carries out a specific function. These so called 'functional amyloids' have all the structural hallmarks of disease-associated amyloids, raising the question as to what differentiates a well-behaved benign amyloid from a lethally destructive one. Here, we review our work on the repeat domain (RPT) from Pmel17, an important functional amyloid involved in melanin biosynthesis. Particularly, we focused our attention on the unique reversible aggregation-disaggregation process of RPT that is controlled strictly by solution pH. This pH dependence of RPT amyloid formation functions as a switch to control fibril assembly and maintains the benign nature that is associated with functional amyloids.


Initial experience with retroperitoneal laparoendoscopic single-site surgery for upper urinary tract surgery.
To report our initial clinical experience and perioperative outcomes of retroperitoneal laparoendoscopic single-site surgery (RLESS) for upper urinary tract surgery. Between June 2009 and October 2010, we performed RLESS in 23 patients for various indications including radical nephrectomy (n=4), nephroureterectomy (n=2), simple nephrectomy (n=10), and renal cyst ablation (n=7). RLESS was performed with a homemade single-port device with a conventional rigid laparoscopic instrument and laparoscope. The parameters analyzed were age, body mass index, operative time, estimated blood loss, transfusion, time of oral intake, visual analogue pain scale score (VAPS), length of hospital stay, and complications. One case of simple nephrectomy was converted to open nephrectomy because of severe adhesion and inadequate surgical exposure. RLESS was completed in 23 patients. Mean operative time was 168.7±29.2, 227.5±50.0, 230.0±56.5, and 70.5±8.9 minutes for simple nephrectomy, radical nephrectomy, nephroureterectomy, and renal cyst ablation, respectively. Estimated blood loss was 113.0±149.8, 170.0±156.8, 400.0±141.4, and 22.8±16.0 ml. The time to oral intake after surgery was 1.4±0.5, 1.2±0.5, 1.5±0.7, and 1.1±0.3 days. The mean VAPS score was 1.1±0.2, 2.1±0.5, 2.0±0.5, and 1.0±0.0 of 10 (range, 0.8 to 2.6). The hospital stay was 4.6±1.5, 3.7±0.5, 6.0±1.4, and 3.2±1.7 days. No major perioperative complications were observed. The initial outcomes of our experience suggest that RLESS is a technically feasible and safe procedure for upper urinary tract surgery. Prospective comparative studies with conventional retroperitoneal laparoscopic surgery are needed to confirm the potential benefits of RLESS.


Hand hygiene and face mask wearing practices for COVID-19 prevention: a non-intrusive observation of patrons of community convenience shops in Accra, Ghana.
in the absence of a vaccine and definitive treatment, non-pharmacological measures of physical distancing, regular hand hygiene and wearing of face covering remain the mainstays of mitigating coronavirus disease 2019 (COVID-19). In Ghana, these measures are mandatory in public places and underpin COVID-19 infection prevention and control (IPC). We assessed adherence and appropriate performance of these measures among patrons of community convenience shops in selected hotspots. we conducted a non-intrusive observation of patrons of convenience shops in COVID-19 burden hotspots. We observed patrons as they entered and exited the shops and collected data on their gender, adherence and appropriate use of face covering and hand hygiene facilities. Data were analyzed descriptively and inferentially to determine factors associated with adherence to IPC guidelines. of 800 patrons observed from eight community shops, 481 (60.1%) were males. Of these, 653 (81.6%) wore face covering and 98 (12.3%) performed hand hygiene; with 92 (11.5%) adhering to both measures. Patrons who wore face mask appropriately were 578; comprising 299 (92.3%) of patrons who wore face mask before entering the shops. Of 89 patrons who washed their hands, appropriate handwashing was recorded among nine (10.1%). Compared to inappropriate handwashing, appropriate handwashing was negatively associated with adherence to IPC guidelines [aOR=0.1 (95% CI=0.01-0.59)]. adherence to and appropriate performance of IPC measures of handwashing and use of face covering in the selected shops was low. There is the need to complement availability of IPC measures with intensification of risk communication messaging targeted at ensuring their appropriate use.


Use of intra-arterial multi-detector row CT angiography for the evaluation of an ischaemic limb in a patient with renal impairment.
The vastly improved scanning speed and z-axis resolution afforded by multi-detector technology has allowed CT to refine its traditional roles and to explore many new applications in imaging. We present a case report of a patient with renal failure and an ischaemic leg, which illustrates a useful new CT vascular imaging application. By carrying out 16-channel multi-detector row CT angiography through a sheath introduced into the common femoral artery, we obtained a high-quality angiographic image of the affected leg, using only 30 mL of iodinated contrast material. The examination definitively showed the number, distribution and patency of the tibial run-off arteries, with significant influence on the patient's subsequent clinical management. This simple and relatively minimally invasive technique is useful in peripheral vascular imaging, when conventional CT angiography using a large volume of i.v. contrast and MR angiography are unsuitable or unavailable.


Microwhip scorpions (Palpigradi) feed on heterotrophic cyanobacteria in Slovak caves--a curiosity among Arachnida.
To date, only morphological and anatomical descriptions of microwhip scorpions (Arachnida: Palpigradi) have been published. This very rare group is enigmatic not only in its relationships to other arachnids, but especially due to the fact that these animals dwell only underground (in caves, soil, and interstitial spaces). We observed the curious feeding habit of the microwhip scorpion Eukoenenia spelaea over the course of one year in Ardovská Cave, located in Slovakia's Karst region. We chose histology as our methodology in studying 17 specimens and based it upon Masson's triple staining, fluorescent light and confocal microscopy. Single-celled cyanobacteria (blue-green algae) were conspicuously predominant in the gut of all studied palpigrades. Digestibility of the consumed cyanobacteria was supported by the presence of guanine crystals, glycogen deposits and haemocytes inside the palpigrade body. Cyanobacteria, the oldest cellular organisms on Earth, are very resistant to severe conditions in caves, including even darkness. Therefore, the cyanobacteria are able to survive in dark caves as nearly heterotrophic organisms and are consumed by cave palpigrades. Such feeding habit is extraordinary within the almost wholly predacious orders of the class Arachnida, and particularly so due to the type of food observed.


Postpartum smoking abstinence and smoke-free environments.
The purpose of this exploratory study was to describe factors that contribute to successful postpartum smoking abstinence among women who quit smoking during pregnancy. Research questions addressed the primary motivators and lifestyle characteristics of women who do not return to postpartum smoking. Participants were recruited from a feasibility study (N = 16) based on their ability to remain smoke free for at least 6 months following delivery. Individual interviews were analyzed using content analysis strategies. Women's narratives described the process of postpartum smoking abstinence. Four themes emerged: (a) child's health as the primary motivator, (b) demanding a smoke-free home or environment, (c) smoking perception changes from one of primarily comfort to one of disgust, and (d) viewing abstinence as a lifelong change. Clinical implications include educating families about the effects of smoke-free environments on the health of their children while redirecting smoking habits with healthy behaviors.


[Cerebrovascular reserve capacity].
Cerebrovascular reserve capacity (CVR) describes how far cerebral perfusion can increase from a baseline value after stimulation. Measurement of cerebral blood flow (CBF) can be done by PET or SPECT. Noninvasive and easily performed transcranial Doppler sonography (TCD) is mostly used as indirect perfusion measurement. Stimulation of cerebral perfusion is often done by CO2 inhalation or acetazolamide injection. Alternative stimuli are breath holding or cerebral activation by hand-gripping. Normal values for these tests are presented. The hemodynamic effect of stenoses of the internal carotid artery (ICA) can be estimated using CVR. The relevance of CVR is discussed controversially, since cerebral infarction due to stenosis of arteries supplying the brain is probably mostly of embolic, not hemodynamic origin. The indication for carotid artery surgery according the NASCET and ECST investigations takes into account only the degree of the stenoses and not the CVR. According to recent studies, the risk of cerebral infarction in these patients is considerably higher with reduced CVR. Therefore, CVR can be used as an additional parameter if the indication for surgery is not defined, especially in asymptomatic carotid artery stenosis. It seems also possible to identify patients who might profit from an extra-intracranial bypass operation and high-risk patients for cerebral ischemia with cerebral microangiopathy. Furthermore, the risk of cerebral infarction during carotid artery surgery and also during heart surgery can be estimated using CVR. More studies with a higher number of patients are needed to confirm the potential predictive diagnostic value of CVR in order to establish CVR measurement as part of a routine diagnostic neuroangiologic program.


Food allergy in children: diagnosis and treatment with sodium cromoglycate.
Food allergy (FA) is a very important problem affecting numbers of infants and children with protean manifestations which are frequent challenges to the pediatrician and other specialists working with children. Adverse reactions to food are very complex, frequently mediated bu IgE mechanisms, and often by other mechanisms. To make the correct diagnosis and to arrive at a proper therapeutic approach requires all the skill a physician can gather. Only an extensive knowledge of the various mechanisms and pharmacologic agents that can be used to prevent or treat these adverse reactions will allow the physician to approach the problem scientifically and come to a reasonable solution for the patient. The role of dietary factors in atopic dermatitis (AD) has long been a subject of controversies. However, it has been shown that FA plays a role in some children with AD. Therefore, the management of this multifaceted disorder is a challenge for pediatricians, dermatologists, and allergists. SCG, which is the salt of a bis-chromone carboxylic acid, has been shown to be of proven efficacy in the prophylaxis of bronchial asthma, allergic rhinitis, and of other disorders associated with mast cell degranulation. The drug has different modes of action, such as inhibition of rat passive cutaneous anaphylaxis, and the antigen-induced histamine release from passively sensitized peritoneal cells. Recently, clinical studies indicated that SCG has a direct effect on inflammatory cells, inhibiting either various leukocyte functions (membrane receptor expression, cytotoxic capacity), or "in vitro" activation of human neutrophils, eosinophils and monocytes. Although SCG has been widely used for the management of respiratory allergy, conflicting results of FA treatment have been reported by several authors. We have reviewed 18 papers on the use of SCG in the management of children with FA, which included 341 children aged 0.5-15 years. In this paper we discuss 12 studies reporting 281 children affected with AD.


Outcomes of High Risk Patients with Febrile Neutropenia at a Tertiary Care Center
Fever during chemotherapy-induced neutropenia continues to be a major cause of morbidity and mortality in cancer patients. Mortality depends on the duration and degree of neutropenia, bacteremia, sepsis, performance status, comorbidities and other parameters. The highest mortality rates in cancer patients hospitalized with febrile neutropenia (FN) are observed in those with documented infection. The objectives of the study were to present available tools for risk assessment, to review pathogens causing infections in adult FN patients and to assess outcomes. Methods: This cross sectional study was conducted on adult culture positive FN patients admitted to the Hematology/Oncology service at the Aga Khan University Hospital, Karachi, Pakistan from 1st January 2009 to 31st December 2012. Highrisk criteria were defined as profound neutropenia, short latency from a previous chemotherapy cycle, sepsis or clinically documented infection at presentation, severe co-morbidity and a performance status greater than or equal to 3. All types of organisms in blood culture and the outcomes of the patients were recorded on Proforma. Results: A total of 156 patients with culture-positive febrile neutropenia were identified during the study period. The mean age was 47 years with a slight male predominance of 54%. One hundred and sixteen patients fulfilled the criteria for the high risk group. Fifty two percent had a single high risk factor and 40 % had two. All patients harbored either single or multiple bacterial organisms including gram positive, gram negative or both types. Some 34% of patients had gram positive bacteremia, 57 % had gram negative and 9 % were infected with both. Among 73 gram positive cultures 44 % were Staphylococcus species and among 123 gram negative cultures 43 % were E. coli. One hundred and fifteen patients recovered uneventfully and could be discharged. Thirty two patients in the high risk and 9 in the low risk groups deceased with an overall mortality of 26 %. The mean hospital stays of patients with solid tumors and hematological malignancies were 7.58 and 15.0 days, respectively. Mortality was higher in the latter group, and also in high risk patients with both gram positive and negative bacteremia. Conclusion: We emphasize the importance of risk stratification and continuous surveillance of the spectrum of locally prevalent pathogens and their susceptibility patterns for formulation of therapeutic regimens for febrile neutropenic patients.


Rescue of the p53 tumor suppressor by a rationally designed molecule.
Extract: The tumor suppressor protein p53 is crucial in preventing cancer as well as for achieving the therapeutic effects of both radiotherapy and much of chemotherapy. p53 responds to oncogene activation, DNA damage, hypoxia and other stresses by activating the expression of factors that trigger cell cycle arrest or programmed cell death. Strong evidence that inactivation of p53 is required for cancer cell survival comes from accumulated data that p53 is inactivated by mutations in some 50% of all human tumors, regardless of patient age or tumor type. This makes p53 the most frequently mutated gene in cancer, with more than 18,000 mutations reported so far. Most of the mutations result in a substitution of just one amino acid residue in the core DNA binding domain of p53, which frequently causes the protein to "melt" or denature at body temperature, and thus abolishes its function. Given the high potency of p53 in the induction of cell death, it is expected that small molecules that can refold p53 and rescue its function will efficiently and selectively kill tumor cells, thus providing a powerful new way to combat cancer. Notably, the accumulation of high levels of mutant p53 in tumor cells allows for a selective targeting of tumors.


Topographic specificity of Diplozoon paradoxum nordmann, 1832 (Monogenea: Diplozoidae) in the bream, Abramis brama (Linnaeus, 1758) in the Vistula Lagoon, Poland.
Location of the monogenean Diplozoon paradoxum on the branchial arches of the Vistula Lagoon bream is described. The highest number of parasites was found on the first gill arch, followed by the numbers recordedon the second and third arches; the lowest numbers of the monogenean were typical of the fourtharch. About 70% of the monogeneas were found to dwell on the dorsal part of the branchial arch. It is concluded that the distribution of parasites is controlled by the direction of water flow through the gills as well as the size of the gill arch occupied by the helminths.


Risk factors for vaginal fistula symptoms in Sub-Saharan Africa: a pooled analysis of national household survey data.
Vaginal fistula (VF) is one of the most severe maternal morbidities with the immediate consequence of chronic urinary and/or fecal incontinence. The epidemiological evidence regarding risk factors for VF is dominated by facility-based studies. Our aim is to estimate the effect size of selected risk factors for VF using population-based survey data. We pooled all available Demographic and Health Surveys and Multiple Indicators Cluster Surveys carried out in sub-Saharan Africa that collected information on VF symptoms. Bayesian matched logistic regression models that accounted for the imperfect sensitivity and specificity of self-reports of VF symptoms were used for effect size estimation. Up to 27 surveys were pooled, including responses from 332,889 women. Being able to read decreased the odds of VF by 13% (95% Credible Intervals (CrI): 1% to 23%), while higher odds of VF symptoms were observed for women of short stature (<150 cm) (Odds Ratio (OR) = 1.31; 95% CrI: 1.02-1.68), those that had experienced intimate partner sexual violence (OR = 2.13; 95% CrI: 1.60-2.86), those that reported sexual debut before the age of 14 (OR = 1.41; 95% CrI: 1.16-1.71), and those that reported a first birth before the age of 14 (OR = 1.39; 95% CrI: 1.04-1.82). The effect of post-primary education, female genital mutilation, and having problems obtaining permission to seek health care were not statistically significant. Increasing literacy, delaying age at first sex/birth, and preventing sexual violence could contribute to the elimination of obstetric fistula. Concomitant improvements in access to quality sexual and reproductive healthcare are, however, required to end fistula in sub-Saharan Africa.


Occurrence of fumonisins in Catalonia (Spain) and an exposure assessment of specific population groups.
Fumonisin B₁ (FB₁) and B₂ (FB₂) are mycotoxins produced by Fusarium verticillioides and F. proliferatum and common contaminants of cereal crops. The objectives of this study were to (1) study the occurrence of fumonisins in Catalonia (north-eastern region of Spain) and (2) assess the exposure of the Catalonian population to these mycotoxins. Contamination data was provided by a wide survey where 928 individual samples were pooled to analyse 370 composite samples. Fumonisins were extracted and purified using immunoaffinity columns and determined by HPLC with fluorescence detection. The raw consumption data came from a nutritional study specifically designed to assess the dietary intake of the main foodstuffs related to fumonisin contamination for all population age groups. In addition, two specific groups were selected with respect to maize consumption: immigrants and celiac sufferers. Contamination and consumption data were combined by simulation using an essentially parametric-parametric (P-P) method. The P-P method draws sampling values from distribution functions fitted to consumption and contamination datasets. Moreover, to quantify the accuracy and reliability of the statistical estimates, we built related confidence intervals using a Pseudo-Parametric bootstrap method. The results of this study show that fumonisins are commonly found in some commodities on the Catalonian market, such as beer, corn snacks and ethnic foods; however, the values were well below the permitted maximum EU levels. The most exposed group were infants followed by immigrants but, in all cases, they were below the TDI of 2 µg/kg bw/day.


Chemical properties and anti-complementary activities of heteroglycans from the leaves of Panax ginseng.
Four anti-complementary neutral (GL-NIa and GL-NIb) and acidic (GL-AIa and GL-AIb) polysaccharides were purified from the leaves of Panax ginseng C. A. Meyer. Only GL-NIa and GL-AIa exhibited potent anti-complementary activities at low concentrations probably through the alternative complement pathway. Glycosyl linkage analysis demonstrated that GL-NIa mainly consisted of arabinogalactan moieties, whereas GL-NIb contained large amounts of (1----4)-linked glucosyl residues. Beta-Elimination indicated that GL-AIa and GL-AIb were pectic polysaccharides consisting of a rhamnogalacturonan core with neutral side chains. GL-AIa reacted strongly with beta-glucosyl-Yariv antigen, GL-NIa reacted weakly, whereas GL-NIb and GL-AIb showed no reaction with the antigen.


A study on nesidioblastosis in hyperinsulinemic hypoglycemia--diagnosis, treatment, and neurologic sequelae.
The medical records of six cases of nesidioblastosis were examined to determine the diagnostic approach, treatment, and neurologic sequelae. All six patients were male, and their ages at the onset of the disease ranged from one day to six months (mean 3.36 +/- 2.5 mo.). Initial clinical features were seizure, cyanosis, poor feeding, and apnea. Other subsequent symptoms were developmental delay, hyperactivity, and cold sweating. The Birth weight of the neonatal onset group was heavier than the postneonatal onset group (4.4 +/- 0.3 vs 3.26 +/- 0.04 kg). Before the diagnosis of hyperinsulinism, steroids of ACTH proved effective for seizure control. Initially, hyperinsulinemia (serum insulin greater than 10 microU/ml) was detected in four cases, but another two cases also showed hyperinsulinism by insulin/glucose(I/G) ratio greater than 0.3 during the fasting test. The glucagon response performed in 2 cases, showed normal and partial responses. Euglycemia was obtained by near total pancreatectomy (95% pancreatic resection)without malabsorption or persistent diabetes. In one case, nesidioblastoma coexisted with nesidioblastosis. Developmental delay was noted in three cases. In this group, the mean duration between symptom onset and operation was longer than the group without developmental delay (1.25 +/- 0.47 vs 0.38 +/- 0.19 yr).


Cell-cycle-dependent, differential prenylation of proteins.
Isoprenylated proteins related to cell growth have been detected during proliferation. Since cholesterogenesis (isoprenoid synthesis) is mandatory for cell proliferation, the observation of a temporally coordinated protein prenylation during the cell division cycle might constitute obligatory processes in the signalling pathway for initiating DNA replication and/or in maintaining the growing state. We have found such a definitive cell-cycle-phase-dependent pattern of prenylation for various classes of cytosolic and nuclear matrix proteins in synchronized HepG2 cells. Characteristic [3H]mevalonate incorporation began to increase during mid-to-late G1, just after cholesterol synthesis reached its apex, and peaked just prior to or coincident with mid S. Incorporation then declined subsequent to S (during G2) as cells approached mitosis. Prior to the rise in mevalonate incorporation into proteins, during early-to-mid G1, steady-state [14C]acetate incorporation into chromatographically resolved cholesterogenic lipid intermediates displayed a maximum only into cholesterol. However, during the late-G1/S interval, a singular peak of 14C incorporation was found for the farnesyl moiety (farnesol/nerolidol plus farnesyl diphosphate). Except for the farnesyl moiety, none of the other polyisoprenoids detected by our procedures showed any fluctuation in 14C incorporation subsequent to mid G1. These results support the proposal that subsequent to peak cholesterol synthesis in early-to-mid G1, the generation of a cholesterol-pathway-dependent set of post-translationally modified, polyisoprenylated proteins could constitute an obligatory step leading to the duplication of the cellular genome, thereby impelling transit through the cell cycle. The well known high flux through cholesterogenesis in tumors, which manifests an intrinsic lack of sensitivity to feedback inhibition and operates continuously, is consonant with this proposal.


Autoimmunity in neuromuscular disease.
A number of confounding factors can be identified from the search for autoimmune mechanisms over the last 2 decades that may be relevant for future studies. (1) An apparently homogeneous clinical disorder may represent more than one disease process and thereby imply antibody/antigen heterogeneity as, for example, in MG with and without detectable anti-AChR antibodies. In some cases, physiologic studies allow the different forms of the disease to be distinguished as in AIDP and acute inflammatory axonal polyneuropathy. (2) A homogeneous disorder (e.g., LEMS) may have at least two different triggering mechanisms (SCLC and an unknown stimulus). (3) Antigen density may be too low to be detected by the immunohistologic techniques available, as initially occurred in MG and LEMS. (4) Autoantibodies may be detected that are irrelevant to the primary disease, such as anti-striated muscle antibodies in MG. (5) Poor antibody cross-reactivity between species may mean that the pathogenic antibody is undetected in binding assays or in experimental passive transfer studies. For example, anti-AChR antibody in MG shows less than 5% reactivity with Torpedo AChR. (6) A poor regenerative capacity of the target antigen may mean that reduction of circulating autoantibodies by either plasma exchange or ISD treatment is not associated with detectable clinical improvement, as may be the case in SSN in which DRG cells appear to be the target. TABLE 5 summarizes the extent to which the data reviewed have established a role for pathogenic antibodies in the light of the postulates for autoimmunity set out earlier and ranks the disorders accordingly. Only in MG with detectable anti-AChR antibody are all the postulates met, including definition of the antigen, experimental passive transfer by the IgG fraction of MG sera, active immunization of experimental animals, and propagation. In both LEMS and the IgM kappa anti-MAG demyelinating neuropathy the antigen is known, although better characterized in LEMS; the epitopes are not yet defined in either. Data relating to passive transfer are more extensive in LEMS, however; systemic passive transfer of anti-MAG has not yet been reported. In neither condition is an animal model available. In the demyelinating neuropathies, the case for autoimmunity is less complete. Neither in AIDP nor in CIDP is the antigen known, and thus the relevance of the different EAN disorders is uncertain. Current evidence thus rests on the demonstration of serum IgM antibodies that react with peripheral nerve myelin and fix complement and on the intraneural passive transfer studies.(ABSTRACT TRUNCATED AT 400 WORDS)


Recent Trends in Infant Car Seat Tolerance Screening Failure Within a Large Health Care System, 2014-2018.
To describe temporal trends in car seat tolerance screening (CSTS) failure within a large hospital system (2014-2018). We conducted a retrospective cohort study using electronic medical record data for infants who underwent a CSTS. Our primary outcome measure was the CSTS failure rate. Covariates included year, CSTS location (well nursery or NICU), gestational age (GA), race, sex, birth weight, CSTS date, and age at CSTS. Associations of covariates with CSTS failure were examined by using χ2 tests, t tests, analysis of variance, and Wilcoxon rank tests. Multivariable logistic regression was used to determine the adjusted odds of CSTS failure. Of 4849 infants tested, the failure rate was 8.1% (n = 394). Most CSTS occurred in the well nursery (79.5%) and involved late preterm (55.2%) or term infants (23.7%). In bivariate analyses, year, unit location, higher birth weight, younger chronological age at testing, and higher GA were positively associated with CSTS failure (P < .05). After stratification by CSTS location, the CSTS failure rate rose in the well nursery but remained stable in the NICU, and use of screening rose among term infants. In the adjusted model, year, GA, and corrected gestational age at CSTS were associated with failure. Each subsequent year was associated with a 19% increase in odds of CSTS failure (P < .001). We found a higher rate of CSTS failure in the well nursery compared with the NICU, and the difference in failure rates increased over time. Improved understanding of infants at the highest risk of CSTS failure could impact routine screening guidelines.


Thermoluminescence dosimetric properties of a new thin beta detector (LiF:Mg, Cu, P; GR-200F) in comparison with highly sensitive Al2O3:C beta dosimeters.
There is an increasing need for efficient beta detectors to fulfil ICRU recommendations for new quantities especially in the field of medical physics and retrospective dosimetry. The thermoluminescence properties of thin LiF:Mg, Cu, P (GR-200F) tapes produced in 1998 by Sange Company, People's Republic of China, are investigated and compared with those of highly sensitive thin Al2O3:C beta detectors as regards their applicability in the detection of low energy photons and beta particles. The radiation dose response, minimum detectable dose, reproducibility of measurements and effect of residual signal at low dose are assessed for the possible low level beta dosimetry use. The radiation dose response and photon and beta detection efficiencies are tested underpractical laboratory conditions. The effects of indoor fluorescent light and residual signal after the first read-out are investigated with a view to optimising handling conditions such as post-irradiation and pre-heating treatments for routine dosimetry. The photon energy responses of the detectors are investigated using 150 keV filtered x-rays and 60Co gamma-rays.


Surface plasmon polaritons in thin-film Weyl semimetals.
We theoretically investigate surface plasmon polaritons propagating in the thin-film Weyl semimetals. We show how the properties of surface plasmon polaritons are affected by hybridization between plasmons localized at the two metal-dielectric interfaces. Generally, this hybridization results in new mixed plasmon modes, which are called short-range surface plasmons and long-range surface plasmons, respectively. We calculate dispersion curves of these mixed modes for three principle configurations of the axion vector describing axial anomaly in Weyl semimetals. We show that the partial lack of the dispersion and the non-reciprocity can be controlled by fine-tuning of the thickness of the Weyl semimetals, the dielectric constants of the outer insulators, and the direction of the axion vector.


Comparative Analysis of Colon Cancer-Derived Fusobacterium nucleatum Subspecies: Inflammation and Colon Tumorigenesis in Murine Models.
Fusobacteria are commonly associated with human colorectal cancer (CRC), but investigations are hampered by the absence of a stably colonized murine model. Further, Fusobacterium nucleatum subspecies isolated from human CRC have not been investigated. While F. nucleatum subspecies are commonly associated with CRC, their ability to induce tumorigenesis and contributions to human CRC pathogenesis are uncertain. We sought to establish a stably colonized murine model and to understand the inflammatory potential and virulence genes of human CRC F. nucleatum, representing the 4 subspecies, animalis, nucleatum, polymorphum, and vincentii. Five human CRC-derived and two non-CRC derived F. nucleatum strains were tested for colonization, tumorigenesis, and cytokine induction in specific-pathogen-free (SPF) and/or germfree (GF) wild-type and ApcMin/+ mice, as well as in vitro assays and whole-genome sequencing (WGS). SPF wild-type and ApcMin/+ mice did not achieve stable colonization with F. nucleatum, whereas certain subspecies stably colonized some GF mice but without inducing colon tumorigenesis. F. nucleatum subspecies did not form in vivo biofilms or associate with the mucosa in mice. In vivo inflammation was inconsistent across subspecies, whereas F. nucleatum induced greater cytokine responses in a human colorectal cell line, HCT116. While F. nucleatum subspecies displayed genomic variability, no distinct virulence genes associated with human CRC strains were identified that could reliably distinguish these strains from non-CRC clinical isolates. We hypothesize that the lack of F. nucleatum-induced tumorigenesis in our model reflects differences in human and murine biology and/or a synergistic role for F. nucleatum in concert with other bacteria to promote carcinogenesis. IMPORTANCE Colon cancer is a leading cause of cancer morbidity and mortality, and it is hypothesized that dysbiosis in the gut microbiota contributes to colon tumorigenesis. Fusobacterium nucleatum, a member of the oropharyngeal microbiome, is enriched in a subset of human colon tumors. However, it is unclear whether this genetically varied species directly promotes tumor formation, modulates mucosal immune responses, or merely colonizes the tumor microenvironment. Mechanistic studies to address these questions have been stymied by the lack of an animal model that does not rely on daily orogastric gavage. Using multiple murine models, in vitro assays with a human colon cancer cell line, and whole-genome sequencing analysis, we investigated the proinflammatory and tumorigenic potential of several F. nucleatum clinical isolates. The significance of this research is development of a stable colonization model of F. nucleatum that does not require daily oral gavages in which we demonstrate that a diverse library of clinical isolates do not promote tumorigenesis.


Q-PINE: A quick to implant peripheral intraneural electrode.
Objective. The implantation of intraneural electrodes in amputees has been observed to be effective in providing subjects with sensory feedback. However, this implantation is challenging and time consuming. Surgeons must be especially trained to execute the implantation. Therefore, we aimed at developing a novel peripheral intraneural electrode and insertion mechanism, which could drastically reduce the overall implantation time while achieving a high neural selectivity.Approach.A new insertion method based on hollow microneedles was developed to realize the prompt and effective simultaneous implantation of up to 14 active sites in a transversal manner. Each needle guided two Pt/Ir microwires through the nervous tissue. After the insertion, the microneedles were released, leaving behind the microwires. Each microwire had one active site, which was coated with poly-3,4-ethylenedioxythiophene (PEDOT) to enhance the electrochemical properties. The active sites were characterized by evaluating the impedance, charge storage capacity, and maximum injectable charge. Twelve quick to implant peripheral intraneural electrodes (Q-PINEs) were implanted in four pig sciatic nerves to evaluate the implantation time and neural selectivity. We compared the stimulation of the sciatic nerve with that of its branches.Main results. The average surgical access time was 23 min. The insertion time for 12 electrodes was 6.7 min (std. ±1.6 min). The overall implantation time was reduced by 40.3 min compared to the previously reported values. The Q-PINE system demonstrated a satisfactory performance duringin vitroandin vivocharacterization. The electrochemical results showed that the PEDOT coating successfully increased the electrochemical parameters of the active sites.Significance.With an average impedance of 1.7 kΩ, a maximum charge level of 76.2 nC could be achieved per active site. EMG recruitment curves showed that 46% of the active sites exhibited selective stimulation of four out of six muscles. The histological analysis indicated that the microwires successfully penetrated the nerve and single fascicles.


Dental care demand: age-specific estimates for the population 65 years of age and over.
This paper derives estimates of the demand for dental care among the U.S. population 65 years of age and over. The analysis is unique in that it focuses on a segment of the population with particular relevance to future policy regarding dental insurance coverage and distinguishes determinants of dental care demand by type of service. The empirical estimates suggest that the use of dental service by elderly persons does respond to price changes and that price-elasticity of demand varies significantly among different dental procedures.


In vivo proximity labeling for the detection of protein-protein and protein-RNA interactions.
Accurate and sensitive detection of protein-protein and protein-RNA interactions is key to understanding their biological functions. Traditional methods to identify these interactions require cell lysis and biochemical manipulations that exclude cellular compartments that cannot be solubilized under mild conditions. Here, we introduce an in vivo proximity labeling (IPL) technology that employs an affinity tag combined with a photoactivatable probe to label polypeptides and RNAs in the vicinity of a protein of interest in vivo. Using quantitative mass spectrometry and deep sequencing, we show that IPL correctly identifies known protein-protein and protein-RNA interactions in the nucleus of mammalian cells. Thus, IPL provides additional temporal and spatial information for the characterization of biological interactions in vivo.


The role of nitric oxide in experimental allergic conjunctivitis.
To evaluate the role of nitric oxide (NO) in the pathogenesis of allergic conjunctivitis and the effect of NO-synthase (NOS) inhibitors. The experimental allergic conjunctivitis was provoked in rabbits and healthy human volunteers by mast cell activators (codeine phosphate, 2.5 mg/mL; compound 48/80, 50 mg/mL; and lipopolysaccharide, 10 ng/eye). NOS inhibitors (aminoguanidine [AG], 1.5%, or N(G)-nitro-L-arginine methyl ester [L-NAME], 200 microg/eye) were applied as a pretreatment. In a rabbit model, concentrations of nitrite plus nitrate in the tear were measured colorimetrically using the Griess reaction after 0.5, 1.5, 3, 6, and 9 h. Immunohistochemical study for NOS was performed. The clinical scoring was performed in human volunteers. The vascular permeability was determined by measuring the albumin content in the tear of the challenged human eyes after 1 h. After the instillation of mast cell activator, the NO level and clinical symptoms were markedly increased within 1.5 h. The NOS inhibitors suppressed the NO level. Vascular permeability was also increased in the activator-treated group. The NO-synthase immunoreactivity has been detected in the conjunctival subepithelial area and stroma for brain and endothelial isoform. L-NAME significantly reduces the immunoreactivity for NOS. These results suggest that the expression of NOS mainly contributes to the allergic symptoms. Therefore, NO is an important factor in the induction and progress of the allergic reaction to ocular surface. The NOS inhibitors may have a beneficial effect for allergic conjunctivitis.


Effects of early discharge planning on length of hospital stay.
This experimental research tests the effect of discharge planning on length of hospital stay. In this study of 432 medical patients in a southwestern medical center, discharge planning implemented within 24 hours of hospital admission significantly reduced length of stay. Projected savings to the institution far exceed the cost of implementation.


Prevention of urinary tract infection in patients with spinal cord injury.
Urinary tract infection (UTI) is a major cause of morbidity and mortality in individuals with spinal cord injury (SCI). Altered voiding dynamics, use of urinary drainage catheters, and frequent exposure to antibiotic agents predispose individuals with SCI to recurrent episodes of UTI, often with resistant organisms. To evaluate the efficacy of various methods of UTI prevention in the SCI population. These methods include type of bladder management, choice of catheter materials, antiseptic agents, oral antibiotics, and experimental approaches. Literature review. Choosing a method of bladder management that minimizes the use of a foreign body, yet drains the bladder effectively, is the best available means to reduce the risk of UTI. The chief drawback to antimicrobial-coated catheters, topical or intravesicular antiseptic agents, and prophylactic oral antibiotics is that, over time, bacteria become resistant and overcome the obstacles to bladder invasion. Therefore, antiinfective catheter materials, antibiotics, and antiseptic agents are not beneficial for long-term prevention of UTI in persons with SCI. Novel approaches that avoid the use of antimicrobial agents offer hope for patients with recurrent UTI, but these techniques are still in the experimental stage. Method of bladder management remains the most influential factor in reducing the risk of UTI in persons with SCI. Experimental approaches that inhibit adhesion and biofilm formation by uropathogens are promising.


Left Ventricular Reverse Remodeling in Cardiac Resynchronization Therapy and Long-Term Outcomes.
The aim of this study was to evaluate the association between improvement in left ventricular end-systolic volume (LVESV) with cardiac resynchronization therapy (CRT) and mortality and whether this relationship was modified by the presence of a left bundle branch block (LBBB) electrocardiographic pattern. Left ventricular reverse remodeling in patients receiving CRT has been shown to predict outcomes. However, the extent to which reverse remodeling contributes to long-term survival is not well understood. Changes in LVESV were assessed in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) patients receiving CRT with a defibrillator (CRT-D) and echocardiograms available at 1 year (n = 752), stratified by LBBB, relative to long-term all-cause mortality, compared with those with implantable cardioverter-defibrillators (ICDs) only (n = 684). In patients with LBBB, a reduction in LVESV of >35% (median) translated into significantly lower risk for long-term mortality (hazard ratio [HR]: 0.34; p < 0.001), heart failure (HF) events (HR: 0.21; p < 0.001), and HF or death (HR: 0.27; p < 0.001) compared with patients with ICDs only. Patients with reductions in LVESV ≤35% had a significantly lower risk for HF, and HF or death, and a nonsignificantly lower rate of death compared with those with ICDs only (HR: 0.74; p = 0.13). Risk reduction in HF events was uniform across all LVESV quartiles. In patients without LBBB, there was no survival benefit (HR: 0.68; p = 0.271) despite an LVESV reduction greater than the median (>27.6%). CRT-D patients without LBBB with the least reverse remodeling (quartile 1) had a more than 3-fold increased risk for death compared with those with ICDs only (HR: 3.11; p < 0.001). In patients with LBBB, CRT-D-induced reduction in LVESV at 1 year is associated with long-term survival benefit. Despite left ventricular reverse remodeling with CRT-D, there is no survival benefit and potential harm in patients without LBBB.


The Clinical and Molecular Epidemiology of Noncarbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae: A Case-Case-Control Matched Analysis.
Risk factors and outcomes associated with carbapenem-resistant Enterobacteriaceae (CRE) acquisitions are derived primarily from cohorts consisting of carbapenemase-producing (CP) strains. Worldwide epidemiology of non-CP-CRE is evolving, but controlled epidemiological analyses are lacking. A matched case-case-control investigation was conducted at Shamir (Assaf Harofeh) Medical Center, Israel, on November 2014-December 2016. Noncarbapenemase-producing CRE (as defined by the US Clinical and Laboratory Standards Institute Standards) carriers were matched to patients with non-CRE Enterobacterales and to uninfected controls (1:1:1 ratio). Matched and nonmatched multivariable regression models were constructed to analyze predictors for acquisition and the independent impact of carriage on multiple outcomes, respectively. Representative isolates were whole genome sequenced and analyzed for resistome and phylogeny. Noncarbapenemase-producing CRE carriers (n = 109) were matched to the 2 comparative groups (overall n = 327). Recent exposure to antibiotics (but not specifically to carbapenems), prior intensive care unit admission, and chronic skin ulcers were all independent predictors for non-CP-CRE acquisition. Acquisitions were almost exclusively associated with asymptomatic carriage (n = 104), and despite strong associations per univariable analyses, none were independently associated with worse outcomes. Genomic analyses of 13 representative isolates revealed polyclonality, confirmed the absence of carbapenemases, but confirmed the coexistence of multiple other genes contributing to carbapenem-resistance phenotype (multiple beta-lactamases and efflux pumps). Noncarbapenemase-producing CRE acquisitions are primarily associated with asymptomatic carriage, specifically among prone populations with extensive recent exposures to antibiotics. The prevalent mode of acquisition is "emergence of resistance" (not "patient-to-patient transmission"), and therefore the role of stewardship interventions in reducing the spread of these therapeutically challenging pathogens should be further explored.


Bortezomib plus thalidomide for newly diagnosed multiple myeloma in China.
The aim of this Phase II study was to determine the efficacy and safety of combined bortezomib and thalidomide (VT) regime as initial treatment for newly diagnosed patients with multiple myeloma (MM) in China. Thirty-four patients have been enrolled in this study and were planned to receive VT regime up to eight 21-day cycles. Bortezomib (1.3 mg/m(2) ) was given intravenously on days 1, 4, 8, and 11, while oral thalidomide (100 mg/day) was given on days 1 to 21. The primary end point was clinical response; the secondary end point was safety. Among 34 patients enrolled, 26 patients were able to complete the planned eight cycles of therapy. After eight cycles, the overall response rate was 100% (complete response 31%; near-complete response 23%; partial response 42%; minimal response 4%). The best response occurred within the first four cycles in 96% of patients. Adverse events included hematologic (53%), peripheral neuropathy (38%), fatigue (35%), gastrointestinal (45%), and fever (32%). Grade 3 nonhematologic adverse events included four patients (12%) with renal failure associated with tumor lysis syndrome, one patient (3%) with peripheral sensory and motor neuropathy that improved with VT dose reduction, and one patient (3%) with hypotension. One patient (3%) experienced Grade 4 thrombocytopenia. No patient experienced deep venous thrombosis, while 1 patient (3%) died due to acute renal failure. In conclusion, Bortezomib in combination with thalidomide is a very effective regimen for newly diagnosed MM patients and the toxicities are manageable.


Utilization of Slaughterhouse Waste in Value-Added Applications: Recent Advances in the Development of Wood Adhesives.
Globally, slaughterhouses generate large volumes of animal byproducts. While these byproducts are an important resource of industrial protein that could potentially be utilized in various value-added applications, they are currently either underutilized in high-value applications or being used for production of relatively low-value products such as animal feed and pet food. Furthermore, some of the byproducts of animal slaughtering cannot enter food and feed chains and thus their disposal possesses a serious environmental concern. An innovative utilization of the proteinaceous waste generated by slaughterhouses comprises of waste processing to extract proteins, which are then incorporated into industrial processes to produce value-added bio-based products. In this report, we review the current processes for extraction of protein from proteinaceous waste of slaughterhouses, and utilization of the recovered protein in the development of protein-based wood adhesives.


Discovery of 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol Derivatives as Glutathione Transferase Inhibitors with Favorable Selectivity and Tolerated Toxicity.
Glutathione transferase (GST P1-1) is a potential target for anticancer drugs. In this work, a series of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) derivatives as GST P1-1 inhibitors were designed, synthesized, and evaluated for their biological activity. Among the target compounds, 4n showed more selective inhibition toward GST P1-1 and GST M2-2, better water solubility, and more potent anticancer activities toward all the tested cancer cells (except for HOS) than its parent molecule. Detailed biological studies on the effect of 4n toward 143b cells revealed that 4n could arrest the cell cycle at the G2 phase and induced cell apoptosis in a dose-dependent manner. Like NBDHEX, 4n displayed good pharmacokinetic characteristics. An in vivo study on 143b xenograft models demonstrated that 4n could significantly reduce tumor growth in a dose-dependent manner, showing stronger antitumor activity than NBDHEX. Thus, 4n deserves to be further investigated as a potential antitumor agent for cancer therapy.


Sudden Death Risk-Stratification in 2018-2019: The Old and the New.
Sudden Cardiac Death (SCD) is a major public health issue, accounting for half of all cardiovascular deaths world-wide. The implantable cardioverter-defibrillator (ICD) has been solidified as the cornerstone therapy in primary prevention of SCD in ischaemic and non-ischaemic cardiomyopathy. However, what has become increasingly clear is that the left ventricular ejection fraction (LVEF) is an inadequate tool to select patients for a prophylactic ICD, despite its widespread use for this purpose. Use of LVEF alone has poor specificity for arrhythmic versus non-arrhythmic death. In addition, the vast majority of sudden deaths occur in patients with more preserved cardiac function. Alternate predictors of sudden death include electrophysiology study, non-invasive markers of electrical instability, myocardial fibrosis, genetic and bio-markers. The challenge for the future is finding a risk stratification test, or combination of tests, that adequately select patients at high risk of SCD with low competing risk of non-sudden death.


Morphologic and functional vascular alterations in patients with polycystic ovary syndrome.
We aimed to investigate morphologic and functional alterations of common carotid arteries (CCA) and femoral arteries and the anteroposterior diameter of the abdominal aorta in patients with polycystic ovary syndrome (PCOS). Fifty consecutive females with the complaint of oligoamenorrhea, infertility or hirsutismus, diagnosed with PCOS and 50 healthy females admitted to the Department of Gynecology and Obstetrics, Ergani State Hospital between January 2010 and January 2011 were included in the study. The mean BMI of 50 patients with PCOS was higher than control subjects (CS) (25.89 +/- 3.3 vs 22.52 +/- 2.7 kg/m2, p < 0.0001). The mean arterial blood pressure was 88.93 +/- 6.4 mmHg in the patient group and was it 85.73 +/- 7.6 mmHg in CS (p = 0.02). The mean plasma glucose level (74.04 +/- 6.7 vs 70.5 +/- 6.4 mg/dl), total cholesterol level (167.88 +/- 30.1 vs 153.38 +/- 27.8 mg/dl), low density lipoprotein level (101.28 +/- 27.0 vs 79.56 +/- 25.5 mg/dl) and triglyceride level (121.22 +/- 49.2 vs 102.54 +/- 36.6 mg/dl) were higher; also the mean high density lipoprotein level (44.56 +/- 8.1 vs 50.90 +/- 12.3 mg/dl) was lower in patients with PCOS than CS (p = 0.009, p = 0.014, p < 0.0001, p = 0.034 and p = 0.003, respectively). CCA-IMT (0.63 +/- 0.2 vs 0.52 +/- 0.1 mm), and CCA-PI (1.44 +/- 0.3 vs 1.28 +/- 0.22) were higher in patients with PCOS (p = 0.018 andp = 0.005, respectively). Femoral-IMT (0.62 +/- 0.6 vs 0.41 +/- 0.1 mm) and anteroposterior diameter of the infrarenal aorta (12.34 +/- 1.5 vs 11.4 +/- 1.0 mm) were higher in patients with PCOS (p = 0.024 and p = 0.001, respectively). The present study showed that IMT and PI of CCA, and anteroposterior diameter of the infrarenal abdominal aorta and femoral-IMT were higher in patients with PCOS. These results are probably related with increased androgens, their effects on insulin resistance and lipid profile, increased BMI and blood pressure. Detection of these functional and/or structural abnormalities are important in predicting prognosis. Larger scale prospective studies are needed to determine the effects of PCOS on the mortality and morbidity, and to clarify the relation between the duration of the disease and development of these alterations.


The solid-probe technique in ultrasound-assisted lipoplasty.
The solid-probe ultrasound-assisted lipoplasty technique is a predictable method for obtaining optimal results in body contouring for select patients. Patients with inelastic skin, cellulite, skin laxity, and those undergoing secondary contouring procedures are ideal candidates for the solid-probe technique. The solid probe is thought to be a more efficient fat emulsification device because it imparts more focal ultrasonic energy per amplitude than hollow probes.


Generic clozapine: a cost-saving alternative to brand name clozapine?
As a consequence of its prevalence, early onset and chronicity, schizophrenia imposes clinical and economic impediments to healthcare practitioners and society alike. Among the many antipsychotics available to treat the symptoms of this devastating illness, clozapine has emerged and differentiated itself from the others as the agent most efficacious for the treatment of refractory patients. Since the patent for Clozaril (Novartis) expired in 1998, three manufacturers of generic clozapine have submitted abbreviated new drug applications to the US FDA for review and approval to market a generic clozapine product. In each case, the US FDA deemed the generic formulations to be bioequivalent to the brand name Clozaril. Apart from case reports, industry-sponsored studies have been conducted comparing Clozaril with two generic formulations. In one case, a generic formulation of clozapine manufactured by Creighton Products Corporation (formerly a subsidiary [generic house] of Sandoz Pharmaceuticals) was found to be bioequivalent to Clozaril. On the other hand, studies (sponsored by Novartis) have challenged the bioequivalence, therapeutic equivalence and interchangeability between Clozaril and a generic formulation manufactured by Zenith Goldline Pharmaceuticals (now IVAX Corporation). The IVAX Corporation-sponsored studies refuted these claims citing data from two patient registry database studies and one small clinical trial. Apart from a single in-house bioequivalence study, no further investigations have been conducted with a third generic formulation manufactured by Mylan Pharmaceutical. Although the clinical significance of the above discrepancy is obvious, what is less than obvious is the pharmacoeconomic implications that arises from this debate. Clearly, if the brand name and generic formulations are 'truly' bioequivalent, then the cost savings realised would be the difference in acquisition cost. On the other hand, if the various formulations are not bioequivalent, then the economic benefits of a lower-priced generic formulation may be compromised. In the worst-case scenario, if a patient decompensates as a result of switching from Clozaril to a generic formulation, the added direct costs (i.e. hospitalisation) and indirect cost (i.e. lost productivity) will most certainly offset any cost savings resulting from the use of a generic formulation. Until further studies have been conducted, we suggest that patients who are treatment refractory and stabilised on Clozaril are not switched to a generic formulation. On the other hand, if a patient is stabilised on Clozaril and not treatment refractory, then cautious switching to a generic formulation may be reasonable. Finally, initiating a generic formulation in a 'clozapine-naïve' individual would be appropriate. The cost implications related to these recommendations will depend on the success or failure of treatment.