CpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by Acinetobacter baumannii That Inactivates Coagulation Factor XII.
Antibiotic-resistant Acinetobacter baumannii is increasingly recognized as a cause of difficult-to-treat nosocomial infections, including pneumonia, wound infections, and bacteremia. Previous studies have demonstrated that the metalloprotease CpaA contributes to virulence and prolongs clotting time when added to human plasma as measured by the activated partial thromboplastin time (aPTT) assay. Here, we show that CpaA interferes with the intrinsic coagulation pathway, also called the contact activation system, in human as well as murine plasma, but has no discernible effect on the extrinsic pathway. By utilizing a modified aPTT assay, we demonstrate that coagulation factor XII (fXII) is a target of CpaA. In addition, we map the cleavage by CpaA to two positions, 279-280 and 308-309, within the highly glycosylated proline-rich region of human fXII, and show that cleavage at the 308-309 site is responsible for inactivation of fXII. At both sites, cleavage occurs between proline and an O-linked glycosylated threonine, and deglycosylation of fXII prevents cleavage by CpaA. Consistent with this, mutant fXII (fXII-Thr309Lys) from patients with hereditary angioedema type III (HAEIII) is protected from CpaA inactivation. This raises the possibility that individuals with HAEIII who harbor this mutation may be partially protected from A. baumannii infection if CpaA contributes to human disease. By inactivating fXII, CpaA may attenuate important antimicrobial defense mechanisms such as intravascular thrombus formation, thus allowing A. baumannii to disseminate.IMPORTANCE Ventilator-associated pneumonia and catheter-related bacteremia are the most common and severe infections caused by Acinetobacter baumannii Besides the capsule, lipopolysaccharides, and the outer membrane porin OmpA, little is known about the contribution of secreted proteins to A. baumannii survival in vivo Here we focus on CpaA, a potentially recently acquired virulence factor that inhibits blood coagulation in vitro We identify coagulation factor XII as a target of CpaA, map the cleavage sites, and show that glycosylation is a prerequisite for CpaA-mediated inactivation of factor XII. We propose adding CpaA to a small, but growing list of bacterial proteases that are specific for highly glycosylated components of the host defense system.


Influence of residency training on occupational medicine practice patterns.
A relatively high proportion of occupational medicine (OM) specialists have not had formal residency training in OM. Members of the Western Occupational and Environmental Medicine Association, a professional organization of OM specialists, completed a postal questionnaire (160 of 561 members). Educational background, practice setting, practice activities, and skills considered relevant were compared between those with and without formal training. Both groups had considerable focus in clinical care, musculoskeletal medicine, and workers' compensation. However, those with formal training practice in a broader variety of settings were less likely to have practiced another specialty, and used additional skills (toxicology, industrial hygiene, and epidemiology) in their practices. Formal education appears to create a greater diversity of skills and opportunities, but it does not appear to create a group of physicians disinterested in "front-line" occupational medicine practice. The data support the need for formal residency programs but also highlight the importance of access to formal training for midcareer physicians.


Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole.
The benefit of cardiac pacing in patients with severe recurrent reflex syncope and asystole induced by tilt testing has not been established. The usefulness of tilt-table test to select candidates for cardiac pacing is controversial. We randomly assigned patients aged 40 years or older who had at least two episodes of unpredictable severe reflex syncope during the last year and a tilt-induced syncope with an asystolic pause longer than 3 s, to receive either an active (pacing ON; 63 patients) or an inactive (pacing OFF; 64 patients) dual-chamber pacemaker with closed loop stimulation (CLS). The primary endpoint was the time to first recurrence of syncope. Patients and independent outcome assessors were blinded to the assigned treatment. After a median follow-up of 11.2 months, syncope occurred in significantly fewer patients in the pacing group than in the control group [10 (16%) vs. 34 (53%); hazard ratio, 0.23; P = 0.00005]. The estimated syncope recurrence rate at 1 year was 19% (pacing) and 53% (control) and at 2 years, 22% (pacing) and 68% (control). A combined endpoint of syncope or presyncope occurred in significantly fewer patients in the pacing group [23 (37%) vs. 40 (63%); hazard ratio, 0.44; P = 0.002]. Minor device-related adverse events were reported in five patients (4%). In patients aged 40 years or older, affected by severe recurrent reflex syncope and tilt-induced asystole, dual-chamber pacemaker with CLS is highly effective in reducing the recurrences of syncope. Our findings support the inclusion of tilt testing as a useful method to select candidates for cardiac pacing. ClinicalTrials.gov identifier NCT02324920, Eudamed number CIV-05-013546.


The immunopathology of canine vector-borne diseases.
The canine vector-borne infectious diseases (CVBDs) are an emerging problem in veterinary medicine and the zoonotic potential of many of these agents is a significant consideration for human health. The successful diagnosis, treatment and prevention of these infections is dependent upon firm understanding of the underlying immunopathology of the diseases in which there are unique tripartite interactions between the microorganism, the vector and the host immune system. Although significant advances have been made in the areas of molecular speciation and the epidemiology of these infections and their vectors, basic knowledge of the pathology and immunology of the diseases has lagged behind. This review summarizes recent studies of the pathology and host immune response in the major CVBDs (leishmaniosis, babesiosis, ehrlichiosis, hepatozoonosis, anaplasmosis, bartonellosis and borreliosis). The ultimate application of such immunological investigation is the development of effective vaccines. The current commercially available vaccines for canine leishmaniosis, babesiosis and borreliosis are reviewed.


Pigmented Macules on the Head and Neck: A Systematic Review of Dermoscopy Features.
Differentiating early melanoma from other flat pigmented lesions on the head and neck is challenging both clinically and dermoscopically, partly due to the wide differential diagnosis and the lack of specific diagnostic algorithms. To review publications covering the dermoscopic features of pigmented macules on the head and neck. Embase and PubMed (Medline) database from January 2015 to January 2021 were searched using a four-step search. Keywords used were dermoscopy/dermatoscopy or epiluminescence microscopy, lentigo maligna, lentigo maligna melanoma, lichen-planus-like-keratosis, solar lentigo, seborrheic keratosis, pigmented actinic keratosis (PAK), pigmented Bowen disease (pBD), pigmented intraepidermal carcinoma (pIEC) and head and neck. The commonest reported dermoscopic features of facial melanoma were irregular dots, atypical dots/globules, asymmetric pigmented follicular openings, rhomboid gray/black structures, increased vascular network, brown globules/dots and a pattern of circles. Pseudopods, radial streaming, blue white veil, irregular blotches, scar-like depigmentation and atypical pigment network were recorded in low frequencies. For PAK, pBD and pIEC perifollicular erythema, white/yellow surface scale, linear wavy vessels around hair follicles, hair follicular openings surrounded by a white halo, evident follicles or follicular or keratotic plugs, rosette sign and sharply demarcated borders were the salient features. Further studies are needed to determine the dermoscopic criteria for pigmented melanocytic and non-melanocytic lesions on the head and neck. Furthermore, there is a gap in the knowledge of site-specific dermoscopic features on specific sites, namely ears, nose, cheeks, scalp and neck which will also benefit from further studies.


Management strategy for patients with gastroesophageal reflux disease: a comparison between empirical treatment with esomeprazole and endoscopy-oriented treatment.
Whether patients with typical gastroesophageal reflux disease (GERD) symptoms and without alarm features should be treated empirically or undergo endoscopy first is a debated issue. In this study, our aim was to assess the efficacy, and to compare the direct costs and impact on health-related quality of life (HRQL), of two treatment strategies (empirical vs endoscopy-oriented treatment) in a large population of patients with GERD. In total, 612 patients were randomized to either empirical treatment with esomeprazole 40 mg once daily (od) (group 1, N = 309) or endoscopy and treatment according to endoscopic findings (group 2, N = 303, esomeprazole 40 mg od in patients with reflux esophagitis and esomeprazole 20 mg od in patients without esophagitis) for 4 wk, followed by esomeprazole 20 mg od maintenance treatment in both groups. Direct costs and HRQL were analyzed in both treatment arms. At the end of the acute treatment phase (week 4), 267 patients in group 1 (86.4%) and 265 patients in group 2 (87.5%) were considered responders to treatment (intention-to-treat analysis, P= 0.878). Empirical treatment proved to be cost-effective by saving 38.72 euros per treated patient. At the end of the maintenance phase (week 24), a similar proportion of patients responded to treatment in the two groups (71.8%vs 68.3%, P= 0.389). HRQL improved from baseline to week 24 in both groups (difference between study groups not significant). In patients with GERD, empirical treatment with esomeprazole proved to be cost-effective compared with endoscopy-oriented treatment, and did not negatively affect patient HRQL. These results should be taken into account in the management of GERD patients in clinical practice.


Virtual suturing simulation based on commodity physics engine for medical learning.
Development of virtual-reality medical applications is usually a complicated and labour intensive task. This paper explores the feasibility of using commodity physics engine to develop a suturing simulator prototype for manual skills training in the fields of nursing and medicine, so as to enjoy the benefits of rapid development and hardware-accelerated computation. In the prototype, spring-connected boxes of finite dimension are used to simulate soft tissues, whereas needle and thread are modelled with chained segments. Spherical joints are used to simulate suture's flexibility and to facilitate thread cutting. An algorithm is developed to simulate needle insertion and thread advancement through the tissue. Two-handed manipulations and force feedback are enabled with two haptic devices. Experiments on the closure of a wound show that the prototype is able to simulate suturing procedures at interactive rates. The simulator is also used to study a curvature-adaptive suture modelling technique. Issues and limitations of the proposed approach and future development are discussed.


The costs of parental care: a meta-analysis of the trade-off between parental effort and survival in birds.
A fundamental premise of life-history theory is that organisms that increase current reproductive investment suffer increased mortality. Possibly the most studied life-history phenotypic relationship is the trade-off between parental effort and survival. However, evidence supporting this trade-off is equivocal. Here, we conducted a meta-analysis to test the generality of this tenet. Using experimental studies that manipulated parental effort in birds, we show that (i) the effect of parental effort on survival was similar across species regardless of phylogeny; (ii) individuals that experienced reduced parental effort had similar survival probabilities than control individuals, regardless of sex; and (iii) males that experienced increased parental effort were less likely to survive than control males, whereas females that experienced increased effort were just as likely to survive as control females. Our results suggest that the trade-off between parental effort and survival is more complex than previously assumed. Finally, our study provides recommendations of unexplored avenues of future research into life-history trade-offs.


Evaluation of a low-cost, portable imaging system for early detection of oral cancer.
There is an important global need to improve early detection of oral cancer. Recent reports suggest that optical imaging technologies can aid in the identification of neoplastic lesions in the oral cavity; however, there is little data evaluating the use of optical imaging modalities in resource limited settings where oral cancer impacts patients disproportionately. In this article, we evaluate a simple, low-cost optical imaging system that is designed for early detection of oral cancer in resource limited settings. We report results of a clinical study conducted at Tata Memorial Hospital (TMH) in Mumbai, India using this system as a tool to improve detection of oral cancer and its precursors. Reflectance images with white light illumination and fluorescence images with 455 nm excitation were obtained from 261 sites in the oral cavity from 76 patients and 90 sites in the oral cavity from 33 normal volunteers. Quantitative image features were used to develop classification algorithms to identify neoplastic tissue, using clinical diagnosis of expert observers as the gold standard. Using the ratio of red to green autofluorescence, the algorithm identified tissues judged clinically to be cancer or clinically suspicious for neoplasia with a sensitivity of 90% and a specificity of 87%. Results suggest that the performance of this simple, objective low-cost system has potential to improve oral screening efforts, especially in low-resource settings.


[Neuronal activity of the cat visual cortex during the sleep--wakefulness cycle].
The changes in background neuronal activity of the visual cortex during the sleep-waking cycle were studied in the dark adapted chronic cats. Neither pattern nor frequency of discharges of the investigated cells were significantly different in waking state and paradoxical sleep. The interspike interval histograms and autocorrelograms were used to evaluate the changes in the patterns of cell discharges. Slow sleep differs noticeably from the wakening state and paradoxical sleep due to the burst-pause pattern appearance in cell discharges.


Budget Impact of Belantamab Mafodotin (Belamaf) Adoption in the Treatment of Patients with Relapsed or Refractory Multiple Myeloma in the United States.
Estimate the budget impact of belantamab mafodotin (belamaf) for patients with relapsed/refractory multiple myeloma (RRMM) who have received ≥4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. A budget impact analysis (BIA) was developed to estimate the cost difference between current (no belamaf) and projected (with belamaf) market scenarios over 3 years. Comparators were identified from a systematic literature review and included selinexor + dexamethasone or best supportive care. The number of treatment-eligible patients were estimated using an epidemiology model. Base-case analyses were conducted from a US commercial payer perspective (cost year: 2019). Model inputs included market share estimates, treatment duration, and costs of drug acquisition/administration, concomitant medications, adverse event (AE) management, treatment monitoring, and subsequent treatments based on published literature/cost databases. Budget impact, calculated as the difference in costs between current and projected scenarios over 3 years, was reported as cost per member per month (PMPM) and per member per year (PMPY). One-way sensitivity analysis assessed which key parameters most affected model outcomes. Alternative scenarios were tested (1- or 5-year time horizon; Medicare perspective; negligible cost of mental status change AE). In a hypothetical commercial payer health plan with 1 million members, 33 patients were identified as treatment-eligible over 3 years. Introducing belamaf for patients with RRMM resulted in an estimated budget-neutral PMPM cost of -$0.0003 and PMPY of -$0.004, based on n=9/33 patients receiving treatment. Sensitivity analyses showed that budget impact in the base case was most sensitive to changes in treatment duration and drug acquisition costs. Base-case results were consistent across all scenarios assessed. BIA indicates that adoption of belamaf in this patient population would be budget neutral for a US health plan.


Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials.
We performed a systematic review and meta-analyses to estimate treatment efficacy and constipation rate of 5-hydroxytryptamine (serotonin) (5-HT(3)) antagonists in patients with nonconstipated (NC) or diarrhea-predominant (D)-irritable bowel syndrome (IBS). Two reviewers independently searched MEDLINE, EMBASE, and Web of Science (January 1, 1966 to December 15, 2006) for randomized controlled trials of 5-HT(3) antagonists in IBS reporting clinical end points of the IBS symptom complex and safety parameters. Study characteristics, markers of methodologic quality, and outcomes for the intention-to-treat population for each randomized controlled trial were extracted independently. We found 14 eligible randomized controlled trials of alosetron (n = 3024) or cilansetron (n = 1116) versus placebo (n = 3043) or mebeverine (n = 304). Random-effects meta-analyses found 5-HT(3) antagonists more effective than the comparators in achieving global improvement in IBS symptoms (pooled relative risk, 1.60; 95% confidence interval [CI], 1.49-1.72; I(2) = 0%) and relief of abdominal pain and discomfort (pooled relative risk, 1.30; 95% CI, 1.22-1.39; I(2) = 22%). Benefit was apparent for both agents, in patients of either sex. These agents were more likely to cause constipation (pooled relative risk, 4.28; 95% CI, 3.28-5.60, I(2) = 65%); there was less constipation with 5-HT(3) antagonists in D-IBS patients than in mixed populations (NC-IBS and D-IBS; relative risk ratio, 0.65; 95% CI, 0.41-0.99). Nine patients (0.2%) using 5-HT(3) antagonists had possible ischemic colitis versus none in control groups. 5-HT(3) antagonists significantly improve symptoms of NC-IBS or D-IBS in men and women. There is an increased risk of constipation with 5-HT(3) antagonists, although the risk is lower in those with D-IBS.


Infant and maternal characteristics in neonatal abstinence syndrome--selected hospitals in Florida, 2010-2011.
Neonatal abstinence syndrome (NAS) is a constellation of physiologic and neurobehavioral signs exhibited by newborns exposed to addictive prescription or illicit drugs taken by a mother during pregnancy. The number of hospital discharges of newborns diagnosed with NAS has increased more than 10-fold (from 0.4 to 4.4 discharges per 1,000 live births) in Florida since 1995, far exceeding the three-fold increase observed nationally. In February 2014, the Florida Department of Health requested the assistance of CDC to 1) assess the accuracy and validity of using Florida's hospital inpatient discharge data, linked to birth and infant death certificates, as a means of NAS surveillance and 2) describe the characteristics of infants with NAS and their mothers. This report focuses only on objective two, describing maternal and infant characteristics in the 242 confirmed NAS cases identified in three Florida hospitals during a 2-year period (2010-2011). Infants with NAS experienced serious medical complications, with 97.1% being admitted to an intensive care unit, and had prolonged hospital stays, with a mean duration of 26.1 days. The findings of this investigation underscore the important public health problem of NAS and add to current knowledge on the characteristics of these mothers and infants. Effective June 2014, NAS is now a mandatory reportable condition in Florida. Interventions are also needed to 1) increase the number and use of community resources available to drug-abusing and drug-dependent women of reproductive age, 2) improve drug addiction counseling and rehabilitation referral and documentation policies, and 3) link women to these resources before or earlier in pregnancy.


Modelling of the tsunami from the December 22, 2018 lateral collapse of Anak Krakatau volcano in the Sunda Straits, Indonesia.
On Dec. 22, 2018, at approximately 20:55-57 local time, Anak Krakatau volcano, located in the Sunda Straits of Indonesia, experienced a major lateral collapse during a period of eruptive activity that began in June. The collapse discharged volcaniclastic material into the 250 m deep caldera southwest of the volcano, which generated a tsunami with runups of up to 13 m on the adjacent coasts of Sumatra and Java. The tsunami caused at least 437 fatalities, the greatest number from a volcanically-induced tsunami since the catastrophic explosive eruption of Krakatau in 1883 and the sector collapse of Ritter Island in 1888. For the first time in over 100 years, the 2018 Anak Krakatau event provides an opportunity to study a major volcanically-generated tsunami that caused widespread loss of life and significant damage. Here, we present numerical simulations of the tsunami, with state-of the-art numerical models, based on a combined landslide-source and bathymetric dataset. We constrain the geometry and magnitude of the landslide source through analyses of pre- and post-event satellite images and aerial photography, which demonstrate that the primary landslide scar bisected the Anak Krakatau volcano, cutting behind the central vent and removing 50% of its subaerial extent. Estimated submarine collapse geometries result in a primary landslide volume range of 0.22-0.30 km3, which is used to initialize a tsunami generation and propagation model with two different landslide rheologies (granular and fluid). Observations of a single tsunami, with no subsequent waves, are consistent with our interpretation of landslide failure in a rapid, single phase of movement rather than a more piecemeal process, generating a tsunami which reached nearby coastlines within ~30 minutes. Both modelled rheologies successfully reproduce observed tsunami characteristics from post-event field survey results, tide gauge records, and eyewitness reports, suggesting our estimated landslide volume range is appropriate. This event highlights the significant hazard posed by relatively small-scale lateral volcanic collapses, which can occur en-masse, without any precursory signals, and are an efficient and unpredictable tsunami source. Our successful simulations demonstrate that current numerical models can accurately forecast tsunami hazards from these events. In cases such as Anak Krakatau's, the absence of precursory warning signals together with the short travel time following tsunami initiation present a major challenge for mitigating tsunami coastal impact.


Splenomegaly, macrothombocytopenia and stomatocytosis in healthy Mediterranean subjects (splenomegaly in Mediterranean macrothrombocytopenia).
Spleen size, stomatocytosis, macrothrombocytopenia, haemoglobin level, white cell count, and abdominal pain episodes were assessed in a coded study of healthy Mediterranean immigrants to Australia. Spleen size was estimated from a length measurement, L, on a standardized plain abdominal radiograph and expressed both as spleen weight and as a spleen length index, L/square root BSA; the platelet count and size parameters were determined electronically and the presence of stomatocytes was evaluated in stained blood films. In relation to 16 Northern European control women 12 of 25 Mediterranean women had radiographic splenomegaly, 10 had macrothrombocytopenia, 9 had stomatocytosis, but none had episodes of abdominal pain. The median spleen weights of the two groups were estimated as 157 and 247 g with ranges from percentile 2.3 to 97.7 of 75 to 328 and 112 to 669 g. Within the Mediterranean group splenomegaly correlated with macrothrombocytopenia (P less than 0.001) but not with stomatocytosis, haemoglobin values or white cell counts. Thus, mild splenomegaly may be expected in Mediterranean macrothrombocytopenia, Mediterranean stomatocytosis appears unrelated, and all of these apparently benign anomalies may be incidental findings in patients from the Italian and Balkan peninsulas.


NMR structure of the human Rad18 zinc finger in complex with ubiquitin defines a class of UBZ domains in proteins linked to the DNA damage response.
Ubiquitin-mediated interactions are critical for the cellular DNA damage response (DDR). Therefore, many DDR-related proteins contain ubiquitin-binding domains, including ubiquitin-binding zinc fingers (UBZs). The majority of these UBZ domains belong to the C2H2 (type 3 Polη-like) or C2HC (type 4 Rad18-like) family. We have used nuclear magnetic resonance (NMR) spectroscopy to characterize the binding to ubiquitin and determine the structure of the type 4 UBZ domain (UBZ4) from human Rad18, which is a key ubiquitin ligase in the DNA damage tolerance pathway responsible for monoubiquitination of the DNA sliding clamp PCNA. The Rad18-UBZ domain binds ubiquitin with micromolar affinity and adopts a β1-β2-α fold similar to the previously characterized type 3 UBZ domain (UBZ3) from the translesion synthesis DNA polymerase Polη. However, despite nearly identical structures, a disparity in the location of binding-induced NMR chemical shift perturbations shows that the Rad18-UBZ4 and Polη-UBZ3 domains bind ubiquitin in distinctly different modes. The Rad18-UBZ4 domain interacts with ubiquitin with the α-helix and strand β1 as shown by the structure of the Rad18-UBZ domain-ubiquitin complex determined in this work, while the Polη-UBZ3 domain exclusively utilizes the α-helix. Our findings suggest the existence of two classes of UBZ domains in DDR-related proteins with similar structures but unique ubiquitin binding properties and provide context for further study to establish the differential roles of these domains in the complex cellular response to DNA damage.


Accuracy assessment of Tri-plane B-mode ultrasound for non-invasive 3D kinematic analysis of knee joints.
Currently the clinical standard for measuring the motion of the bones in knee joints with sufficient precision involves implanting tantalum beads into the bones. These beads appear as high intensity features in radiographs and can be used for precise kinematic measurements. This procedure imposes a strong coupling between accuracy and invasiveness. In this paper, a tri-plane B-mode ultrasound (US) based non-invasive approach is proposed for use in kinematic analysis of knee joints in 3D space. The 3D analysis is performed using image processing procedures on the 2D US slices. The novelty of the proposed procedure and its applicability to the unconstrained 3D kinematic analysis of knee joints is outlined. An error analysis for establishing the method's feasibility is included for different artificial compositions of a knee joint phantom. Some in-vivo and in-vitro scans are presented to demonstrate that US scans reveal enough anatomical details, which further supports the experimental setup used using knee bone phantoms. The error between the displacements measured by the registration of the US image slices and the true displacements of the respective slices measured using the precision mechanical stages on the experimental apparatus is evaluated for translation and rotation in two simulated environments. The mean and standard deviation of errors are shown in tabular form. This method provides an average measurement precision of less than 0.1 mm and 0.1 degrees, respectively. In this paper, we have presented a novel non-invasive approach to measuring the motion of the bones in a knee using tri-plane B-mode ultrasound and image registration. In our study, the image registration method determines the position of bony landmarks relative to a B-mode ultrasound sensor array with sub-pixel accuracy. The advantages of our proposed system over previous techniques are that it is non-invasive, does not require the use of ionizing radiation and can be used conveniently if miniaturized.


Control of directed cell migration in vivo by membrane-to-cortex attachment.
Cell shape and motility are primarily controlled by cellular mechanics. The attachment of the plasma membrane to the underlying actomyosin cortex has been proposed to be important for cellular processes involving membrane deformation. However, little is known about the actual function of membrane-to-cortex attachment (MCA) in cell protrusion formation and migration, in particular in the context of the developing embryo. Here, we use a multidisciplinary approach to study MCA in zebrafish mesoderm and endoderm (mesendoderm) germ layer progenitor cells, which migrate using a combination of different protrusion types, namely, lamellipodia, filopodia, and blebs, during zebrafish gastrulation. By interfering with the activity of molecules linking the cortex to the membrane and measuring resulting changes in MCA by atomic force microscopy, we show that reducing MCA in mesendoderm progenitors increases the proportion of cellular blebs and reduces the directionality of cell migration. We propose that MCA is a key parameter controlling the relative proportions of different cell protrusion types in mesendoderm progenitors, and thus is key in controlling directed migration during gastrulation.


Epidemiology and outcome of tuberculosis in immunocompromised patients.
The United States Renal Data System showed 1.2% and 1.6% incidences of tuberculosis (TB) in patients on peritoneal dialysis and hemodialysis (HD), respectively. Kidney transplant (KTX) patients have higher rates. We studied the epidemiology and outcome of TB in patients with kidney dysfunction in a tertiary care hospital in the past decade. We examined data of patients with TB with and without kidney dysfunction from 2006 to 2015 through an electronic system. Statistical analysis was completed using Stata software, Chicago, IL, USA. We found 581 patients with active TB of whom 37 had renal dysfunction including chronic kidney disease, HD, and KTX. No difference was found in the prevalence, age, or gender predilection. The age ranged from 1 to 95 with a mean (standard deviation) of 38.6 (21.1) years. The incidence of TB is 3 per 100,000. The number of patients per year with active TB ranges from 52 to 128 and 3 to 4 in the general population and kidney dysfunction group, respectively. Sixty-five percent of patients with kidney dysfunction had pulmonary TB, 5% had pleurisy, and 30% had extrapulmonary TB. Eighty-four percent of patients with kidney dysfunction completed the course of treatment with 16% treatment failure and 0.4% developed multidrug-resistant TB; 8% were lost to follow-up and 8% died during the treatment period. This study showed no gender predilection for TB in the general population and immunocompromised. Duration of symptoms before diagnosis of TB was shorter in kidney dysfunction patients in comparison to the general population. TB cultures were the most positive tests whereas bronchoalveolar lavage and skin test were the least positive for detecting TB in the kidney dysfunction group. Improvement in registries and screening is required to enhance the capturing rate and detection among this group, as well as providing accurate data to health authorities and the public about the magnitude, future trends, treatments, and outcomes regarding TB in kidney dysfunction.


Gas chromatographic and mass spectrometric investigations of organic residues from Roman glass unguentaria.
A combination of gas chromatographic (GC) and mass spectrometric (MS) techniques, including direct exposure-MS (DE-MS), high-temperature GC-MS (HTGC-MS) and GC-MS of neutral and acid fractions, was employed to study the composition and recognise origin of the organic materials used to manufacture balm residues surviving in a series of glass unguentaria recovered from excavations of a Roman villa (Villa B) in the ancient town of Oplontis (Naples, Italy). DE-MS provided comprehensive 'fingerprint' information on the solvent soluble components of the contents of the unguentaria, while GC-MS analyses provided detailed molecular compositions, highlighting the presence of a wide range of compound classes including mid- and long-chain fatty acids, long-chain hydroxy-acids, n-alkanols, alkandiols, n-alkanes, long-chain monoesters, phytosterols and diterpenoid acids. Characteristic biomarkers and their distributions indicate the presence of beeswax, Pinaceae resin and another wax, as the main organic constituents of all of the preparations examined. In particular, the occurrence of phytosterols and long-chain monoesters, in which the acyl moiety was not exclusively palmitic acid, suggested the presence of a second waxy-lipid constituent of plant origin. The results are consistent with beeswax being used in the preparation of the cosmetics preserved in the unguentaria, while the other lipids are most likely the residue of some as yet unidentified plant extract(s), possibly deriving from the cuticular waxes of flowers and/or leaves. The composition of the extracts are consistent with the ancient practices of maceration and/or "enfleurage", in which lipid-based materials, such as beeswax, animal fat or vegetables oils, were used to extract aromatic and fragrant substances from resin, flowers, spices and scented wood, in order to produce unguents and balms.


A Factored Generalized Additive Model for Clinical Decision Support in the Operating Room.
Logistic regression (LR) is widely used in clinical prediction because it is simple to deploy and easy to interpret. Nevertheless, being a linear model, LR has limited expressive capability and often has unsatisfactory performance. Generalized additive models (GAMs) extend the linear model with transformations of input features, though feature interaction is not allowed for all GAM variants. In this paper, we propose a factored generalized additive model (F-GAM) to preserve the model interpretability for targeted features while allowing a rich model for interaction with features fixed within the individual. We evaluate F-GAM on prediction of two targets, postoperative acute kidney injury and acute respiratory failure, from a single-center database. We find superior model performance of F-GAM in terms of AUPRC and AUROC compared to several other GAM implementations, random forests, support vector machine, and a deep neural network. We find that the model interpretability is good with results with high face validity.


Morphologic alteration of Paranaplasma caudata following treatment of calves with oxytetracycline.
The morphologic features of Paranaplasma caudata were determined in whole blood, blood clots, and liver biopsy specimens after treating infected calves with oxytetracycline. Following staining of blood smears with new methylene blue, light microscopy showed that paranaplasma bodies in erythrocytes of treated calves were vacuolated, but tails were normal in appearance. By electron microscopic examination of parasitized erythrocytes of treated calves, paranaplasma bodies were found to be degenerated (aggregation of nucleoprotein granules in initial bodies and condensation and coalescence of initial bodies), but tails were normal. The identical degenerative changes of paranaplasma bodies and lack of alteration of tails were evident in erythrocytes in sinusoids of liver biopsy specimens from treated calves.


Treatment of otitis media with cefuroxime axetil.
Cefuroxime axetil and cefaclor were compared for efficacy in the treatment of acute otitis media with effusion. Sixty-four pediatric outpatients had tympanocentesis for culture, and then were randomized to a ten-day course of treatment with cefuroxime axetil or cefaclor. Streptococcus pneumoniae and Haemophilus influenzae were isolated from 25 (39%) and 23 (36%) patients, respectively. Treatment was beneficial in 26 (90%) of the patients who received cefuroxime axetil, and in 16 (76%) of the cefaclor-treated patients. Treatment failed in five (24%) of the cefaclor-treated patients, and in only three (10%) patients who received cefuroxime axetil. Haemophilus influenzae was the initial causative pathogen in a disproportionate number of treatment failures. This study demonstrates the efficacy of cefuroxime axetil in the treatment of otitis media.


Prophylaxis against venous thromboembolism in hospitalized medical patients: an evidence-based and practical approach.
To discuss the evidence regarding the efficacy and safety of anticoagulant prophylaxis against deep vein thrombosis (DVT) in hospitalized medical patients; to understand barriers to implementation of prophylaxis and how they can be overcome; and to have a practical approach as to which patients should and should not receive anticoagulant prophylaxis. The frequency of DVT in hospitalized medical patients, in the absence of prophylaxis varies from 10-15%. Autopsy studies have shown that pulmonary embolism (PE) is associated with 5-10% of deaths in hospitalized patients. With appropriate use of anticoagulant prophylaxis, there is a 57% reduction in the risk for symptomatic PE (relative risk [RR] 0.43, 95% CI 0.26-0.71), a 62% reduction in the risk for fatal PE (RR 0.38, 95% CI 0.21-0.69), and a 53% reduction in the risk for symptomatic DVT (RR 0.47, 95% CI 0.22-1.00). Anticoagulant prophylaxis is also associated with a non-significant increased risk for major bleeding (RR 1.32, 95% CI 0.73-2.37). Risk factors for DVT and bleeding in medical patients may help to identify patients in whom anticoagulant prophylaxis is indicated or contraindicated but validated risk stratifications schemes are lacking. Among hospitalized medical patients, randomized trials have established an acceptable therapeutic benefit-to-risk ratio of anticoagulant prophylaxis to reduce the incidence of clinically silent and symptomatic venous thromboembolism, including a reduction in the incidence of fatal PE. Additional research is needed to develop a validated risk stratification model for hospitalized medical patients that can help identify patients who would benefit most from anticoagulant prophylaxis.


[The registration of complications of medical treatment].
The National Surgical Adverse Event Registration (LHCR) software has been fully implemented in 25 (18.7%) departments of surgery in the Netherlands. This is a relatively low percentage considering that 92.5% of all hospitals are already using a local registration system for complications. Software difficulties in creating a link between the LHCR and local systems is suggested to be the main impeding factor. There are still a number of questions, notably concerning the validity of the system for registration of all complications versus a selected group of (severe) complications, the issue of the implications of the registration system in terms of quality control and subsequent regulation or centralization of procedures, and the importance for other specialists, in particular those performing invasive procedures, to introduce a complication registration system to establish a quality control system in those areas as well.


Bacteria and irritable bowel syndrome: the evidence for small intestinal bacterial overgrowth.
Irritable bowel syndrome (IBS) is a complex, yet common diagnosis in gastroenterology. Recent data suggest the increasing importance of bacteria in the pathophysiology of IBS. Some studies have shown that IBS can be precipitated by an acute case of gastroenteritis. These pathogenic organisms may contribute to long-term gut dysfunction. In another line of effort, a growing body of evidence links IBS to the presence of excessive bacteria in the small bowel, called bacterial overgrowth. Although the means by which this is determined have been indirect, studies demonstrating the benefit of unabsorbed antibiotics suggest that reduction in gut flora is important. Further work has also examined bacterial overgrowth in the context of the various symptoms of patients with IBS. These symptom complexes include constipation, diarrhea, and alternating forms of the condition. Although this idea seems initially counterintuitive, it has been demonstrated that the fermentation of methane in the gut is associated with and can result in the slowing of intestinal transit, resulting in constipation. In this review, these topics are discussed and outlined.


Urine release in freely moving catheterised lobsters (Homarus americanus) with reference to feeding and social activities.
Previous studies suggest that urine-borne pheromones play an important role in lobster agonistic and sexual behaviour. This paper investigates the pattern of urine release in catheterised, but otherwise freely moving, adult lobsters with respect to feeding, social and non-social activities. Lobsters on average released 4.1 ml (1 % of body mass) of urine over a 12 h period; this more than doubled to 10.6 ml over the 12 h period after feeding. Hourly monitoring revealed that most urine was released in the first hour after feeding (2.84 ml). With the exception of the first hours after feeding, urine release was intermittent, with pauses lasting up to 17 h. The probability of urine release per hour in unfed lobsters was 0.34 (median); this value increased during agonistic interactions elicited by the introduction of a conspecific (median 0. 63) and during activity initiated by non-social disturbance (median 0.56). Mean urine volume during output hours in unfed lobsters amounted to 1.09 ml h-1. This volume was significantly increased by the presence of a conspecific (1.88 ml h-1) and decreased during activity initiated by non-social disturbances (0.56 ml h-1). No sex-specific differences in urine release were found. The data demonstrate that lobsters control their urine release in a manner dependent on behavioural context. This supports recent findings suggesting the use of urine for chemical signalling in agonistic interactions.


Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study.
The association between testosterone deficiency and insulin resistance in men with type 2 diabetes is well established and current endocrine society guidelines recommend the measurement of testosterone levels in all men with type 2 diabetes or erectile dysfunction. We report the first double-blind, placebo-controlled study conducted exclusively in a male type 2 diabetes population to assess metabolic changes with long-acting testosterone undecanoate (TU). The type 2 diabetes registers of seven general practices identified 211 patients for a 30-week double-blind, placebo-controlled study of long-acting TU 1,000 mg followed by 52 weeks of open-label use. Because of the established impact of age, obesity, and depression on sexual function, these variables were also assessed for influence on metabolic parameters. Changes in glycated hemoglobin (HbA1c) and the level of testosterone at which response are achieved. Treatment with TU produced a statistically significant reduction in HbA1c at 6 and 18 weeks and after a further 52 weeks of open-label medication most marked in poorly controlled patients with baseline HbA1c greater than 7.5 where the reduction was 0.41% within 6 weeks, and a further 0.46% after 52 weeks of open-label use. There was significant reduction in waist circumference, weight, and body mass index in men without depression, and improvements were related to achieving adequate serum levels of testosterone. There were no significant safety issues. Testosterone replacement therapy significantly improved HbA1c, total cholesterol, and waist circumference in men with type 2 diabetes. Improvements were less marked in men with depression at baseline, and therapeutic responses were related to achieving adequate serum testosterone levels. Current advice on 3- to 6-month trials of therapy may be insufficient to achieve maximal response. Patients reported significant improvements in general health.


Chaperoning a cellular upheaval in malaria: heat shock proteins in Plasmodium falciparum.
In addition to their ability to help newly synthesized proteins to fold, molecular chaperones are also recognized for their participation in cellular processes ranging from protein trafficking, signal transduction, differentiation and development. Novel roles for this group of proteins have come to light through studies on important human pathogens like Leishmania, Trypanosoma as well as Plasmodia species. This review analyzes our current state of knowledge on molecular chaperones in human malarial parasite Plasmodium falciparum. In addition to a comparative analysis of their structures, complexes, client proteins and functions, a discussion on their potential as vaccine candidates as well as drug targets is also presented. The major chaperone classes of Hsp90, Hsp70, Hsp60 and Hsp40 family are well represented in the malarial parasite. Genomic cataloguing of all the parasite chaperone homologs indicates that about 2% of the total number of genes are dedicated to this function. While Hsp90 and Hsp70 are the most abundantly expressed, the Hsp40 class appears to be the best represented among the 92 chaperones encoded by the parasite genome. Importantly PfHsp70 is considered a potential vaccine candidate and PfHsp90 has been implicated as a drug target against the parasite. Available information suggests fascinating roles for chaperones in the life cycle of the parasite. In addition to their value as therapeutic targets, the study of chaperones in parasitic systems may likely reveal new principles of chaperone function in biology.


[Intubation granulomas of the lacrimal ducts in patients with silicone implants].
The results of 315 endonasal operations on the lacrimal duct with long intubation are analyzed. The most incident complication of long intubation of the lacrimal duct is formation of intubation granulomas, which are most often localized in the inferior lacrimal canaliculus; their etiology is sometimes allergic--they form as a response of adjacent tissues to the material of the intubation tube, and the findings of our recent histological study prove it. The diagnosis of intubation granulomas is easy in the majority of cases. The treatment consists in removal and obligatory adequate total and local antiallergic therapy decelerating the growth and relapses of granulomas. After removal of the intubation tube the growth of granulations ceases and a fine cicatrix forms.


Compilation of a panel of informative single nucleotide polymorphisms for bovine identification in the Northern Irish cattle population.
Animal identification is pivotal in governmental agricultural policy, enabling the management of subsidy payments, movement of livestock, test scheduling and control of disease. Advances in bovine genomics have made it possible to utilise inherent genetic variability to uniquely identify individual animals by DNA profiling, much as has been achieved with humans over the past 20 years. A DNA profiling test based on bi-allelic single nucleotide polymorphism (SNP) markers would offer considerable advantages over current short tandem repeat (STR) based industry standard tests, in that it would be easier to analyse and interpret. In this study, a panel of 51 genome-wide SNPs were genotyped across panels of semen DNA from 6 common breeds for the purposes of ascertaining allelic frequency. For SNPs on the same chromosome, the extent of linkage disequilbrium was determined from genotype data by Expectation Maximization (EM) algorithm. Minimum probabilities of unique identification were determined for each breed panel. The usefulness of this SNP panel was ascertained by comparison to the current bovine STR Stockmarks II assay. A statistically representative random sampling of bovine animals from across Northern Ireland was assembled for the purposes of determining the population allele frequency for these STR loci and subsequently, the minimal probability of unique identification they conferred in sampled bovine animals from Northern Ireland. 6 SNPs exhibiting a minor allele frequency of less than 0.2 in more than 3 of the breed panels were excluded. 2 Further SNPs were found to reside in coding areas of the cattle genome and were excluded from the final panel. The remaining 43 SNPs exhibited genotype frequencies which were in Hardy Weinberg Equilibrium. SNPs on the same chromosome were observed to have no significant linkage disequilibrium/allelic association. Minimal probabilities of uniquely identifying individual animals from each of the breeds were obtained and were observed to be superior to those conferred by the industry standard STR assay. The 43 SNPs characterised herein may constitute a starting point for the development of a SNP based DNA identification test for European cattle.


Trends in incidence and survival of women with invasive vulvar cancer in the United States and Canada: a population-based study.
The aim of this study is to estimate trends in incidence and relative survival in women diagnosed with invasive squamous cell vulvar cancer in the United States (U.S.) and Canada over the periods of 1973-2010 for U.S. and 1992-2008 for Canada. We identified patients with primary invasive squamous cell vulvar cancers in the Surveillance, Epidemiology, and End Results cancer registry database and the Canadian Cancer Registry dataset. Women younger than 40 years were excluded because of the small number of patients in this age group. A flexible parametric model was used to estimate two- and five-year relative survival ratios and excess mortality rate. In total 15,041 patients diagnosed with invasive squamous cell vulvar cancer were included in this analysis. The incidence rate of vulvar cancer increased in both U.S. and Canada. Two- and five-year relative survival ratios decreased over time for both countries, particularly for patients 80 years and over. The incidence rate of invasive vulvar cancer continued to increase in U.S. and Canada while its two- and five-year relative survival ratios gradually decreased for all age groups over the last few decades. Also, excess mortality rate reaches to its peak after about 6 months from diagnosis and then starts to decline. This is the first report that examine relative survival ratio for vulvar cancer in Canada and U.S. and serves as a basis for future similar studies.


Photoacoustic Doppler measurement of flow using tone burst excitation.
In this paper a novel technique for flow measurement which is based on the photoacoustic (PA) Doppler effect is described. A significant feature of the proposed approach is that it can be implemented using tone burst optical excitation thus enabling simultaneous measurement of both velocity and position. The technique, which is based on external modulation and heterodyne detection, was experimentally demonstrated by measurement of the flow of a suspension of carbon particles in a silicon tube and successfully determined the particles mean velocity up to values of 130 mm/sec, which is about 10 times higher than previously reported PA Doppler set-ups. In the theoretical part a rigorous derivation of the PA response of a flowing medium is described and some important simplifying approximations are highlighted.


A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism.
The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.


Unlocking the opportunity of tight glycaemic control. Far from goal.
The long-term benefits of providing intensive insulin therapy to control blood glucose levels have been demonstrated in people with type 1 or type 2 diabetes mellitus. However, achieving good glycaemic control in clinical practice continues to be a major challenge with only a small proportion of people with diabetes achieving current treatment goals. Some of the reasons for this include ineffectual diet and weight control initiatives, limited efficacy of therapeutic agents or association with excessive adverse events, delayed initiation of insulin therapy and poor patient acceptance and compliance with a regimen of multiple daily insulin injections. New ways of delivering insulin without the need for subcutaneous injections may overcome many of these limitations and thus help in the early adoption of insulin treatment by patients, assist in achieving and maintaining long-term optimal glycaemic control and improve patients' quality of life.


Benefits of extra-pair mating may depend on environmental conditions-an experimental study in the blue tit (Cyanistes caeruleus).
Extra-pair mating constitutes a relatively common reproductive strategy in many socially monogamous bird species. This strategy may considerably improve reproductive success of males, but female benefits from extra-pair matings still remain unclear and empirical evidence is scarce. This may be because genetic benefits of extra-pair mating are not always revealed. It is possible that they are shown only in unfavourable environmental conditions and hence problems arise with detecting differences between within- and extra-pair offspring whose performance is measured under favourable conditions. In order to test this prediction, we manipulated environmental conditions by altering brood sizes of blue tits and compared phenotypic characteristics of within- and extra-pair offspring in mixed-paternity broods. We found that extra-pair young exhibited a higher response to phytohemagglutinin in comparison to within-pair young, but this was only observed among nestlings from experimentally enlarged broods. These results indicate that genetic benefits may interact with the environment, and thus benefits of extra-pair mating are likely to become visible only when conditions are relatively unfavourable.


The Quick Response Team: a pilot project.
The Quick Response Team, consisting of physicians, nurses and social workers in an emergency room setting, conducted a five month pilot project whose overall goal was to eliminate unnecessary admissions to an acute care hospital. This paper reports on the three social work objectives of the program: high risk screening and direct intervention, including assessment, short-term counselling, information, and referral; follow-up services; and social work coverage to all units after hours. Over a 4 month period 11.6% of all patients in the emergency room were assessed by the social work staff and 24 non-acute admissions were deferred. The results of the study confirm the effectiveness of a social work presence in the emergency department in reducing non-acute admissions and in providing continuity of care for patients at high social risk.


[The relationship between insulin-dependent diabetes mellitus and acute infections in children].
The morbidity of insulin-dependent diabetes mellitus (IDDM) in children develops not evenly. Epidemiological leaps are periodically registered. This character of dynamics suggests the existence of environmental factors having the influence on the IDDM morbidity. One of these environmental factors is viral infection. We have set ourselves as an object to analyze the relationship between the primary morbidity of IDDM and some infectious diseases in children, to build up the prognostic models for the dynamics of IDDM morbidity and to evaluate their quality. Statistic analysis of the relationship between the primary morbidity of chicken pox, scarlet fever, measles, mumps, viral hepatitis, acute intestinal infectious diseases (AIID), acute upper respiratory infections (AURI) and insulin-dependent diabetes mellitus in children of Grodno region covering the period from 1980 to 2001 years has been performed. It has been established, that morbidity rate of IDDM reliably positively correlated with morbidity of AURJ and AIID (accordingly r=0.62; and p=0.02 and r=0.46; p=0.04) and negatively with the scarlet fever and mumps morbidity (accordingly r=-0.55; p=0.008 and r=-0.53; p=0.01). But cluster analysis has shown, that really only indices of AURI and AIID morbidity were connected and formed one cluster. Morbidity rate of IDDM in children in the current year is most closely connected with AURI and AIID frequency in the previous year, but frequency of the above-mentioned infections registered in the same year influences less on diabetes morbidity, not mentioning the infections of 2-years standing which practically have no influence. If the increase in AURI morbidity accounts for 10% as compared to the previous year one may prognosticate with high reliability an increase of primary morbidity of IDDM by 7.7% on the average during the same year, and by 8.3% in the following year. For AIID these indices account for 3.5% and 4.4% correspondingly. In the increase of the morbidity rate of AIID the morbidity rate of IDDM reduces.


Association between functional capacity tests and fractures: an eight-year prospective population-based cohort study.
This study of postmenopausal women (n=2,928) with an eight-year follow-up revealed that impairment in functional status associated with the increased fracture risk. The standing-on-one-foot and grip strength tests and a question about self-assessed ability to move can be used to identify women with a high risk of suffering a fracture. Poor functional status has pointed to associate with injurious falls and consequent fractures. Our aim was to define association between functional capacity and fractures. This study was based on the Osteoporosis Risk Factor and Prevention Study (OSTPRE). A total of 2,928 postmenopausal women took part in the functional capacity and muscle strength tests. The duration of fracture follow-up varied from 6.43 to 9.86 (mean 8.37) years and the first fracture was the end-point event for the statistical analyses. All analyses were done with Cox-regression. A total of 261 end-point fractures occurred. In multivariate analysis the inability to stand-on-one-foot for 10 seconds increased the risk of hip fracture (hazard ratio with 95% CI) 9.11-fold (1.98-42.00). Decreased grip strength associated with 1.05-fold (1.01-1.09) increased risk of hip fractures. Low leg extension strength associated with 1.02-fold (1.00-1.03) higher risk for all fractures. The self-assessed ability to walk less than 100 meters at baseline increased the risk of ankle 2.36-fold (1.10-5.08), hip 11.57-fold (2.73-49.15) and clinical vertebral fractures 3.85-fold (1.45-10.22). According to these results the standing-on-one-foot less than 10 seconds, grip strength and a question about ability to walk less than 100 meters may help to predict postmenopausal fractures.


[Nerve tissue ultrastructure in experimental brain injuries in animals with increased immunobiologic reactivity following treatment with certain desensitizing drugs].
The effects of aminazin and aspirin on brain injuries in animals with immunological hypersensitivity of the body were studied. It was shown that the ultrastructural changes of the nervous tissue and the edema in the perifocal zone of the injury at early periods after ist inflicting were less marked in those animals than in sensitized animals which received no preliminary drug treatment. The capacity of aminazin and aspirin to inhibit the activity of oxidative enzymes, probably, creates conditions in which the development of the dystrophic changes is delayed. This is important for further development and course of the pathological process. Examinations of the aspirin effect under the conditions of the experiment revealed its inhibitory role in the formation of the antigen-antibody complex in the zone of the injury. Taking into account possible sensitization of the body even in clinically healthy persons one can hope that the use of desensitizing drugs may contribute to diminution of brain edema and the morphological changes resulting from surgical interventions in some diseases of the nervous system.


Ambulatory antibiotic use and prescription drug coverage in older adults.
Several studies have shown that use of medications to treat chronic conditions is highly sensitive to out-of-pocket price and influenced by changes in insurance coverage. Because antibiotics target infections and are used for a short period, one may expect antibiotic use to be less responsive to price. However, no studies have evaluated how antibiotic use changes with drug coverage. We evaluate changes in ambulatory oral antibiotic use after implementation of the Medicare drug benefit (Part D). We conducted a comparison group analysis 2 years before and after implementation of Part D using insurance claims data from a large Medicare Advantage plan (January 1, 2004, through December 31, 2007). Outcomes included the likelihood of using any oral antibiotics and major antibiotic subclasses among 35 102 older adults and rates of antibiotic use among those with pneumonia and other acute respiratory tract infections. Overall antibiotic use increased most among those who did not previously have drug coverage (relative odds ratio [OR], 1.58; 95% confidence interval [CI], 1.36-1.85). Use of the broad spectrum antibiotic subclasses of quinolones (OR, 1.70; 95% CI, 1.35-2.15) and macrolides (1.59; 1.26-2.01) increased more than the use of other subclasses, especially for those with prior drug coverage. Rates of ambulatory antibiotic use associated with pneumonia increased (OR, 3.60; 95% CI, 2.35-5.53) more than those associated with other acute respiratory tract infections (2.29; 1.85-2.83). Antibiotic use increased among older adults whose drug coverage improved after Part D implementation, with the largest increases for broad spectrum, newer, and more expensive antibiotics. Our study suggests reimbursement may play a role in addressing inappropriate antibiotic use.


Autoantibodies against Leydig cells in patients after spermatic cord torsion.
This study is aimed at searching for the presence of circulating antibodies against frozen sections of human testis, ovary and trophoblast in patients that had spermatic cord torsion. Sixty-eight sera samples were studied. Nine patients (13.2%) were positive for organ specific anti-testis autoantibodies. Six patients were positive for antibodies against Leydig cells: five were positive only with the indirect immunofluorescence technique of complement fixing (ITT/CF), the sixth patient was positive only with the indirect immunofluorescence technique (ITT). The other three patients were positive for antibodies against germ line cells: two patients were positive with both techniques, the third was positive only with indirect immunofluorescence technique. Eight of these patients were negative for antibodies against adrenal cortex while only one case was positive with indirect immunofluorescence technique both on adrenal cortex and Leydig cells. Human lyophilized testis absorbed the reactive antibodies against Leydig cells and germ line cells, while adrenal cortex and lyophilized testosterone were ineffective. This study shows the identification of a specific antibody against Leydig cells and germ line cells in patients after spermatic cord torsion.


Identification of critical steps governing the two-component alkanesulfonate monooxygenase catalytic mechanism.
The alkanesulfonate monooxygenase enzyme (SsuD) catalyzes the oxygenolytic cleavage of a carbon-sulfur bond from sulfonated substrates. A mechanism involving acid-base catalysis has been proposed for the desulfonation mechanism by SsuD. In the proposed mechanism, base catalysis is involved in abstracting a proton from the alkane peroxyflavin intermediate, while acid catalysis is needed for the protonation of the FMNO(-) intermediate. The pH profiles of k(cat) indicate that catalysis by SsuD requires a group with a pK(a) of 6.6 ± 0.2 to be deprotonated and a second group with a pK(a) of 9.5 ± 0.1 to be protonated. The upper pK(a) value was not present in the pH profiles of k(cat)/K(m). Several conserved amino acid residues (His228, His11, His333, Cys54, and Arg226) have been identified as having potential catalytic importance due to the similar spatial arrangements with close structural and functional relatives of SsuD. Substitutions to these amino acid residues were generated, and the pH dependencies were evaluated and compared to wild-type SsuD. Although a histidine residue was previously proposed to be the active site base, the His variants possessed similar steady-state kinetic parameters as wild-type SsuD. Interestingly, R226A and R226K SsuD variants possessed undetectable activity, and there was no detectable formation of the C4a-(hydro)peroxyflavin intermediate for the Arg226 SsuD variants. Guanidinium rescue with the R226A SsuD variant resulted in the recovery of 1.5% of the wild-type SsuD k(cat) value. These results implicate Arg226 playing a critical role in catalysis and provide essential insights into the mechanistic steps that guide the SsuD desulfonation process.


Detection of tumor-specific genetic alterations in bone marrow from early-stage breast cancer patients.
Detection of genetic markers associated with early breast cancer may prove clinically relevant for identifying patients at increased risk for relapse. Loss of heterozygosity (LOH), a specific genetic aberration, commonly occurs during breast cancer initiation and metastasis. Early detection of tumor metastasis to bone marrow (BM) using conventional histochemical techniques has been limited because of suboptimal efficiency and sensitivity. Because bone is such a common site of breast cancer recurrence, we sought to determine whether microsatellite markers associated with breast cancer could be detected in BM aspirates from patients with early-stage breast cancer. Cell-free plasma from BM aspirates in 48 patients was assessed for LOH using a panel of eight polymorphic microsatellite markers. LOH was detected in 11 (23%) of 48 patients' BM aspirates. Advancing American Joint Committee on Cancer (AJCC) stage was associated with an increased incidence of LOH. Concordance was present between LOH identified in BM aspirates and matched-pair primary tumors. No samples contained detectable tumor cells on routine histology. In 24 patients, paired peripheral blood serum samples were available for analysis. In these cases, BM detection of LOH was more frequent than serum. This study demonstrates the novel finding of tumor-related genetic markers in BM aspirate plasma of early-stage breast cancer patients and provides a unique approach for assessing subclinical systemic disease progression and the monitoring of breast cancer patients.


Action of CAP on the malT promoter in vitro.
DNase I footprinting experiments demonstrated that CAP, the cyclic AMP receptor protein of Escherichia coli, binds around position -70 at the promoter of malT, the positive regulator gene of the maltose regulon. The binding of CAP in the presence of cyclic AMP favored the subsequent specific binding of RNA polymerase. Initiation of malT transcription in vitro displayed an absolute requirement for CAP at all tested RNA polymerase concentrations. However this was not the case with a mutant promoter (malTp1), which leads to CAP-independent malT expression in vivo. In that case an effect of CAP was seen only at the lower concentrations of RNA polymerase. These results, which suggest that CAP stimulates malT expression by promoting the binding of polymerase to the promoter, are compared with those obtained in other systems.


2016 updated MASCC/ESMO consensus recommendations: prevention of radiotherapy-induced nausea and vomiting.
Radiotherapy-induced nausea and vomiting (RINV) are distressing symptoms. Evidence-based guidelines should facilitate the prescription of the best possible antiemetic prophylaxis. As part of the MASCC/ESMO Antiemetic Guidelines Update 2016, a thorough review of the literature concerning RINV since the 2009 update was required. A systematic review of the literature including data published from June 2009 to May 2015 was performed. Committee VII (RINV) under the MASCC/ESMO Antiemetic Guidelines Update Committee assessed the literature. The searches yielded 926 records, 906 records were excluded, leaving 20 records for full text assessment, and 18 publications were finally included. The only fully published randomized studies in prevention of RINV were two negative studies in acupuncture and green tea, respectively. No data to support new recommendations for antiemetic prophylaxis in RINV was available. However, based on expert opinions, the committee agreed on changes in emetic risk level for certain sites of irradiation. The serotonin receptor antagonists are still the corner stone in antiemetic prophylaxis of nausea and vomiting induced by high and moderate emetic risk radiotherapy. The studies available since the last update did not change recommendations for antiemetic prophylaxis. The emetogenicity of craniospinal radiotherapy was reclassified from low to moderate emetic level along with some other minor changes. In the future, RINV prophylaxis in single fraction, multiple fraction, and in concomitant chemo-radiotherapy still need to be explored with regard to the different classes and combinations of antiemetic drugs.


The prevalence, risk factors, and screening measure for prediabetes and diabetes among Emirati overweight/obese children and adolescents.
The aim of the study was to estimate the prevalence of prediabetes and type 2 diabetes (T2D) among overweight/obese children and adolescents using different diagnostic/screening methods in comparison. We recruited overweight/obese Emirati students; grade 6-12 (age 11-17 years) from 16 government schools in Sharjah (UAE). Anthropometric, demographic, and clinical history data was measured by standard methods. Body mass index (BMI) was categorized according to BMI percentile charts for age and sex - CDC. Capillary fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) were measured by finger prick test, followed by confirmatory oral glucose tolerance tests (OGTT) and venous HbA1c for students with abnormal capillary FBG and/or HbA1c. Of a total of 1034 participants (45 % females) median age 14.7 years, 443 (43 %) students had abnormal screening results. The prevalence of prediabetes and T2D was 5.4 % and 0.87 %, respectively, based on OGTT (gold standard). HbA1c showed a considerable discrepancy regarding the prevalence of prediabetes (21.9 %), but not diabetes. There was a statistically significant difference in the BMI Z-scores between the three different groups of students showing normal glycemic testing, prediabetes and T2D (p = 0.041). Univariate logistic regression analysis showed that glycemic status was significantly associated with family history of T2D first-degree relatives [OR 1.87: 95 % CI: 1.04-3.36; P = 0.036], parents employment [OR 1.79: 95 % CI: 1.06-3.02; P = 0.029] and levels of triglycerides [OR 2.28: 95 % CI: 1.11-4.68; P = 0.024]. The prevalence of prediabetes and diabetes was high among overweight/obese Emirati children and adolescents. The numbers for prediabetes were considerably higher when using HbA1c as compared to OGTT. Overall adiposity, family history of T2D, employment and high levels of triglycerides were risk factors associated with abnormal glycemic testing.


Induction chemotherapy followed by concurrent chemoradiation for patients with non-operable stage III non-small-cell lung cancer.
Combined modality treatment with chemotherapy (CT) and radiotherapy (RT) in stage III non-small-cell lung cancer is considered as standard therapy. As concomitant CT appears to be beneficial, the choice of anticancer agents and the role of induction chemotherapy is still unresolved. We present our experience based on an induction CT scheme with carboplatin plus paclitaxel followed by RT and concomitant CT. 31 patients with non-operable stage IIIA or IIIB NSCLC without pleural effusion were included in this study: 30 males, 1 female; median age 66 years (range: 50-81); 32% with non-operable stage IIIA and 68% with stage IIIB without pleural effusion; 61% squamous cell carcinoma, 32% adenocarcinoma and 7% other histologies. Regarding performance status (PS), 9.7% PS 0 and 90% PS 1 were included. Patients received 3 courses of induction CT with carboplatin AUC=6 and paclitaxel 175 mg/m(2), administrated i.v. on day 1 of each 21-day cycle, followed by thoracic irradiation (total dose 60-65 Gy, daily fractions 1.8-2 Gy) with two concurrent courses of carboplatin/paclitaxel. 16.2% of the patients achieved complete response, 48.4% partial response, 25.8% stable disease and 9.6% progression of disease. Median progression-free and overall survival was 12 and 18 months, respectively. The most frequent haematological toxicities were grade (G) 3 anaemia in 19.3%, G3 neutropenia in 9.6% and G4 neutropenia in 12.9%. Esophageal G2 toxicity (RTOG) was observed in 28.1% of cases. The induction CT followed by concomitant chemoradiation used in this study appears feasible, safe and effective when administered to an unselected inoperable NSCLC stage III patient cohort in the everyday routine clinical practice. Further, our results are comparable to previously published phase III studies.


Restoration of radiation therapy-induced salivary gland dysfunction in mice by post therapy IGF-1 administration.
Radiotherapy for head and neck cancer results in severe and chronic salivary gland dysfunction in most individuals. This results in significant side effects including xerostomia, dysphagia, and malnutrition which are linked to significant reductions in patients' quality of life. Currently there are few xerostomia treatment approaches that provide long-term results without significant side effects. To address this problem we investigated the potential for post-therapeutic IGF-1 to reverse radiation-induced salivary gland dysfunction. FVB mice were treated with targeted head and neck radiation and significant reductions in salivary function were confirmed 3 days after treatment. On days 4-8 after radiation, one group of mice was injected intravenously with IGF-1 while a second group served as a vehicle control. Stimulated salivary flow rates were evaluated on days 30, 60, and 90 and histological analysis was performed on days 9, 30, 60, and 90. Irradiated animals receiving vehicle injections have 40-50% reductions in stimulated salivary flow rates throughout the entire time course. Mice receiving injections of IGF-1 have improved stimulated salivary flow rates 30 days after treatment. By days 60-90, IGF-1 injected mice have restored salivary flow rates to unirradiated control mice levels. Parotid tissue sections were stained for amylase as an indicator of functioning acinar cells and significant reductions in total amylase area are detected in irradiated animals compared to unirradiated groups on all days. Post-therapeutic injections of IGF-1 results in increased amylase-positive acinar cell area and improved amylase secretion. Irradiated mice receiving IGF-1 show similar proliferation indices as untreated mice suggesting a return to tissue homeostasis. Post-therapeutic IGF-1 treatment restores salivary gland function potentially through normalization of cell proliferation and improved expression of amylase. These findings could aid in the rational design of therapy protocols or drugs for the treatment of radiation-induced salivary gland dysfunction in patients who have completed their anti-cancer therapies.


Avalanche dynamics of human brain oscillations: relation to critical branching processes and temporal correlations.
Human brain oscillations fluctuate erratically in amplitude during rest and exhibit power-law decay of temporal correlations. It has been suggested that this dynamics reflects self-organized activity near a critical state. In this framework, oscillation bursts may be interpreted as neuronal avalanches propagating in a network with a critical branching ratio. However, a direct comparison of the temporal structure of ongoing oscillations with that of activity propagation in a model network with critical connectivity has never been made. Here, we simulate branching processes and characterize the activity propagation in terms of avalanche life-time distributions and temporal correlations. An equivalent analysis is introduced for characterizing ongoing oscillations in the alpha-frequency band recorded with magnetoencephalography (MEG) during rest. We found that models with a branching ratio near the critical value of one exhibited power-law scaling in life-time distributions with similar scaling exponents as observed in the MEG data. The models reproduced qualitatively the power-law decay of temporal correlations in the human data; however, the correlations in the model appeared on time scales only up to the longest avalanche, whereas human data indicate persistence of correlations on time scales corresponding to several burst events. Our results support the idea that neuronal networks generating ongoing alpha oscillations during rest operate near a critical state, but also suggest that factors not included in the simple classical branching process are needed to account for the complex temporal structure of ongoing oscillations during rest on time scales longer than the duration of individual oscillation bursts.


Unconventional mixed-valent complexes of ruthenium and osmium.
Recent developments have helped to extend the repertoire of mixed-valent ruthenium and osmium complexes beyond conventional systems. This extension has been achieved by using sophisticated ligands and by creating more variegated coordination patterns. The strategies employed include the use of multidentate ligands (which give rise to multinuclear and chelate complexes) and the use several redox active components (non-innocent ligands and oxidation-state ambivalence). The results offer enhanced chemical insight into metal-ligand electron-transfer situations and suggest that mixed-valent materials may eventually be exploited in molecular electronics and molecular computing.


Glutathione s-transferase p1: gene sequence variation and functional genomic studies.
Glutathione S-transferase P1 (GSTP1) is of importance for cancer research because of its role in detoxifying carcinogens, activating antineoplastic prodrugs, metabolizing chemotherapeutic agents, and its involvement in cell cycle and apoptosis regulation. Two common GSTP1 genetic polymorphisms have been studied extensively. However, the full range of GSTP1 genetic variation has not been systematically characterized in the absence of disease pathology. We set out to identify common GSTP1 polymorphisms in four ethnic groups, followed by functional genomic studies. All exons, splice junctions, and the 5'-flanking region of GSTP1 were resequenced using 60 DNA samples each from four ethnic groups. The 35 single-nucleotide polymorphisms (SNP) identified included six nonsynonymous SNPs and 17 previously unreported polymorphisms. GSTP1 variant allozymes were then expressed in COS-1 cells, and five displayed significantly altered levels of enzyme activity. One decreased to 22% of the wild-type (WT) activity. Four variant allozymes had K(m) values that differed significantly from that of the WT, and five showed altered levels of immunoreactive protein compared with WT, with a significant correlation (r = 0.79, P < 0.007) between levels of immunoreactive protein and enzyme activity in these samples. In the Mexican American population, five linked SNPs were significantly associated with GSTP1 mRNA expression, one of which was found by electrophoretic mobility shift assay to alter protein binding. These studies have identified functionally significant genetic variation, in addition to the two frequently studied GSTP1 nonsynonymous SNPs, that may influence GSTP1's contribution to carcinogen and drug metabolism, and possibly disease pathogenesis and/or drug response.


Potentiometric sensors enabling fast screening of the benign prostatic hyperplasia drug alfuzosin in pharmaceuticals, urine and serum.
The construction and characterization of potentiometric membrane electrodes are described for the quantification of alfuzosin, a drug used in a mono- and combined therapy of benign prostatic hyperplasia (BPH). The membranes of these electrodes consist of alfuzosin hydrochloride-tetraphenyl borate, (Az-TPB), chlorophenyl borate (Az-ClPB), and phosphotungstate (Az(3)-PT) ion associations as molecular recognition reagent dispersed in PVC matrix with dioctylpthalate as plasticizer. The performance characteristics of these electrodes, which were evaluated according to IUPAC recommendations, revealed a fast, stable and liner response for alfuzosin over the concentration ranges of 8.3 x 10(-6) to 1.0 x 10(-2) M, 3.8 x 10(-6) to 1.0 x 10(-2) M, 7.5 x 10(-7) to 1.0 x 10(-2) M AzCl with cationic slopes of 57.0, 56.0 and 58.5 mV/decade, respectively. The solubility product of the ion-pair and the formation constant of the precipitation reaction leading to the ion-pair formation were determined conductometrically. The electrodes, fully characterized in terms of composition, life span and usable pH range, were applied to the potentiometric determination of alfuzosin hydrochloride ion in different pharmaceutical preparations and biological fluids without any interference from excipients or diluents commonly used in drug formulations. The potentiometric method was also used in the determination of alfuzosin hydrochloride in pharmaceutical preparations in four batches with different expiration dates. Validation of the method showed suitability of the proposed electrodes for use in the quality control assessment of alfuzosin hydrochloride. This potentiometric method offers the advantages of high-throughput determination, simplicity, accuracy, automation feasibility, and applicability to turbid and colored sample solutions.


The Pt-catalyzed ethylene hydroamination by aniline: a computational investigation of the catalytic cycle.
A full QM DFT study without system simplification and with the inclusion of solvation effects in aniline as solvent has addressed the addition of aniline to ethylene catalyzed by PtBr(2)/Br(-). The resting state of the catalytic cycle is the [PtBr(3)(C(2)H(4))](-) complex (II). A cycle involving aniline activation by N-H oxidative addition was found energetically prohibitive. The operating cycle involves ethylene activation followed by nucleophilic addition of aniline to the coordinated ethylene, intramolecular transfer of the ammonium proton to the metal center to generate a 5-coordinate (16-electron) Pt(IV)-H intermediate, and final reductive elimination of the PhNHEt product. Several low-energy ethylene complexes, namely trans- and cis-PtBr(2)(C(2)H(4))(PhNH(2)) (IV and V) and trans- and cis-PtBr(2)(C(2)H(4))(2) (VII and VIII) are susceptible to aniline nucleophilic addition to generate zwitterionic intermediates. However, only [PtBr(3)CH(2)CH(2)NH(2)Ph](-) (IX) derived from PhNH(2) addition to II is the productive intermediate. It easily transfers a proton to the Pt atom to yield [PtHBr(3)(CH(2)CH(2)NHPh)](-) (XX), which leads to rate-determining C-H reductive elimination through transition state TS(XX-L) with formation of the σ-complex [PtBr(3)(κ(2):C,H-HCH(2)CH(2)NHPh)](-) (L), from which the product can be liberated via ligand substitution by a new C(2)H(4) molecule to regenerate II. Saturated (18-electron) Pt(IV)-hydride complexes obtained by ligand addition or by chelation of the aminoalkyl ligand liberate the product through higher-energy pathways. Other pathways starting from the zwitterionic intermediates were also explored (intermolecular N deprotonation followed by C protonation or chelation to produce platina(II)azacyclobutane derivatives; intramolecular proton transfer from N to C, either direct or assisted by an external aniline molecule) but all gave higher-energy intermediates or led to the same rate-determining TS(XX-L).


Using nurses to identify HAART eligible patients in the Republic of Mozambique: results of a time series analysis.
The most pressing challenge to achieving universal access to highly active anti-retroviral therapy (HAART) in sub-Saharan Africa is the shortage of trained personnel to handle the increased service requirements of rapid roll-out. Overcoming the human resource challenge requires developing innovative models of care provision that improve efficiency of service delivery and rationalize use of limited resources. We conducted a time-series intervention trial in two HIV clinics in central Mozambique to discern whether expanding the role of basic-level nurses to stage HIV-positive patients using CD4 counts and WHO-defined criteria would lead to more rapid information on patient status (including identification of HAART eligible patients), increased efficiency in the use of higher-level clinical staff, and increased capacity to start HAART-eligible patients on treatment. Overall, 1,880 of the HAART-eligible patients were considered in the study of whom 48.5% started HAART, with a median time of 71 days from their initial blood draw. After adjusting for time, expanding the role of nurses to stage patients was associated with more rational use of higher-level clinical staff at one site (Beira OR 1.9, 95% CI 1.1-3.3; Chimoio OR 0.2, 95% CI 0.1-0.5). In multivariate analyses, the rate of starting HAART in patients with CD4 counts of less than 200/mm3 increased over time (HR = 1.07, 95% CI 1.02-1.13), as did the total number of new patients initiating HAART (beta = 7.3, 95% CI 1.3-13.3). However, the intervention was not independently associated with either of these outcomes in multivariate analyses (HR = 0.9, 95% CI 0.7-1.2) for starting HAART in patients with CD4 counts of less than 200/mm3; (beta = -5.2, p = 0.75) for the total number of new patients initiating HAART per month. No effect of the intervention was found in these outcomes when stratifying by site. The CD4 nurse intervention, when implemented correctly, was associated with a more rational use of higher-level clinical providers, which may improve overall clinic flow and efficient use of the limited supply of human resources. However, this intervention did not lead to an increase in the number of patients starting HAART or a reduction in the time to HAART initiation. Study month appears to play an important role in all outcomes, suggesting that general improvements in clinic efficiency may have overshadowed the effect of the intervention. The lack of observed effect in these outcomes may be due to additional health systems bottlenecks that delay the initiation of treatment in HAART-eligible patients.


Increased serum concentrations of visfatin and its production by different joint tissues in patients with osteoarthritis.
The goal of this study was to investigate the distribution of visfatin in paired serum and synovial fluid (SF) samples from patients with osteoarthritis (OA), and in serum from healthy controls. In addition, we wished to determine the potential sources of visfatin in joint tissue. Twenty-three patients with OA requiring total knee arthroplasty (TKA), 17 healthy subjects and ten donors requiring amputation were included in the study. Concentrations of visfatin in serum and SF were analyzed using an enzyme-linked immunosorbent assay (ELISA). The concentration of visfatin was also measured in conditioned media from cultured joint tissues. We found serum visfatin concentrations to be higher in patients with OA compared to healthy controls (p<0.05), and SF-visfatin concentrations exceeded those in paired serum (p=0.004). In addition, infrapatellar fat pad and synovium were important sources of visfatin, while osteophytes released largest amounts of visfatin. Therefore, osteophytes can be considered a major source of visfatin in the knee joint in patients with OA. These results suggest that visfatin may be involved in the pathophysiology of OA and may have local effects in the joint during the process of OA.


Differential responses of the mangrove Avicennia marina to salinity and abscisic acid.
Salinisation of the soil can cause plant water deficits, ion and nutrient imbalances and toxic reactions. The halophyte, Avicennia marina (Forssk.) Vierh., is a mangrove that tolerates a wide range of soil salinities. In order to understand how salinity affects plant growth and functioning and how salinity responses are influenced by the water deficit signalling hormone abscisic acid (ABA) we grew A. marina seedlings under two non-growth limiting salinities: 60% seawater and 90% seawater and with and without exogenously supplied ABA. We measured growth, photosynthesis, sap flow, aquaporin gene expression, hydraulic anatomy and nutrient status as well as sap ABA concentrations. ABA addition resulted in a drought phenotype (reduced sap flow, transpiration rates and photosynthesis and increased water use efficiency and aquaporin expression). In contrast, growth in high salinity did not lead to responses that are typical for water deficits, but rather, could be characterised as drought avoidance strategies (no reduction in sap flow, transpiration rates and photosynthesis and reduced aquaporin expression). Tissue nutrient concentrations were higher in seedlings grown at high salinities. We did not find evidence for a role for ABA in the mangrove salinity response, suggesting ABA is not produced directly in response to high concentrations of NaCl ions.


The Japanese Breast Cancer Society Clinical Practice Guidelines for surgical treatment of breast cancer, 2022 edition.
The 2022 revision of the Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for surgical treatment of breast cancer was updated following a systematic review of the literature using the Medical Information Network Distribution Service (MINDS) procedure, which focuses on the balance of benefits and harms for various clinical questions (CQs). Experts in surgery designated by the JBCS addressed five areas: breast surgery, axillary surgery, breast reconstruction, surgical treatment for recurrent and metastatic breast cancer, and other related topics. The revision of the guidelines encompassed 4 CQs, 7 background questions (BQs), and 14 future research questions (FRQs). A significant revision in the 2022 edition pertained to axillary management after neoadjuvant chemotherapy in CQ2. The primary aim of the 2022 JBCS Clinical Practice Guidelines is to provide evidence-based recommendations to empower patients and healthcare professionals in making informed decisions regarding surgical treatment for breast cancer.


Adverse trends of cardiovascular risk factors among low risk populations (1983-1994)--a cohort study of workers and farmers in Guangzhou, China.
The levels and trends of cardiovascular risk factors vary greatly throughout China. We examine 10-year trends of cardiovascular risk factors (1983-1994) and the factors related to these trends among low-risk cohorts of workers and farmers in Guangzhou, China. This is a cohort study of 3,131 workers and 3,493 farmers aged 25-64 years at baseline with 10 years of follow-up. We performed a longitudinal analysis to account for the aging of the cohorts and the repeated measures of the same individual. At baseline the prevalence of overweight (including obese) ranged from 1.0% to 11.8%, hypertension ranged from 3.8% to 10.5%, and mean serum total cholesterol (TC) ranged from 155.4 mg/dl to 187.2 mg/dl. Although prevalence of smoking declined, blood pressure levels and body mass index (BMI) increased significantly, and lipid profiles changed unfavorably during the 10-year follow-ups. The prevalence of hypertension increased from 5.0 percentage points (female farmers) to 12.3 percentage points (male farmers). Mean TC increased significantly (e.g., +22.8 mg/dl and +17.0 mg/dl in male and female farmers, respectively). In the longitudinal data analyses, increase in BMI was associated with increase in blood pressure levels and TC. Significant adverse trends of risk factors persisted after adjustment for aging, education, BMI, smoking, and alcohol intake. Urgent action is needed to prevent and reverse the unhealthy trends occurring among these low risk Chinese workers and farmers.


[Probability of premature mortality caused by non-communicable diseases in Beijing, 2010-2015].
Objective: To understand the probability of premature mortality caused by non-communicable diseases (NCD) in Beijing from 2010 to 2015. Methods: The data of deaths from Beijing vital registration system were used to analyze age-standardized NCD mortality rates, proportion of NCD deaths in age group <70 years and premature NCD mortality. Results: NCD deaths accounted for 90% of the total deaths in Beijing. Age-standardized NCD death rate decreased from 332.43/100 000 in 2010 to 280.02/100 000 in 2015. Meanwhile, the probability of deaths from four NCDs between in age group 30-70 years (premature NCD mortality) decreased from 12.81% to 11.11% in Beijing. The premature mortality of four NCDs in men was 14.63%, and compared with 2015 baseline, it would decrease by 16.4% to reach 2025 goal (12.23%), and the probability of premature mortality four NCDs in women was 7.54%, and compared with 2015 baseline, it would decrease by 6.8% to reach the 2025 goal (7.03%). People living in suburb areas had a higher probability of premature NCD mortality (13.67%) than those living in urban areas (9.72%) in Beijing in 2015. Conclusions: The premature NCD mortality was much higher in men than in women in Beijing. More attention should be paid to the control of risk factors for NCD premature deaths, especially in men and in suburb residents, to reach the 25×25 goal.


Arrowsmith two-node search interface: a tutorial on finding meaningful links between two disparate sets of articles in MEDLINE.
The Arrowsmith two-node search is a strategy that is designed to assist biomedical investigators in formulating and assessing scientific hypotheses. More generally, it allows users to identify biologically meaningful links between any two sets of articles A and C in PubMed, even when these share no articles or authors in common and represent disparate topics or disciplines. The key idea is to relate the two sets of articles via title words and phrases (B-terms) that they share. We have created a free, public web-based version of the two-node search tool (http://arrowsmith.psych.uic.edu), have described its development and implementation, and have presented analyses of individual two-node searches. In this paper, we provide an updated tutorial intended for end-users, that covers the use of the tool for a variety of potential scientific use case scenarios. For example, one can assess a recent experimental, clinical or epidemiologic finding that connects two disparate fields of inquiry--identifying likely mechanisms to explain the finding, and choosing promising follow-up lines of investigation. Alternatively, one can assess whether the existing scientific literature lends indirect support to a hypothesis posed by the user that has not yet been investigated. One can also employ two-node searches to search for novel hypotheses. Arrowsmith provides a service that cannot be carried out feasibly via standard PubMed searches or by other available text mining tools.


Integrating Financial Coaching and Referrals into a Smoking Cessation Program for Low-income Smokers: a Randomized Waitlist Control Trial.
Financial distress is a barrier to cessation among low-income smokers. To evaluate an intervention that integrated financial coaching and benefits referrals into a smoking cessation program for low-income smokers. Randomized waitlist control trial conducted from 2017 to 2019. Adult New York City residents were eligible if they reported past 30-day cigarette smoking, had income below 200% of the federal poverty level, spoke English or Spanish, and managed their own funds. Pregnant or breastfeeding people were excluded. Participants were recruited from two medical centers and from the community. The intervention (n = 208) offered smoking cessation coaching, nicotine replacement therapy, money management coaching, and referral to financial benefits and empowerment services. The waitlist control (n=202) was usual care during a 6-month waiting period. Treatment engagement, self-reported 7-day abstinence, and financial stress at 6 months. At 6 months, intervention participants reported higher abstinence (17% vs. 9%, P=0.03), lower stress about finances (β, -0.8 [SE, 0.4], P=0.02), and reduced frequency of being unable to afford activities (β, -0.8 [SE, 0.4], P=0.04). Outcomes were stronger among participants recruited from the medical centers (versus from the community). Among medical center participants, the intervention was associated with higher abstinence (20% vs. 8%, P=0.01), higher satisfaction with present financial situation (β, 1.0 [SE, 0.4], P=0.01), reduced frequency of being unable to afford activities (β, -1.0 [SE, 0.5], P=0.04), reduced frequency in getting by paycheck-to-paycheck (β, -1.0 [SE, 0.4], P=0.03), and lower stress about finances in general (β, -1.0 [SE, 0.4], P = 0.02). There were no group differences in outcomes among people recruited from the community (P>0.05). Among low-income smokers recruited from medical centers, the intervention produced higher abstinence rates and reductions in some markers of financial distress than usual care. The intervention was not efficacious with people recruited from the community. ClinicalTrials.gov Identifier: NCT03187730.