Transoral Robotic Thyroidectomy for Papillary Thyroid Carcinoma: Perioperative Outcomes of 100 Consecutive Patients.
Endoscopic transoral thyroidectomy is a recently introduced technique of remote access thyroidectomy. We previously reported the feasibility of the robotic approach (TORT). Nevertheless, experience to date is limited, with scant data on outcomes in patients with papillary thyroid carcinoma (PTC). This was a retrospective analysis of prospectively collected data. Patients with PTC, who underwent TORT at a single center between March 2016 and February 2017, were analyzed. There were a total of 100 patients (85 women, 15 men) with a mean age of 40.7 ± 9.8 years, and a mean tumor size of 0.8 ± 0.5 cm. Nine patients underwent a total thyroidectomy, and 91 underwent a lobectomy. The operative time for a total thyroidectomy and lobectomy was 270.0 ± 9.3 and 210.8 ± 32.9 min, respectively. Ipsilateral prophylactic central neck compartment dissection was performed routinely with retrieval of 5.0 ± 3.6 lymph nodes. Perioperative morbidity was present in nine patients including transient recurrent laryngeal nerve palsy (n = 1), postoperative bleeding requiring surgical intervention (n = 1), zygomatic bruising (n = 2), chin flap perforation (n = 1), oral commissure tearing (n = 2), and chin dimpling (n = 2). There was no conversion to endoscopic or conventional open thyroid surgery. In this study, TORT could be safely performed in a large series of patients with PTC without serious complications. In selected patients, TORT by experienced surgeons could be considered an alternative approach for remote access thyroidectomy.


Intravenous dexmedetomidine versus clonidine for prolongation of bupivacaine spinal anesthesia and analgesia: A randomized double-blind study.
Alpha2-adrenergic agonists have synergistic action with local anesthetics and may prolong the duration of sensory, motor blockade and postoperative analgesia obtained with spinal anesthesia. The objectives of this study are to compare and evaluate the efficacy of intravenous dexmedetomidine premedication with clonidine and placebo on spinal blockade duration, postoperative analgesia and sedation in patients undergoing surgery under bupivacaine intrathecal block. In this prospective, randomized, double-blind placebo-controlled study, 75 patients of the American Society of Anesthesiologists status I or II, scheduled for orthopedic lower limb surgery under spinal anesthesia, were randomly allocated into three groups of 25 each. Group DE received dexmedetomidine 0.5 μgkg(-1), group CL received clonidine 1.0 μgkg(-1) and placebo group PL received 10 ml of normal saline intravenously before subarachnoid anesthesia with 15 mg of 0.5% hyperbaric bupivacaine. Onset time and regression times of sensory and motor blockade, the maximum upper level of sensory blockade were recorded. Duration of postoperative analgesia and sedation scores along with side effects were also recorded. Data was analyzed using analysis of variance or Chi-square test, and the value of P < 0.05 was considered statistically significant. The sensory block level was higher with dexmedetomidine (T4 ± 1) than clonidine (T6 ± 1) or placebo (T6 ± 2). Dexmedetomidine also increased the time (243.35 ± 56.82 min) to first postoperative analgesic request compared with clonidine (190.93 ± 42.38 min, P < 0.0001) and placebo (140.75 ± 28.52 min, P < 0.0001). The maximum Ramsay sedation score was greater in the dexmedetomidine group than other two groups (P < 0.0001). Premedication with intravenous dexmedetomidine is better than intravenous clonidine to provide intraoperative sedation and postoperative analgesia during bupivacaine spinal anesthesia.


Coronary Computed Tomography Angiography Versus Traditional Care: Comparison of One-Year Outcomes and Resource Use.
Three large, multicenter, randomized, clinical trials have shown that coronary computed tomography (CT) angiography allows efficient evaluation and safe discharge of patients with low- to intermediate-risk chest pain who present to the emergency department (ED). We report 1-year event rates and resource use from the American College of Radiology Imaging Network-Pennsylvania 4005 multicenter trial. Patients with low- to intermediate-risk chest pain and presenting to the ED were randomized in a 2:1 ratio to a coronary CT angiography care pathway or traditional care. Subjects were contacted by telephone at least 1 year after ED presentation. Medical record review was performed for all cardiac hospitalizations, procedures and diagnostic tests, and adverse cardiac events. Our main outcome was the composite of cardiac death and myocardial infarction within 1 year. The secondary outcome was resource use. One thousand three hundred sixty-eight patients enrolled and 1,285 (94%) had direct participant or proxy contact at 1 year. All others had record review or death index search. From index presentation through 1 year, there was no difference between patients in the coronary CT angiography arm versus traditional care with respect to major adverse cardiac event (1.4% versus 1.1%; difference 0.3%; 95% CI -5.5% to 6.0%). From hospital discharge through 1 year, there was also no difference in ED revisits (36% versus 38%; difference -2.1%; 95% CI -7.9% to 3.7%), hospital admissions (16% versus 17%; difference -0.9%; 95% CI -6.7% to 4.9%), or subsequent cardiac testing (13% versus 13%; difference -0.4%; 95% CI -6.2% to 5.5%). One of 640 subjects with a negative coronary CT angiography result had a major adverse cardiac event within 1 year of presentation (0.16%; 95% CI 0.004% to 0.87%). A coronary CT angiography-based strategy for evaluation of patients with low- to intermediate-risk chest pain who present to the ED does not result in increased resource use during 1 year. A negative coronary CT angiography result is associated with a less than 1% major adverse cardiac event rate during the first year after testing.


Transcriptomic analysis reveals similarities in genetic activation of detoxification mechanisms resulting from imidacloprid and chlorothalonil exposure.
The Colorado potato beetle, Leptinotarsa decemlineata (Say), is an agricultural pest of commercial potatoes in parts of North America, Europe, and Asia. Plant protection strategies within this geographic range employ a variety of pesticides to combat not only the insect, but also plant pathogens. Previous research has shown that field populations of Leptinotarsa decemlineata have a chronological history of resistance development to a suite of insecticides, including the Group 4A neonicotinoids. The aim of this study is to contextualize the transcriptomic response of Leptinotarsa decemlineata when exposed to the neonicotinoid insecticide imidacloprid, or the fungicides boscalid or chlorothalonil, in order to determine whether these compounds induce similar detoxification mechanisms. We found that chlorothalonil and imidacloprid induced similar patterns of transcript expression, including the up-regulation of a cytochrome p450 and a UDP-glucuronosyltransferase transcript, which belong to protein families associated with xenobiotic metabolism. Further, transcriptomic responses varied among individuals within the same treatment group, suggesting individual insects' responses vary within a population and may cope with chemical stressors in a variety of manners.


Planning to be routine: habit as a mediator of the planning-behaviour relationship in healthcare professionals.
Gaps in the quality of care provided to people with type 2 diabetes are regularly identified. Healthcare professionals often have a strong intention to follow practice guidelines during consultations with people with type 2 diabetes; however, this intention does not always translate into action. Action planning (planning when, where and how to act) and coping planning (planning how to overcome pre-identified barriers) have been hypothesised to help with the enactment of intentions by creating mental cue-response links that promote habit formation. This study aimed to investigate whether habit helps to better understand how action and coping planning relate to clinical behaviour in the context of type 2 diabetes care. The study utilised a prospective correlational design with six nested sub-studies. General practitioners and practice nurses (n = 427 from 99 UK primary care practices) completed measures of action planning, coping planning and habit at baseline and then self-reported their enactment of guideline-recommended advising, prescribing and examining behaviours 12 months later. Bootstrapped mediation analyses were used to test the indirect effect of action and coping planning on healthcare professionals' clinical behaviour via their relationship with habit. Healthcare professionals who reported higher degrees of action or coping planning for performing six guideline recommended behaviours in the context of type 2 diabetes care were more likely to report performing these behaviours in clinical practice. All 12 bootstrapped mediation analyses showed that the positive relationship between planning (action and coping planning) and healthcare professionals' clinical behaviour operated indirectly through habit. These findings suggest that habit mediates the relationship between planning (action and coping planning) and healthcare professional behaviour. Promoting careful action and coping planning may support routinised uptake of guideline-recommended care by healthcare professionals in the primary care setting. Given the competing demands on healthcare professionals, exploring the behavioural processes involved in promoting more routinisation of behaviours where possible and appropriate could free up cognitive capacity for clinical behaviours that rely on more deliberation.


Systematic evasion of the restriction-modification barrier in bacteria.
Bacteria that are recalcitrant to genetic manipulation using modern in vitro techniques are termed genetically intractable. Genetic intractability is a fundamental barrier to progress that hinders basic, synthetic, and translational microbiology research and development beyond a few model organisms. The most common underlying causes of genetic intractability are restriction-modification (RM) systems, ubiquitous defense mechanisms against xenogeneic DNA that hinder the use of genetic approaches in the vast majority of bacteria and exhibit strain-level variation. Here, we describe a systematic approach to overcome RM systems. Our approach was inspired by a simple hypothesis: if a synthetic piece of DNA lacks the highly specific target recognition motifs for a host's RM systems, then it is invisible to these systems and will not be degraded during artificial transformation. Accordingly, in this process, we determine the genome and methylome of an individual bacterial strain and use this information to define the bacterium's RM target motifs. We then synonymously eliminate RM targets from the nucleotide sequence of a genetic tool in silico, synthesize an RM-silent "SyngenicDNA" tool, and propagate the tool as minicircle plasmids, termed SyMPL (SyngenicDNA Minicircle Plasmid) tools, before transformation. In a proof-of-principle of our approach, we demonstrate a profound improvement (five orders of magnitude) in the transformation of a clinically relevant USA300 strain of Staphylococcus aureus This stealth-by-engineering SyngenicDNA approach is effective, flexible, and we expect in future applications could enable microbial genetics free of the restraints of restriction-modification barriers.


Palbociclib and cetuximab in platinum-resistant and in cetuximab-resistant human papillomavirus-unrelated head and neck cancer: a multicentre, multigroup, phase 2 trial.
Most head and neck squamous-cell carcinomas (HNSCCs) are driven by p16INK4A inactivation and cyclin D1 overexpression that results in hyperactivation of cyclin-dependent kinase 4 and 6 (CDK4/6), rather than by the human papillomavirus (HPV). Deregulated cyclin D1 expression also causes resistance to EGFR inhibitors. We previously reported that palbociclib (a selective CDK4/6 inhibitor) given with cetuximab (an EGFR inhibitor) was safe. The aim of this study was to establish the proportion of patients achieving an objective response with palbociclib and cetuximab in recurrent or metastatic HNSCC. We did a multicentre, multigroup, phase 2 trial to evaluate the activity of palbociclib and cetuximab in platinum-resistant (group 1) and cetuximab-resistant (group 2) HPV-unrelated HNSCC. The study was done across eight university sites in the USA. Eligibility required measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1·1 [RECIST 1·1]), Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, age of 18 years or older, and disease progression on platinum but cetuximab-naive (group 1) or disease progression on cetuximab (group 2). All patients received palbociclib orally (125 mg/day, on days 1-21) and intravenous cetuximab (400 mg/m2 on cycle one, day 1, then 250 mg/m2 once per week) in 28-day cycles. The primary endpoint was objective response (complete responses and partial responses per RECIST 1·1). Analyses were done per protocol. This trial was registered with ClinicalTrials.gov, NCT02101034, and is ongoing, but both groups are closed to accrual. Between Oct 19, 2015, and Nov 7, 2018, 62 patients were enrolled onto the trial: 30 patients were enrolled in group 1 and 32 in group 2. Median follow-up was 5·4 months (IQR 4·4-12·1) for group 1 and 5·5 months (4·3-8·3) for group 2. In group 1, of 28 evaluable patients, an objective response was achieved by 11 (39%; 95% CI 22-59). In group 2, of 27 evaluable patients, an objective response was achieved by five (19%; 6-38) in group 2. The most common grade 3-4 palbociclib-related adverse event was neutropenia (in 21 [34%] of 62 patients). No treatment-related deaths occurred. In patients with platinum-resistant or cetuximab-resistant HPV-unrelated HNSCC, palbociclib and cetuximab results in promising activity outcomes. Further studies of CDK4/6 inhibitors are warranted in HPV-unrelated HNSCC. Pfizer.


Indomethacin therapy in premature infants with patent ductus arteriosus--determination of therapeutic plasma levels.
To determine the therapeutic range of plasma indomethacin levels for ductus closure, we evaluated the ductus response and renal side effects on two therapeutic regimens using different dosage; regimen I received 0.3 mg/kg q 24 h for a maximum of 3 doses, and regimen II received 0.1, 0.2 and 0.3 mg/kg at 24-hour intervals, for a maximum of 3 doses if needed. Infants in regimen I had significantly higher plasma indomethacin and higher ductus response rate than infants in regimen II. Urine output (U/O) was comparable between the regimens, but serum sodium was lower in regimen I than in regimen II. In both regimens, U/O and serum sodium return to normal by 72 h. The plasma indomethacin levels at 12 h after 1 dose correlated significantly with ductus response and hyponatremia. There appeared to be a minimal level of plasma indomethacin above which U/O decreased; with a plasma level greater than 170 ng/ml the majority (greater than 97%) of infants showed a decrease in U/O. While there was a 50% or greater chance that ductus would close when the plasma levels reached 600 ng/ml or more, a great proportion of infants would also develop renal side effects. Thus, a safe therapeutic range of plasma indomethacin appeared to be very narrow. However, when the dose of indomethacin is increased to optimize constrictive response, there is no significant increase in incidence and severity of renal adverse effects. In view of the transient nature of renal side effects, they should not hinder indomethacin therapy if ductus closure is indicated.


The genetic control of direct-repeat recombination in Saccharomyces: the effect of rad52 and rad1 on mitotic recombination at GAL10, a transcriptionally regulated gene.
We have previously shown direct-repeat recombination events leading to loss of a plasmid integrated at the GAL10 locus in Saccharomyces cerevisiae are stimulated by transcription of the region. We have examined the role of two recombination- and repair-defective mutations, rad1 and rad52, on direct repeat recombination in transcriptionally active and inactive sequences. We show that the RAD52 gene is required for transcription-stimulated recombination events leading to loss of the integrated plasmid. Similarly, Gal+ events between the duplicated repeats that retain the integrated plasmid DNA (Gal+ Ura+ replacement events) are reduced 20-fold in the rad52 mutant in sequences that are constitutively expressed. In contrast, in sequences that are not expressed, the rad52 mutation reduces plasmid loss events by only twofold and Gal+ Ura+ replacements by fourfold. We also observe an increase in disome-associated plasmid loss events in the rad52 mutant, indicative of chromosome gain. This event is not affected by expression of the region. Plasmid loss events in rad1 mutant strains are reduced only twofold in transcriptionally active sequences and are not affected in sequences that are repressed. However, the rad1 and rad52 double mutant shows a decrease in plasmid loss events greater than the sum of the decreases in the rates of this event displayed by either single mutant in both constitutive and repressed DNA, indicating a synergistic interaction between these two genes. The synergism is limited to recombination since the rad1 rad52 double mutant is no more sensitive when compared with either single mutant in its ability to survive radiation damage. Finally, the recombination pathway that remains in the double mutant is positively affected by transcription of the region.


Relationship between HLA-DR gene polymorphisms and outcomes of hepatitis B viral infections: a meta-analysis.
To assess the rigorous relationship between human leukocyte antigens (HLA)-DR alleles and outcomes of hepatitis B virus (HBV) infections by means of meta-analysis. Medline/PubMed, EMBASE, CNKI and VIP were searched to identify relevant studies. Study quality was evaluated using the Newcastle-Ottawa Scale. Odds ratios (OR) and 95% confidence interval (95% CI) were pooled using Stata 11.0. Subgroup analyses were performed by ethnicity. Heterogeneity and publication bias analyses were performed to validate the credibility. A total of 2609 patients with chronic hepatitis B and 2606 controls spontaneously recovering from prior HBV infection were included. Meta-analysis showed that HLA-DR*04 (OR = 0.72, 95% CI: 0.60-0.85) and DR*13 (OR = 0.27, 95% CI: 0.19-0.37) alleles were significantly associated with HBV clearance while patients carrying HLA-DR*03 (OR = 1.47, 95% CI: 1.16-1.87) or DR*07 (OR = 1.59, 95% CI: 1.24-2.03) alleles had a significantly increased risk of chronic HBV persistence. For the HLA-DR*01 polymorphism, a significantly association with HBV clearance was found in Chinese Han group (OR = 0.48, 95% CI: 0.26-0.86), but not found in other ethnic groups (P = 0.191). For other polymorphisms, no association with the HBV infection outcome was found. HLA-DR*04 and DR*13 alleles may be the protective factors for HBV clearance and HLA-DR*03, and DR*07 alleles may be the risk factors for HBV persistence.


The graphical representation of ADME-related molecule properties for medicinal chemists.
The importance of striving for and maintaining drug-like physicochemical properties during the hit and lead optimization process is now well documented, and many published studies have suggested optimal ranges and/or limits for key molecule descriptors such as size, lipophilicity, H-bonding characteristics, rotatable bond and aromatic ring counts, particularly with regard to the design of orally administered drugs. The aim of this article is to review various approaches that have been used to represent molecule properties graphically in the context of oral 'drug likeness', with the goal of improving the decision making of medicinal chemists during the drug discovery process.


Depressed contractile responses to neurokinin A in idiopathic but not neurogenic overactive human detrusor muscle.
The role of tachykinins such as neurokinin A in regulating bladder function is unclear, but NK2 receptors seem to mediate contraction in the human bladder and it has been suggested that these peptides may have a role in the pathophysiology of bladder dysfunction. The present study investigates neurokinin receptor-mediated contractility of detrusor muscle in the idiopathic overactive and neurogenic overactive bladder and investigates the neurokinin receptor subtypes involved. Human bladder was obtained from patients undergoing cystectomy (normal) or clam cystoplasty (idiopathic overactive) and from patients with spinal injuries (neurogenic overactive). Strips of isolated detrusor muscle were mounted in physiological Krebs-bicarbonate solution and cumulative concentration-response curves to 1 nM to 300 microM neurokinin A (NKA) were obtained in the absence and presence of neurokinin receptor antagonists, either the NK2 receptor-selective antagonist SR 48968 or the NK3 receptor-selective antagonist SB 223412. NKA evoked concentration-dependent contraction of normal, idiopathic, and neurogenic overactive detrusor strips. In idiopathic overactive detrusor muscle, NKA-induced contraction was significantly reduced relative to normal detrusor (0.031 +/- 0.005 mg/g, n = 11 versus 0.193 +/- 0.039 mg/g, n = 7). Sensitivity to the peptide was also significantly (p < 0.01) reduced in idiopathic overactive detrusor, with mean pEC50 values (concentration producing 50% maximal response) of 6.62+/-0.16 (n = 11) compared to 7.47+/-0.19 (n = 7) in normal detrusor. In contrast, NKA-induced responses of neurogenic overactive detrusor were similar to those in normal detrusor, with a mean maximum contraction of 0.199 +/- 0.036 mg/g (n = 10) and mean pEC50 value of 7.85+/-0.16 (n = 10). NKA curves in all groups were shifted to the right by the NK2 receptor-selective antagonist SR 48968 with high affinity, pK(B) values being similar in normal, idiopathic, and neurogenic overactive detrusor (8.85 + 0.08, n = 14; 8.97 +/- 0.13, n = 12; 8.73 +/- 0.12, n = 8, respectively). In contrast the NK3 receptor-selective antagonist SB 223412 had a minimal effect on NKA responses and affinity values were low (pK(B) 5.81 +/- 0.11, n = 12 in normal; 5.75 +/- 0.08, n = 12 in idiopathic overactive, and 5.77 +/- 0.13, n = 11 in neurogenic overactive). These data indicate that NKA-induced responses are impaired in detrusor muscle from idiopathic overactive human bladder, but not in detrusor muscle from neurogenic overactive bladder. The NK2 receptor subtype appears to mediate NKA responses in the normal, idiopathic overactive, and neurogenic overactive detrusor. This is important evidence suggesting a difference between the bladder pathophysiology observed in idiopathic versus neurogenic overactive detrusor.


WHO essential medicines policies and use in developing and transitional countries: an analysis of reported policy implementation and medicines use surveys.
Suboptimal medicine use is a global public health problem. For 35 years the World Health Organization (WHO) has promoted essential medicines policies to improve quality use of medicines (QUM), but evidence of their effectiveness is lacking, and uptake by countries remains low. Our objective was to determine whether WHO essential medicines policies are associated with better QUM. We compared results from independently conducted medicines use surveys in countries that did versus did not report implementation of WHO essential medicines policies. We extracted survey data on ten validated QUM indicators and 36 self-reported policy implementation variables from WHO databases for 2002-2008. We calculated the average difference (as percent) for the QUM indicators between countries reporting versus not reporting implementation of specific policies. Policies associated with positive effects were included in a regression of a composite QUM score on total numbers of implemented policies. Data were available for 56 countries. Twenty-seven policies were associated with better use of at least two percentage points. Eighteen policies were associated with significantly better use (unadjusted p<0.05), of which four were associated with positive differences of 10% or more: undergraduate training of doctors in standard treatment guidelines, undergraduate training of nurses in standard treatment guidelines, the ministry of health having a unit promoting rational use of medicines, and provision of essential medicines free at point of care to all patients. In regression analyses national wealth was positively associated with the composite QUM score and the number of policies reported as being implemented in that country. There was a positive correlation between the number of policies (out of the 27 policies with an effect size of 2% or more) that countries reported implementing and the composite QUM score (r=0.39, 95% CI 0.14 to 0.59, p=0.003). This correlation weakened but remained significant after inclusion of national wealth in multiple linear regression analyses. Multiple policies were more strongly associated with the QUM score in the 28 countries with gross national income per capita below the median value (US$2,333) (r=0.43, 95% CI 0.06 to 0.69, p=0.023) than in the 28 countries with values above the median (r=0.22, 95% CI -0.15 to 0.56, p=0.261). The main limitations of the study are the reliance on self-report of policy implementation and measures of medicine use from small surveys. While the data can be used to explore the association of essential medicines policies with medicine use, they cannot be used to compare or benchmark individual country performance. WHO essential medicines policies are associated with improved QUM, particularly in low-income countries. Please see later in the article for the Editors' Summary.


Mixing metaphors in the cerebral hemispheres: what happens when careers collide?
Are processes of figurative comparison and figurative categorization different? An experiment combining alternative-sense and matched-sense metaphor priming with a divided visual field assessment technique sought to isolate processes of comparison and categorization in the 2 cerebral hemispheres. For target metaphors presented in the right visual field/left cerebral hemisphere (RVF/LH), only matched-sense primes were facilitative. Literal primes and alternative-sense primes had no effect on comprehension time compared to the unprimed baseline. The effects of matched-sense primes were additive with the rated conventionality of the targets. For target metaphors presented to the left visual field/right cerebral hemisphere (LVF/RH), matched-sense primes were again additively facilitative. However, alternative-sense primes, though facilitative overall, seemed to eliminate the preexisting advantages of conventional target metaphor senses in the LVF/RH in favor of metaphoric senses similar to those of the primes. These findings are consistent with tightly controlled categorical coding in the LH and coarse, flexible, context-dependent coding in the RH.


Recent advances in the application of hydrophilic interaction chromatography for the analysis of biological matrices.
Hydrophilic interaction chromatography (HILIC) is being increasingly used for the analysis of hydrophilic compounds in biological matrices. The complexity of biological samples demands adequate sample preparation procedures, specifically adjusted for HILIC analyses. Currently, most bioanalytical assays are performed on bare silica and ZIC-HILIC columns. Trends in HILIC for bioanalysis include smaller particle sizes and miniaturization of the analytical column. For complex biological samples, multidimensional techniques can separate and identify more compounds than 1D separations. The high volatility of the mobile phase, the added separation power and high sensitivity make MS the detection method of choice for bioanalysis using HILIC, although other detectors such as evaporative light scattering detection, charged aerosol detection and nuclear magnetic resonance have been reported.


Evolution of group I introns in Porifera: new evidence for intron mobility and implications for DNA barcoding.
Mitochondrial introns intermit coding regions of genes and feature characteristic secondary structures and splicing mechanisms. In metazoans, mitochondrial introns have only been detected in sponges, cnidarians, placozoans and one annelid species. Within demosponges, group I and group II introns are present in six families. Based on different insertion sites within the cox1 gene and secondary structures, four types of group I and two types of group II introns are known, which can harbor up to three encoding homing endonuclease genes (HEG) of the LAGLIDADG family (group I) and/or reverse transcriptase (group II). However, only little is known about sponge intron mobility, transmission, and origin due to the lack of a comprehensive dataset. We analyzed the largest dataset on sponge mitochondrial group I introns to date: 95 specimens, from 11 different sponge genera which provided novel insights into the evolution of group I introns. For the first time group I introns were detected in four genera of the sponge family Scleritodermidae (Scleritoderma, Microscleroderma, Aciculites, Setidium). We demonstrated that group I introns in sponges aggregate in the most conserved regions of cox1. We showed that co-occurrence of two introns in cox1 is unique among metazoans, but not uncommon in sponges. However, this combination always associates an active intron with a degenerating one. Earlier hypotheses of HGT were confirmed and for the first time VGT and secondary losses of introns conclusively demonstrated. This study validates the subclass Spirophorina (Tetractinellida) as an intron hotspot in sponges. Our analyses confirm that most sponge group I introns probably originated from fungi. DNA barcoding is discussed and the application of alternative primers suggested.


Short Term Test-Retest Reliability of Contralateral Inhibition of Distortion Product Otoacoustic Emissions.
Strength of medial olivocochlear reflex can be measured reliably using contralateral inhibition of distortion product otoacoustic emissions (DPOAEs) when its fine structure is considered. However, measurement of fine structure of DPOAE is difficult with clinical equipment. Thus, this study investigated the clinically relevant test-retest reliability of contralateral inhibition of DPOAEs. Subjects and. Twenty-six young adults with normal hearing sensitivity participated. DPOAEs were recorded at 27 discrete f2 frequencies between 800 Hz and 8,000 Hz at frequency resolution of 8 points per octave with and without contralateral white noise presented at 50 dB SPL. To check for short term inter-session reliability, contralateral inhibition of DPOAEs were recorded in three sessions, two recording sessions on first day separated by 30 minutes and third time after one week of the first session. Within each session, DPOAEs were recorded twice in single probe-fit condition to test for intra-session reliability. Cronbach's alpha was calculated having poor reliability (α≤ 0.7) of contralateral inhibition of DPOAEs in both intra-session and inter-session conditions for most of the tested frequencies. 95% confidence intervals of contralateral inhibition magnitude also showed large variability. The current results showed that though DPOAE amplitudes were highly reliable across sessions, amount of inhibition of DPOAEs was not reliable when DPOAEs were measured at discrete frequencies. These findings are concurrent with the literature.


Unilateral fibroepithelial hyperplasia of the mammary gland in a goat.
A 2.5-year-old female Nubian goat was admitted because of a mass involving the right mammary gland. Ultrasonography and cytologic examination of the mass revealed a benign or hyperplastic condition. A right mastectomy was performed. Results of histologic and immunohistochemical tests indicated mammary fibroepithelial hyperplasia (fibroadenomatous change), which is a condition usually found in cats. The mammary mass had not redeveloped in the goat after 1 year.


MCT8 deficiency: extrapyramidal symptoms and delayed myelination as prominent features.
Monocarboxylate transporter 8 (MCT8) deficiency is an X-linked disorder resulting from an impairment of the transcellular transportation of thyroid hormones. Within the central nervous system thyroid hormone transport is normally mediated by MCT8. Patients are described as affected by a static or slowly progressive clinical picture which consists of variable degrees of mental retardation, hypotonia, spasticity, ataxia and involuntary movements, occasionally paroxysmal. The authors describe the clinical and neuroradiological picture of 3 males patients with marked delayed brain myelination and in which the clinical picture was dominated by early onset nonparoxysmal extrapyramidal symptoms. In one subject a novel mutation is described.


Transcriptional activation of human immunodeficiency virus type 1 by herpesvirus infection: an in vivo footprinting study.
The process of transcriptional activation directed by the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) was investigated by in vivo footprinting using ligation-mediated polymerase chain reaction in a human epithelial cell line infected with human herpes simplex virus type 1 (HSV-1) or human herpes virus 6 (HHV-6). Infection with both viruses induces a remarkable enhancement in LTR-mediated gene expression that correlates with a change in the pattern of protein binding to the downstream kappa B site of the enhancer region. In HHV-6 infected cells, this change in the genomic footprinting pattern is concomitant with the induction of specific enhancer-binding proteins in the nucleus. The similarity of these events to those detected in other previously investigated experimental systems suggests that the LTR enhancer region is the ultimate target for the induction of the HIV-1 transcriptional response upon stimuli acting through different upstream pathways.


Peptide microarray analysis of in silico-predicted epitopes for serological diagnosis of Toxoplasma gondii infection in humans.
Toxoplasma gondii infections occur worldwide in humans and animals. In immunocompromised or prenatally infected humans, T. gondii can cause severe clinical symptoms. The identification of specific epitopes on T. gondii antigens is essential for the improvement and standardization of the serological diagnosis of toxoplasmosis. We selected 20 peptides mimicking linear epitopes on GRA1, GRA2, GRA4, and MIC3 antigenic T. gondii proteins in silico using the software ABCpred. A further 18 peptides representing previously published epitopes derived from GRA1, SAG1, NTPase1, and NTPase2 antigens were added to the panel. A peptide microarray assay was established to prove the diagnostic performance of the selected peptides with human serum samples. Seropositive human serum samples (n = 184) were collected from patients presenting with acute toxoplasmosis (n = 21), latent T. gondii infection (n = 53), and inactive ocular toxoplasmosis (n = 10) and from seropositive forest workers (n = 100). To adjust the cutoff values for each peptide, sera from seronegative forest workers (n = 75) and patients (n = 65) were used. Univariate logistic regression suggested the significant diagnostic potential of eight novel and two previously published peptides. A test based on these peptides had an overall diagnostic sensitivity of 69% (100% in ocular toxoplasmosis patients, 86% in acutely infected patients, 81% in latently infected patients, and 57% in seropositive forest workers). The analysis of seronegative sera performed with these peptides revealed a diagnostic specificity of 84%. The results of our study suggest that the use of a bioinformatic approach for epitope prediction in combination with peptide microarray testing is a powerful method for the selection of T. gondii epitopes as candidate antigens for serological diagnosis.


Treatment of nonvariceal gastrointestinal hemorrhage by transcatheter embolization.
Purpose. To investigate the sensitivity of mesenteric angiography, technical success of hemostasis, clinical success rate, and complications of transcatheter embolization for the treatment of acute nonvariceal gastrointestinal hemorrhage. Material and Methods. A retrospective review of 200 consecutive patients who underwent mesenteric arteriography for acute nonvariceal gastrointestinal hemorrhage between February 2004 and February 2011 was done. Results. Of 200 angiographic studies, 114 correctly revealed the bleeding site with mesenteric angiography. 47 (41%) patients had upper gastrointestinal hemorrhage and 67 (59%) patients had lower gastrointestinal hemorrhage. Out of these 114, in 112 patients (98%) technical success was achieved with immediate cessation of bleeding. 81 patients could be followed for one month. Clinical success was achieved in 72 out of these 81 patients (89%). Seven patients rebled. 2 patients developed bowel ischemia. Four patients underwent surgery for bowel ischemia or rebleeding. Conclusion. The use of therapeutic transcatheter embolization for treatment of acute gastrointestinal hemorrhage is highly successful and relatively safe with 98% technical success and 2.4% postembolization ischemia in our series. In 89% of cases it was definitive without any further intervention.


Substrate-assisted catalysis by PARP10 limits its activity to mono-ADP-ribosylation.
ADP-ribosylation controls many processes, including transcription, DNA repair, and bacterial toxicity. ADP-ribosyltransferases and poly-ADP-ribose polymerases (PARPs) catalyze mono- and poly-ADP-ribosylation, respectively, and depend on a highly conserved glutamate residue in the active center for catalysis. However, there is an apparent absence of this glutamate for the recently described PARP6-PARP16, raising questions about how these enzymes function. We find that PARP10, in contrast to PARP1, lacks the catalytic glutamate and has transferase rather than polymerase activity. Despite this fundamental difference, PARP10 also modifies acidic residues. Consequently, we propose an alternative catalytic mechanism for PARP10 compared to PARP1 in which the acidic target residue of the substrate functionally substitutes for the catalytic glutamate by using substrate-assisted catalysis to transfer ADP-ribose. This mechanism explains why the novel PARPs are unable to function as polymerases. This discovery will help to illuminate the different biological functions of mono- versus poly-ADP-ribosylation in cells.


Importance of including refractive error tests in school children's vision screening.
This study determined the importance of including tests for refractive errors in vision screening. In this cross-sectional study, we performed a random cluster sampling of schoolchildren in the city of Dezful, Iran. After sampling and obtaining informed written consents from their parents, children underwent examinations at the school sites. Students underwent tests of visual acuity, cover tests and cycloplegic refractions. Elementary and middle school students who had a visual acuity of 20/20 or better in both eyes were included in the study. From 3673 elementary and middle school students, 2957 (80.5%) had 20/20 vision or better. Of these, 16.1% [95% confidence interval (CI): 14.8 - 17.4] were ametropic, 0.4% had myopia and 10.1% had hyperopia. Mean sphere in those with hyperopia was +2.6±0.7 (range: +2.0 to +7.28) diopter (D). Astigmatism was detected in 6.6% and the mean cylinder was -0.9 (range: -0.75 to -3.25) D. The rate of anisometropia was 1.5% (95% CI: 0.8 - 2.0). Screening results of 20/20 vision for schoolchildren does not necessarily indicate normal eye status because hyperopia and astigmatism may still be sources of visual discomfort. To identify these cases and increase the sensitivity of screening tests, measurement of refractive errors by cycloplegic refraction tests might be included in vision screening.


Drinking-water safety: challenges for community-managed systems.
A targeted review of documented waterborne disease outbreaks over the past decades reveals some recurring themes that should be understood by drinking-water suppliers. Evidence indicates the outbreaks are often linked to some significant change in conditions that provides a sudden challenge to a water system. Severe weather events, such as heavy rainfall or runoff from snow melt, as well as treatment process and system changes, are common risk factors for drinking-water outbreaks. Failure to recognise warning signs and complacency are important contributors to drinking water becoming unsafe. Drinking-water suppliers must focus on competence and vigilance in maintaining effective multiple barriers appropriate to the challenges facing the drinking-water system. Understanding the risk factors and failure modes of waterborne disease outbreaks is an essential component for effective management of community drinking-water supplies and ensuring the delivery of safe drinking-water to consumers.


The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens.
The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function. Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory. We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.


The neutrophil as a cellular source of chemokines.
Neutrophils are known to play an important role in inflammatory responses by virtue of their ability to perform a series of effector functions that collectively represent a major mechanism of innate immunity against injury and infection. In recent years, however, it has become obvious that the contribution of neutrophils to host defence and natural immunity extends well beyond their traditional role as professional phagocytes. Indeed, neutrophils can be induced to express a number of genes whose products lie at the core of inflammatory and immune responses. These include not only Fc receptors, complement components, cationic antimicrobial and NADPH oxidase proteins, but also a variety of cytokines (including tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-1R alpha, IL-12 and vascular endothelial growth factor), and chemokines such as IL-8, growth-related gene product, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, interferon-gamma-inducible protein of 10 kDa and monokine induced by interferon-gamma. Because these chemokines are primarily chemotactic for neutrophils, monocytes, immature dendritic cells and T-lymphocyte subsets, a potential role for neutrophils in orchestrating the sequential recruitment of distinct leukocyte types to the inflamed tissue is likely to occur. The purpose of this review is to summarize the essential features of the production of chemokines by polymorphonuclear neutrophil leukocytes and the contribution that we have made to characterize some aspects of this newly discovered crucial function of neutrophils.


An extra dimension to decision-making in animals: the three-way trade-off between speed, effort per-unit-time and accuracy.
The standard view in biology is that all animals, from bumblebees to human beings, face a trade-off between speed and accuracy as they search for resources and mates, and attempt to avoid predators. For example, the more time a forager spends out of cover gathering information about potential food sources the more likely it is to make accurate decisions about which sources are most rewarding. However, when the cost of time spent out of cover rises (e.g. in the presence of a predator) the optimal strategy is for the forager to spend less time gathering information and to accept a corresponding decline in the accuracy of its decisions. We suggest that this familiar picture is missing a crucial dimension: the amount of effort an animal expends on gathering information in each unit of time. This is important because an animal that can respond to changing time costs by modulating its level of effort per-unit-time does not have to accept the same decrease in accuracy that an animal limited to a simple speed-accuracy trade-off must bear in the same situation. Instead, it can direct additional effort towards (i) reducing the frequency of perceptual errors in the samples it gathers or (ii) increasing the number of samples it gathers per-unit-time. Both of these have the effect of allowing it to gather more accurate information within a given period of time. We use a modified version of a canonical model of decision-making (the sequential probability ratio test) to show that this ability to substitute effort for time confers a fitness advantage in the face of changing time costs. We predict that the ability to modulate effort levels will therefore be widespread in nature, and we lay out testable predictions that could be used to detect adaptive modulation of effort levels in laboratory and field studies. Our understanding of decision-making in all species, including our own, will be improved by this more ecologically-complete picture of the three-way tradeoff between time, effort per-unit-time and accuracy.


A randomized controlled phase II trial of riluzole in early multiple sclerosis.
We evaluated the effect of riluzole versus placebo added to weekly IM interferon beta-1a in early multiple sclerosis (MS). This is a randomized (1:1), double-blind, placebo-controlled trial of riluzole 50 mg twice daily in subjects with MS onset less than 1 year prior. Trial participation was up to 3 years. The primary endpoint was change in percent brain volume change. Secondary endpoints included changes in normalized gray and normal-appearing white matter volumes, retinal nerve fiber layer thickness (RNFL), MS Functional Composite and Symbol Digit Modalities Test scores. Mixed model regression analysis was used to compare the changes over time between groups. Forty-three subjects were randomized to study drug (22 riluzole, 21 placebo). Baseline characteristics were overall similar between groups except for older age (P = 0.042), higher normalized cerebrospinal fluid volume (P = 0.050), lower normalized gray matter volume (P = 0.14), and thinner RNFL (P = 0.043) in the riluzole group. In the primary analysis, percent brain volume change in the placebo group decreased at a rate of 0.49% per year whereas the riluzole group decreased by 0.86% per year (0.37% more per year; 95% CI -0.78, 0.024; P = 0.065). Although age did not influence the rate of brain volume decline, the difference between groups was attenuated after adjustment for baseline normalized gray matter and lesion volume (0.26% more per year in riluzole group; 95% CI -0.057, 0.014; P = 0.22). Analyses of secondary outcomes showed no differences between groups. This trial provides class 1 evidence that riluzole treatment does not meaningfully reduce brain atrophy progression in early MS.


Plasma membrane repair is mediated by Ca(2+)-regulated exocytosis of lysosomes.
Plasma membrane wounds are repaired by a mechanism involving Ca(2+)-regulated exocytosis. Elevation in intracellular [Ca(2+)] triggers fusion of lysosomes with the plasma membrane, a process regulated by the lysosomal synaptotagmin isoform Syt VII. Here, we show that Ca(2+)-regulated exocytosis of lysosomes is required for the repair of plasma membrane disruptions. Lysosomal exocytosis and membrane resealing are inhibited by the recombinant Syt VII C(2)A domain or anti-Syt VII C(2)A antibodies, or by antibodies against the cytosolic domain of Lamp-1, which specifically aggregate lysosomes. We further demonstrate that lysosomal exocytosis mediates the resealing of primary skin fibroblasts wounded during the contraction of collagen matrices. These findings reveal a fundamental, novel role for lysosomes: as Ca(2+)-regulated exocytic compartments responsible for plasma membrane repair.


The orange-brown patina of Salisbury Cathedral (West Porch) surfaces: evidence of its man-made origin.
In this paper, we attempt to elucidate the composition and origin of the orange patina on the surfaces of the West-Porch of Salisbury Cathedral by comparison to other known patinas: (i) the orange-brown patina on the marble surfaces of the Acropolis in Athens and the Arch of Titus in Rome whose analyses have shown very high amounts of phosphates, and generally amino acids from animal-skin glue or other protein binders; (ii) the phosphated patinas which also contain oxalates, found in 1996 on Catalonian calcareous sandstones and in the calcareous dolomites of the Monastery of Silos, Spain, whose origin is either the application of calcium caseinate, or egg yolk and animal glue; and (iii) the patinas with only oxalates found in some of Verona's monuments (St. Zeno) and Spanish sites as in the Monastery of Guadalupe and Cuenca cathedral, formed either by the mineralization of algal filaments or by biological reactions yielding oxalate from yolk egg (added to stone as part of preservative empirical treatments). In the winter of 2003, the West-Porch of Salisbury Cathedral received conservation works, but the old patina was not entirely removed. This fact has allowed us to collect the samples for its study. The IR spectra were registered with a Golden Gate ATR Mk II system using attenuated total reflectance Fourier transform infrared (ATR/FTIR) spectrometry. Mineral composition was determined by XRD (Philips PW 1710 spectrometer with Cu tube), whereas major and trace elements analyses were performed by XRF (Philips PW1480 PW). Microscopy examination was performed on a Leica M655 microscope. Phosphate, oxalate, calcium and sulphate contents were analysed by usual chemical methods. ATD-FTIR spectra of the Salisbury's patina exhibit peaks at 2361, 2341 and 671 cm(-1) (assigned to phosphates); 3410, 1680, 1620, 1122 and 602 cm(-1) (assigned to sulphates); and 1447/1437 and 876 cm(-1) (attributed to carbonates). The little peaks at 1620 and 798 cm(-1) could be assigned to oxalates. XRD and XRF have led to identify the carbonates, phosphates and sulphates as pertaining to the species dolomite, hydroxyapatite and gypsum, respectively. Oxalates are detected only in small amounts by chemical analyses but wewellite and weddellite have not been well identified. The interface between the patina and the calcareous dolomite is very uneven and full of cavities in certain cases, but well-defined and rather smooth in other cases. In accordance with the very small amounts of the oxalates found, remnants of micro-organisms are not detected in the patinas. The Salisbury's patina is a composite material formed by particulates and matrix constituents. Regarding the patina particulate, e.g. animal bones, it is necessary to refer to the apatite phase composition. The bone mineral contains 4-8 wt % of carbonate in animal body and its presence in the apatite phase is advantageous as it increases the mechanical strength. We think that FTIR bands at around 1440 and 876 cm(-1) arise from vibration of CO3(2-) ions, but not necessarily from the limestone. They could be attributed to carbonated hydroxyapatite through the substitution of groups PO4(3-) for CO3(2-) in the lattice of hydroxyapatite. Concerning the matrix and also from the FTIR spectra, the absence of specific bands of the following species: proteins (3350-3225, 1660, 1550-1535, 1270-1230 and 620 cm(-1)), oils (1778, 1738 and 1051 cm(-1)), bee waxes (3000, 1470, 720-730 and 1700 cm(-1)) and aged egg-yolk (2954, 2920, 2850, 1650, 1549, 1465 and 1240 cm(-1)) had led us to exclude these usual binders. On the other hand, the amount of sulphates in the paste that covers the walls of the Salisbury's Cathedral is excessively high (above 20% in weight) to consider it as a biotransformation product of calcium oxalate from fungal biofilms. Consequently, we must think that the gypsum found in the samples has a man-made origin (it was deliberately added as part of a protective paste) and that it is the matrix searched for. Thus, we deduce that the patina of Salisbury's Cathedral is a special stucco made mixing plaster with powdered bone (the colour of the bones is the same that it exhibits in the patina), low quantities of an uncharacterized binder (collagen, possibly) and water. We believe that the patina of the Salisbury's Cathedral is a variant of the Greco-Latin empirical protective treatment that included bone as a hardening material. Nevertheless, we also think that the presence of the bones in the paste could be related to an aesthetical intention: gaining a warm tone for the original stone through the ochre colour of the bones. Our results have been an excuse to contribute to the controversy started at the 80's on the origin of orange-brown patinas observed on stone surfaces of Greco-Latin and medieval monuments. There are two major theories on provenance: biological vs. man-made. In Salisbury Cathedral, neither of them has been proven through scientific evidence as yet. Our opinion is that Salisbury patina can be classified into the man-made group.


Health promotion for people with disabilities: the emerging paradigm shift from disability prevention to prevention of secondary conditions.
The premise of this article is that, until recently, health promotion for people with disabilities has been a neglected area of interest on the part of the general health community. Today, researchers, funding agencies, and health care providers and consumers are leading an effort to establish higher-quality health care for the millions of Americans with disabilities. The aims of a health promotion program for people with disabilities are to reduce secondary conditions (eg, obesity, hypertension, pressure sores), to maintain functional independence, to provide an opportunity for leisure and enjoyment, and to enhance the overall quality of life by reducing environmental barriers to good health. A greater emphasis must be placed on community-based health promotion initiatives for people with disabilities in order to achieve these objectives.


Plasma folate concentration and cognitive performance: Rotterdam Scan Study.
Evidence is increasing for beneficial and independent effects of folate on cognitive function, but the underlying biologic mechanism is as yet unknown. We examined the independent association of plasma folate concentration with cognitive performance and explored the nature of this association by evaluating brain-imaging markers for cerebrovascular disease and brain cell loss. In the population-based Rotterdam Scan Study, 1033 nondemented participants aged 60-90 y underwent extensive cognitive testing and brain imaging. We cross-sectionally examined the association between plasma folate concentration and cognitive test performance by multivariate linear regression. To evaluate the role of vascular or other mechanisms in this association, we subsequently studied whether plasma folate was related to the presence of white matter lesions and hippocampal and amygdalar volumes. After multivariate adjustment, the mean change in test score per 1-SD increase in plasma folate was 0.05 (95% CI: 0.01, 0.09) for global cognitive function, 0.08 (95% CI: 0.04, 0.13) for psychomotor speed, and 0.02 (95% CI: -0.04, 0.07) for memory function. Adjustment for homocysteine concentration only slightly diminished these associations. The odds ratio relating a 1-SD increase in plasma folate to the presence compared with the absence of severe white matter lesions was 0.79 (95% CI: 0.66, 0.94), whereas no relation was seen between folate status and hippocampal or amygdalar volume. Higher plasma folate concentrations are associated with better global cognitive function and better performance on tests of psychomotor speed, regardless of homocysteine concentration. These associations may be mediated by vascular mechanisms.


Mechanisms of triazole resistance in Aspergillus fumigatus.
The ubiquitous fungal pathogen Aspergillus fumigatus is the primary cause of opportunistic mould infections in humans. Aspergilli disseminate via asexual conidia passively travelling through air currents to germinate within a broad range of environs, wherever suitable nutrients are found. Though the average human inhales hundreds of conidia daily, A. fumigatus invasive infections primarily affect the immunocompromised. At-risk individuals can develop often fatal invasive disease for which therapeutic options are limited. Regrettably, the global insurgence of isolates resistant to the triazoles, the frontline antifungal class used in medicine and agriculture to control A. fumigatus, is complicating the treatment of patients. Triazole antifungal resistance in A. fumigatus has become recognized as a global, yet poorly comprehended, problem. Due to a multitude of factors, the magnitude of resistant infections and their contribution to treatment outcomes are likely underestimated. Current studies suggest that human drug-resistant infections can be either environmentally acquired or de novo host selected during patient therapy. While much concerning development of resistance is yet unknown, recent investigations have revealed assorted underlying mechanisms enabling triazole resistance within individual clinical and environmental isolates. This review will provide an overview of triazole resistance as it is currently understood, as well as highlight some of the prominent biological mechanisms associated with clinical and environmental resistance to triazoles in A. fumigatus.


Legislation an essential tool for ensuring access to medicines policy goals.
Effective national legislation is critical to support the activities of a Medicines Regulatory Authority. However, the law is an under-recognized mechanism for managing issues in the implementation of access to medicines and other medicines policy goals. Regulations are a more flexible tool, have legal effect and the advantage that they can be created or changed without the need to go to the Parliament. Closer collaboration between the health and legal sectors is important as is political commitment for enforcement of the law. Some regional case studies illustrate the opportunities to use the law as an effective tool to implement medicine policies and to meet access to medicine challenges.


Meta-analysis of temporary ileostomy versus colostomy for colorectal anastomoses.
Defunctioning stoma is a common surgical procedure, it is now generally acknowledged that defunctioning stoma significantly reduce the rates of complications in colorectal surgery, but the choice of temporary ileostomy or temporary colostomy for defunctioning colorectal anastomoses remains controversial. This meta-analysis evaluated two types of defunctioning stoma to determine whether one is superior to the other. Studies and relevant literatures comparing temporary ileostomy with temporary colostomy for defunctioning colorectal anastomoses were searched though PubMed, Embase and The Cochrane Library. The rates of complications were pooled and compared using a meta-analysis. The risk ratios were calculated with 95% confidence intervals to evaluate the safety and efficacy of each technique. Five randomized controlled trials and seven non-randomized studies were included, with 1687 patients in total. The meta-analysis of the RCTs demonstrated a lower risk of stoma prolapse (RR 0.15; 95% CI: 0.04-0.48, p = 0.001) in the temporary ileostomy group. Meta-analysis of the non-randomized studies showed a lower risk of stoma prolapse (RR 0.26; 95% CI 0.10-0.67, p = 0.005) and wound infection after stoma closure (RR 0.28; 95% CI 0.5-0.52, p < 0.0001) in the temporary ileostomy group. No other statistically significant difference was observed for complications. Each type of defunctioning stoma has its advantages and disadvantages, and there is not a strong evidence for the superiority of one temporary stoma over another for colorectal anastomoses. According to this, large scale RCTs and high quality studies are needed to conduct.


Emerging therapeutic potential for peptide YY for obesity-diabetes.
The vast majority of research to date on the gut hormone Peptide YY (PYY) has focused on appetite suppression and body weight regulation effects. These biological actions are believed to occur through interaction of PYY with hypothalamic Y2 receptors. However, more recent studies have added additional knowledge to understanding of the physiological, and potential therapeutic, roles of PYY beyond obesity alone. Thus, PYY has now been shown to impart improvements in pancreatic beta-cell survival and function, with obvious benefits for diabetes. This effect has been linked mainly to binding and activation of Y1 receptors by PYY, but more evidence is still required in this regard. Given the potential therapeutic promise of PYY-derived compounds, and complexity of receptor interactions, it is important to fully understand the complete biological action profile of PYY. Therefore, the current review aims to compile, evaluate and summarise current knowledge on PYY, with particular emphasis on obesity and diabetes treatment, and the importance of specific Y receptor interactions for this.


Protein energy malnutrition during vaccination has limited influence on vaccine efficacy but abolishes immunity if administered during Mycobacterium tuberculosis infection.
Protein energy malnutrition (PEM) increases susceptibility to infectious diseases, including tuberculosis (TB), but it is not clear how PEM influences vaccine-promoted immunity to TB. We demonstrate that PEM during low-level steady-state TB infection in a mouse model results in rapid relapse of Mycobacterium tuberculosis, as well as increased pathology, in both Mycobacterium bovis BCG-vaccinated and unvaccinated animals. PEM did not change the overall numbers of CD4 T cells in BCG-vaccinated animals but resulted in an almost complete loss of antigen-specific cytokine production. Furthermore, there was a change in cytokine expression characterized by a gradual loss of multifunctional antigen-specific CD4 T cells and an increased proportion of effector cells expressing gamma interferon and tumor necrosis factor alpha (IFN-γ(+) TNF-α(+) and IFN-γ(+) cells). PEM during M. tuberculosis infection completely blocked the protection afforded by the H56-CAF01 subunit vaccine, and this was associated with a very substantial loss of the interleukin-2-positive memory CD4 T cells promoted by this vaccine. Similarly, PEM during the vaccination phase markedly reduced the H56-CAF01 vaccine response, influencing all cytokine-producing CD4 T cell subsets, with the exception of CD4 T cells positive for TNF-α only. Importantly, this impairment was reversible and resupplementation of protein during infection rescued both the vaccine-promoted T cell response and the protective effect of the vaccine against M. tuberculosis infection.


Turbulent superstructures in Rayleigh-Bénard convection.
Turbulent Rayleigh-Bénard convection displays a large-scale order in the form of rolls and cells on lengths larger than the layer height once the fluctuations of temperature and velocity are removed. These turbulent superstructures are reminiscent of the patterns close to the onset of convection. Here we report numerical simulations of turbulent convection in fluids at different Prandtl number ranging from 0.005 to 70 and for Rayleigh numbers up to 107. We identify characteristic scales and times that separate the fast, small-scale turbulent fluctuations from the gradually changing large-scale superstructures. The characteristic scales of the large-scale patterns, which change with Prandtl and Rayleigh number, are also correlated with the boundary layer dynamics, and in particular the clustering of thermal plumes at the top and bottom plates. Our analysis suggests a scale separation and thus the existence of a simplified description of the turbulent superstructures in geo- and astrophysical settings.


FUNCTIONALITY OF UPPER GASTROINTESTINAL CANCER PATIENTS WHICH HAVE UNDERTAKEN SURGERY IN HOSPITAL PHASE.
Cancer patients present various physiological, metabolic, social and emotional changes as a consequence of the disease's own catabolism, and may be potentiated in the gastrointestinal tract cancer by their interference with food intake, digestion and absorption. o evaluate the functionality of upper gastrointestinal cancer patients which have undertaken surgery and analyze the factors associated with changes in strength and functionality during hospitalization time. Prospective analytical study in patients with cancer of the upper gastrointestinal tract which have undertaken surgery. Was evaluated the handgrip strength using a hand dynamometer and functionality through the functional independence measure and Functional Status Scale for Intensive Care Unit in the preoperative period, 2nd and 7th postoperative day. Were included 12 patients, 75% men, and mean age was 58.17 years old. The most prevalent tumor site was stomach (66.7%). There was a progressive reduction from the pre-operative palmar grip strength to the 2nd and 7th postoperative day, respectively. There was a decrease in functional performance from the preoperative period to the 2nd and a gain from the 2nd to the 7th postoperative day (p<0.001). An important reduction in the handgrip strength and functionality was evidenced during the postoperative period in relation to the basal value in the pre-operative period.


Multi-omic measurements of heterogeneity in HeLa cells across laboratories.
Reproducibility in research can be compromised by both biological and technical variation, but most of the focus is on removing the latter. Here we investigate the effects of biological variation in HeLa cell lines using a systems-wide approach. We determine the degree of molecular and phenotypic variability across 14 stock HeLa samples from 13 international laboratories. We cultured cells in uniform conditions and profiled genome-wide copy numbers, mRNAs, proteins and protein turnover rates in each cell line. We discovered substantial heterogeneity between HeLa variants, especially between lines of the CCL2 and Kyoto varieties, and observed progressive divergence within a specific cell line over 50 successive passages. Genomic variability has a complex, nonlinear effect on transcriptome, proteome and protein turnover profiles, and proteotype patterns explain the varying phenotypic response of different cell lines to Salmonella infection. These findings have implications for the interpretation and reproducibility of research results obtained from human cultured cells.


Building a Digital Tool for the Adoption of the World Health Organization's Antenatal Care Recommendations: Methodological Intersection of Evidence, Clinical Logic, and Digital Technology.
One of the key mandates of the World Health Organization (WHO) is to develop guidelines, defined as "a document containing recommendations for clinical practice or public health policy." Guidelines represent the global standard for information sources shaping clinical practice and public health policies. Despite the rigorous development process and the value of guidelines for setting standards, implementing such standards within local contexts and at the point of care is a well-documented challenge. Digital technologies enable agile information management and may facilitate the adaptation of guidelines to diverse settings of health services delivery. The objective of this paper is to detail the systematic and iterative process involved in transforming the WHO Antenatal Care (ANC) guidelines into a digital decision-support and patient-record application for routine use in primary health care settings, known as the WHO digital ANC module. The WHO convened a team of clinical and digital health experts to develop the WHO digital ANC module as a tool to assist health care professionals in the implementation of WHO evidence-based recommendations for pregnant women. The WHO digital ANC module's creation included the following steps: defining a minimum viable product (MVP), developing clinical workflows and algorithms, algorithm testing, developing a data dictionary, and the creation of a user interface or application development. The overall process of development took approximately 1 year to reach a stable prototype and to finalize the underlying content requirements of the data dictionary and decision support algorithms. The first output is a reference software reflecting the generic WHO ANC guideline content, known as the WHO digital ANC module. Within it, all actionable ANC recommendations have related data fields and algorithms to confirm whether the associated task was performed. WHO recommendations that are not carried out by the health care worker are saved as pending tasks on a woman's health record, and those that are adequately fulfilled trigger messages with positive reinforcement. The second output consists of the structured documentation of the different components which contributed to the development of the WHO digital ANC module, such as the data dictionary and clinical decision support workflows. This is a novel approach to facilitate the adoption and adaptation of recommendations through digital systems at the health service delivery level. It is expected that the WHO digital ANC module will support the implementation of evidence-based practices and provide information for monitoring and surveillance; however, further evidence is needed to understand how the WHO digital ANC module impacts the implementation of WHO recommendations. Further, the module's implementation will inform the WHO's ongoing efforts to create a pathway to adaptive and integrated (Smart) Guidelines in Digital Systems to improve health system quality, coverage, and accountability.


Biological Pretreatment of Chicken Feather and Biogas Production from Total Broth.
Chicken feathers are available in large quantities around the world causing environmental challenges. The feathers are composed of keratin that is a recalcitrant protein and is hard to degrade. In this work, chicken feathers were aerobically pretreated for 2-8 days at total solid concentrations of 5, 10, and 20 % by Bacillus sp. C4, a bacterium that produces both α- and β-keratinases. Then, the liquid fraction (feather hydrolysate) as well as the total broth (liquid and solid fraction of pretreated feathers) was used as substrates for biogas production using anaerobic sludge or bacteria granules as inoculum. The biological pretreatment of feather waste was productive; about 75 % of feather was converted to soluble crude protein after 8 days of degradation at initial feather concentration of 5 %. Bacteria granules performed better during anaerobic digestion of untreated feathers, resulting in approximately two times more methane yield (i.e., 199 mlCH4/gVS compared to 105 mlCH4/gVS when sludge was used). Pretreatment improved methane yield by 292 and 105 % when sludge and granules were used on the hydrolysate. Bacteria granules worked effectively on the total broth, yielded 445 mlCH4/gVS methane, which is 124 % more than that obtained with the same type of inoculum from untreated feather.


Regulation of β2-adrenergic receptor function by conformationally selective single-domain intrabodies.
The biologic activity induced by ligand binding to orthosteric or allosteric sites on a G protein-coupled receptor (GPCR) is mediated by stabilization of specific receptor conformations. In the case of the β2 adrenergic receptor, these ligands are generally small-molecule agonists or antagonists. However, a monomeric single-domain antibody (nanobody) from the Camelid family was recently found to allosterically bind and stabilize an active conformation of the β2-adrenergic receptor (β2AR). Here, we set out to study the functional interaction of 18 related nanobodies with the β2AR to investigate their roles as novel tools for studying GPCR biology. Our studies revealed several sequence-related nanobody families with preferences for active (agonist-occupied) or inactive (antagonist-occupied) receptors. Flow cytometry analysis indicates that all nanobodies bind to epitopes displayed on the intracellular receptor surface; therefore, we transiently expressed them intracellularly as "intrabodies" to test their effects on β2AR-dependent signaling. Conformational specificity was preserved after intrabody conversion as demonstrated by the ability for the intracellularly expressed nanobodies to selectively bind agonist- or antagonist-occupied receptors. When expressed as intrabodies, they inhibited G protein activation (cyclic AMP accumulation), G protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation, β-arrestin recruitment, and receptor internalization to varying extents. These functional effects were likely due to either steric blockade of downstream effector (Gs, β-arrestin, GRK) interactions or stabilization of specific receptor conformations which do not support effector coupling. Together, these findings strongly implicate nanobody-derived intrabodies as novel tools to study GPCR biology.


Life-threatening dermatologic adverse events in oncology.
The incidences of life-threatening toxicities such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are inconsistently reported. The potential association of anticancer agents with SJS or TEN has not been systematically investigated. We searched the literature (Ovid: 1950 to June 2013 and PubMed: 1948 to June 2013) using terms for SJS/TEN and anticancer therapies. Primary case reports, case series, and clinical trials were included. In addition, MedWatch, the Food and Drug Administration Adverse Event Reporting System (FAERS), was searched (1968 to August 2012) for SJS/TEN reports associated with anticancer therapies. Proportional reporting ratios (PRR>2, N>3), empirical Bayes geometric mean (EBGM>2, N>3), and lower 95% confidence interval (EBGM0.05>2) were used as thresholds to constitute a signal of association between SJS/TEN and anticancer drugs. There were 46 SJS and 37 TEN cases associated with 18 and 22 anticancer drugs in the literature, respectively. Among cases in the FAERS, significant signals were associated with SJS for bendamustine and with TEN for bendamustine, busulfan, chlorambucil, fludarabine, lomustine, and procarbazine. Several drugs reported in the published literature to be associated with SJS/TEN were not found to have significant signals in FAERS. Proactive pharmacovigilance to detect and define safety signals serves to aid oncology practitioners in the recognition of possible, yet uncommon, serious, and/or life-threatening skin reactions.


Parameterized Complexity of Eulerian Deletion Problems.
We study a family of problems where the goal is to make a graph Eulerian, i.e., connected and with all the vertices having even degrees, by a minimum number of deletions. We completely classify the parameterized complexity of various versions: undirected or directed graphs, vertex or edge deletions, with or without the requirement of connectivity, etc. The collection of results shows an interesting contrast: while the node-deletion variants remain intractable, i.e., W[1]-hard for all the studied cases, edge-deletion problems are either fixed-parameter tractable or polynomial-time solvable. Of particular interest is a randomized FPT algorithm for making an undirected graph Eulerian by deleting the minimum number of edges, based on a novel application of the color coding technique. For versions that remain NP-complete but fixed-parameter tractable we consider also possibilities of polynomial kernelization; unfortunately, we prove that this is not possible unless NP⊆coNP/poly.


A Comprehensive Analysis of Deep Regression.
Deep learning revolutionized data science, and recently its popularity has grown exponentially, as did the amount of papers employing deep networks. Vision tasks, such as human pose estimation, did not escape from this trend. There is a large number of deep models, where small changes in the network architecture, or in the data pre-processing, together with the stochastic nature of the optimization procedures, produce notably different results, making extremely difficult to sift methods that significantly outperform others. This situation motivates the current study, in which we perform a systematic evaluation and statistical analysis of vanilla deep regression, i.e., convolutional neural networks with a linear regression top layer. This is the first comprehensive analysis of deep regression techniques. We perform experiments on four vision problems, and report confidence intervals for the median performance as well as the statistical significance of the results, if any. Surprisingly, the variability due to different data pre-processing procedures generally eclipses the variability due to modifications in the network architecture. Our results reinforce the hypothesis according to which, in general, a general-purpose network (e.g., VGG-16 or ResNet-50) adequately tuned can yield results close to the state-of-the-art without having to resort to more complex and ad-hoc regression models.


Informed Consent and Shared Decision Making in Obstetrics and Gynecology: ACOG Committee Opinion, Number 819.
Meeting the ethical obligations of informed consent requires that an obstetrician-gynecologist gives the patient adequate, accurate, and understandable information and requires that the patient has the ability to understand and reason through this information and is free to ask questions and to make an intentional and voluntary choice, which may include refusal of care or treatment. Shared decision making is a patient-centered, individualized approach to the informed consent process that involves discussion of the benefits and risks of available treatment options in the context of a patient's values and priorities. Some informed consent challenges are universal to medicine, whereas other challenges arise more commonly in the practice of obstetrics and gynecology than in other specialty areas. This Committee Opinion focuses on informed consent for adult patients in clinical practice and provides new guidance on the practical application of informed consent through shared decision making. The principles outlined in this Committee Opinion will help support the obstetrician-gynecologist in the patient-centered informed consent process.


p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa.
ProNGF signaling through p75NTR has been associated with neurodegenerative disorders. Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies that causes progressive photoreceptor cell degeneration and death, at a rate dependent on the genetic mutation. There are more than 300 mutations causing RP, and this is a challenge to therapy. Our study was designed to explore a common mechanism for p75NTR in the progression of RP, and assess its potential value as a therapeutic target. The proNGF/p75NTR system is present in the dystrophic retina of the rd10 RP mouse model. Compared with wild-type (WT) retina, the levels of unprocessed proNGF were increased in the rd10 retina at early degenerative stages, before the peak of photoreceptor cell death. Conversely, processed NGF levels were similar in rd10 and WT retinas. ProNGF remained elevated throughout the period of photoreceptor cell loss, correlating with increased expression of α2-macroglobulin, an inhibitor of proNGF processing. The neuroprotective effect of blocking p75NTR was assessed in organotypic retinal cultures from rd10 and RhoP mouse models. Retinal explants treated with p75NTR antagonists showed significantly reduced photoreceptor cell death, as determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and by preservation of the thickness of the outer nuclear layer (ONL), where photoreceptor nuclei are located. This effect was accompanied by decreased retinal-reactive gliosis and reduced TNFα secretion. Use of p75NTR antagonist THX-B (1,3-diisopropyl-1-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetyl]-urea) in vivo in the rd10 and RhoP mouse models, by a single intravitreal or subconjunctival injection, afforded neuroprotection to photoreceptor cells, with preservation of the ONL. This study demonstrates a role of the p75NTR/proNGF axis in the progression of RP, and validates these proteins as therapeutic targets in two different RP models, suggesting utility irrespective of etiology.


Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment.
Hepatosplenic T-cell lymphoma (HSTCL) is a rare peripheral T-cell lymphoma; treatment with standard anthracycline-containing chemotherapy regimens has been disappointing, and an optimal treatment strategy for this patient population has not yet been determined. We identified 15 cases of pathologically confirmed HSTCL in the institution's database. Clinical characteristics and treatment results were reviewed. Complete responses (CRs) were achieved in 7 of 14 patients who received chemotherapy. Achievement of CR was followed by hematopoietic stem-cell transplantation in three patients. Median duration of CR was 8 months (range 2 to 32+ months) with four patients currently alive and in CR at 5, 8, 12, and 32 months, respectively. Median overall survival (OS) was 11 months (range 2 to 36+ months). Patients who achieved a CR had a median OS of 13 months, compared with 7.5 months in patients who did not achieve a CR. Risk factors associated with worse outcome included male gender, failure to achieve a CR, history of immunocompromise, and absence of a T-cell receptor gene rearrangement in the gamma chain. A better understanding of the pathophysiology of HSTCL and new therapeutic strategies are needed.


Isolation and structural analysis of a 1.2-megabase N-myc amplicon from a human neuroblastoma.
Oncogene amplification is observed frequently in human cancers, but little is known about the mechanism of gene amplification or the structure of amplified DNA in tumor cells. We have studied the N-myc amplified domain from a representative neuroblastoma cell line, SMS-KAN, and compared the map of the amplicon in this cell line with that seen in normal DNA. The SMS-KAN cell line DNA was cloned into yeast artificial chromosomes (YACs), and clones were identified by screening the YAC library with amplified DNA probes that were obtained previously (B. Zehnbauer, D. Small, G. M. Brodeur, R. Seeger, and B. Vogelstein, Mol. Cell. Biol. 8:522-530, 1988). In addition, YAC clones corresponding to the normal N-myc locus on chromosome 2 were obtained by screening two normal human YAC libraries with these probes, and the restriction maps of the two sets of overlapping YACs were compared. Our results suggest that the amplified domain in this cell line is a approximately 1.2-Mb circular molecule with a head-to-tail configuration, and the physical map of the normal N-myc locus generally is conserved in the amplicon. These results provide a physical map of the amplified domain of a neuroblastoma cell line that has de novo amplification of an oncogene. The head-to-tail organization, the general conservation of the normal physical map in the amplicon, and the extrachromosomal location of the amplified DNA are most consistent with the episome formation-plus-segregation mechanism of gene amplification in these tumors.


Aerobic exercise training improves insulin-induced vasorelaxation in a vessel-specific manner in rats with insulin-treated experimental diabetes.
Vascular insulin resistance often precedes endothelial dysfunction in type 1 diabetes mellitus. Strategies to limit vascular dysfunction include intensive insulin therapy (4-9 mM) and aerobic training. To avoid the risk of hypoglycaemia, individuals often prescribed conventional insulin therapy (9-15 mM) and participate in resistance training. In a model of type 1 diabetes mellitus, this study examined insulin-induced vasomotor function in the aorta and femoral artery to determine (1) whether resistance training with conventional insulin therapy provides the same benefits as aerobic training with conventional insulin therapy, (2) whether aerobic training or resistance training, when paired with conventional insulin therapy, results in superior vasomotor function compared to intensive insulin therapy alone and (3) whether vessel-specific adaptations exist. Groups consisted of conventional insulin therapy, intensive insulin therapy, aerobic training with conventional insulin therapy and resistance training with conventional insulin therapy. Following multiple low doses of streptozotocin, male Sprague-Dawley rats were supplemented with insulin to maintain blood glucose concentrations (9-15 mM: conventional insulin therapy, aerobic training and resistance training; 4-9 mM: intensive insulin therapy) for 12 weeks. Aerobic training performed treadmill exercise and resistance training consisted of weighted climbing. Coinciding with increased Akt signalling, aerobic training resulted in enhanced insulin-induced vasorelaxation in the femoral artery. Intensive insulin therapy displayed increased mitogen-activated protein kinase signalling and no improvement in insulin-stimulated vasorelaxation compared to all other groups. These data suggest that aerobic training may be more beneficial for limiting the pathogenesis of vascular disease in type 1 diabetes mellitus than merely intensive insulin therapy.


The mechanism of error induction by the antibiotic viomycin provides insight into the fidelity mechanism of translation.
Applying pre-steady state kinetics to an Escherichia-coli-based reconstituted translation system, we have studied how the antibiotic viomycin affects the accuracy of genetic code reading. We find that viomycin binds to translating ribosomes associated with a ternary complex (TC) consisting of elongation factor Tu (EF-Tu), aminoacyl tRNA and GTP, and locks the otherwise dynamically flipping monitoring bases A1492 and A1493 into their active conformation. This effectively prevents dissociation of near- and non-cognate TCs from the ribosome, thereby enhancing errors in initial selection. Moreover, viomycin shuts down proofreading-based error correction. Our results imply a mechanism in which the accuracy of initial selection is achieved by larger backward rate constants toward TC dissociation rather than by a smaller rate constant for GTP hydrolysis for near- and non-cognate TCs. Additionally, our results demonstrate that translocation inhibition, rather than error induction, is the major cause of cell growth inhibition by viomycin.


Effectiveness of acupuncture combined with rehabilitation for treatment of acute or subacute stroke: a systematic review.
To determine whether the combination of acupuncture and rehabilitation produces better results in the treatment of acute or subacute stroke sequelae than rehabilitation alone. A systematic review was carried out. A search was conducted in March 2014 using PubMed, Medline, the Cochrane Library, Chinese National Knowledge Infrastructure database (CNKI) and Wanfang databases. English and Chinese language articles published within 10 years of the search were reviewed for inclusion. Randomised control trials comparing combined treatment with acupuncture and rehabilitation and rehabilitation alone in patients with acute or subacute stroke (onset until 3 months after stroke) were included in this review. Three review authors independently checked the titles and abstracts of trials for inclusion based on selection criteria. Studies measuring changes of motor function, activities of daily living, neurological deficit or spasticity/range of motion during the treatment period and at the end of follow-up were included. 17 trials met the inclusion criteria, of which five were of good quality. 14 trials had results favourable to acupuncture combined with rehabilitation, compared with conventional rehabilitation treatment alone. Acupuncture in combination with rehabilitation may have benefits for the treatment of acute and subacute stroke sequelae in comparison with rehabilitation alone. However, many of the studies were at risk of bias. Future studies should focus on reaching a consensus about the most appropriate modality of acupuncture intervention, and the appropriate length of treatment for both interventions, to maximise the potential synergistic outcomes.


Quality of hospital care for sick newborns and severely malnourished children in Kenya: a two-year descriptive study in 8 hospitals.
Given the high mortality associated with neonatal illnesses and severe malnutrition and the development of packages of interventions that provide similar challenges for service delivery mechanisms we set out to explore how well such services are provided in Kenya. As a sub-component of a larger study we evaluated care during surveys conducted in 8 rural district hospitals using convenience samples of case records. After baseline hospitals received either a full multifaceted intervention (intervention hospitals) or a partial intervention (control hospitals) aimed largely at improving inpatient paediatric care for malaria, pneumonia and diarrhea/dehydration. Additional data were collected to: i) examine the availability of routine information at baseline and their value for morbidity, mortality and quality of care reporting, and ii) compare the care received against national guidelines disseminated to all hospitals. Clinical documentation for neonatal and malnutrition admissions was often very poor at baseline with case records often entirely missing. Introducing a standard newborn admission record (NAR) form was associated with an increase in median assessment (IQR) score to 25/28 (22-27) from 2/28 (1-4) at baseline. Inadequate and incorrect prescribing of penicillin and gentamicin were common at baseline. For newborns considerable improvements in prescribing in the post baseline period were seen for penicillin but potentially serious errors persisted when prescribing gentamicin, particularly to low-birth weight newborns in the first week of life. Prescribing essential feeds appeared almost universally inadequate at baseline and showed limited improvement after guideline dissemination. Routine records are inadequate to assess newborn care and thus for monitoring newborn survival interventions. Quality of documented inpatient care for neonates and severely malnourished children is poor with limited improvement after the dissemination of clinical practice guidelines. Further research evaluating approaches to improving care for these vulnerable groups is urgently needed. We also suggest pre-service training curricula should be better aligned to help improve newborn survival particularly.


Downregulation of Bcl-2 by podocytes is associated with progressive glomerular injury and clinical indices of poor renal prognosis in human IgA nephropathy.
Bcl-2 defines a new class of proto-oncogenes that block cell death without promoting cell proliferation. To elucidate the role of Bcl-2 in the development of glomerular lesions in human IgA nephropathy (IgAN), we applied immunohistochemistry coupled with in situ hybridization to detect the expression of Bcl-2 products and their association with Bax, p27(kip1), and p57(kip2) in modulating the apoptotic, proliferative, and sclerotic events in progressive glomerular injury. Glomerular cell apoptosis was examined by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. A total of 51 IgAN cases were categorized into four subgroups (A to D) according to the severity of their histopathological lesions. Creatinine levels, creatinine clearance, and magnitude of proteinuria based on 24-h urine collections at the time of diagnostic renal biopsy were available for the majority of subjects. Bcl-2 expression was observed predominantly in podocytes in IgAN. Podocyte expression of Bcl-2 was found to be upregulated in early-stage disease and downregulated in late-stage disease. Bcl-2 downregulation in progressive IgAN was associated with an increased Bax/Bcl-2 ratio in glomerular epithelial cells and correlated with the downregulation of high endogenous podocyte p27(kip1) and p57(kip2) expression. Bax/Bcl-2 ratios positively correlated with glomerular cell apoptosis and the degree of glomerulosclerosis, whereas p27(kip1) and p57(kip2) expression levels were inversely correlated with mesangial hypercellularity and glomerulosclerosis. Clinicopathologic correlations demonstrated that downregulation of Bcl-2 protein expression was associated with indices of poor renal prognosis in human IgAN. The results suggest that Bcl-2 expression by podocytes may exert modulatory effects on cellular processes that contribute to progressive glomerular injury and play an important role in determining renal outcome in human IgA nephropathy.


Records of medical malpractice litigation: a potential indicator of health-care quality in China.
To assess the characteristics and incidence of medical litigation in China and the potential usefulness of the records of such litigation as an indicator of health-care quality. We investigated 13 620 cases of medical malpractice litigation that ended between 2010 and 2015 and were reported to China's Supreme Court. We categorized each case according to location of the court, the year the litigation ended, the medical specialization involved, the severity of the reported injury, the type of allegation raised by the plaintiff - including any alleged shortcomings in the health care received - and the outcome of the litigation. The annual incidence of medical malpractice litigation increased from 75 in 2010 to 6947 in 2014. Most cases related to general surgery (1350 litigations), internal medicine (3500 litigations), obstetrics and gynaecology (1251 litigations) and orthopaedics (1283 litigations). Most of the reported injuries were either minor (1358 injuries) or fatal (4111 deaths). The most frequent allegation was of lack of consent or notification (1356 litigations), followed by misdiagnosis (1172 litigations), delay in treatment (1145 litigations) and alteration or forgery of medical records (975 litigations). Of the 11 014 plaintiffs with known litigation outcomes, 7482 (67.9%) received monetary compensation. Over our study period, the incidence of litigation over potential medical malpractice increased in China. As many of the cases related to alleged inadequacies in the quality of health care, records of medical malpractice litigation in China may be worth exploring as an indicator of health-care quality.


Molecular cloning, expression, and chromosomal localization of the gene encoding a human myeloid membrane antigen (gp150).
DNA from a tertiary mouse cell transformant containing amplified human sequences encoding a human myeloid membrane glycoprotein, gp150, was used to construct a bacteriophage lambda library. A single recombinant phage containing 12 kilobases (kb) of human DNA was isolated, and molecular subclones were then used to isolate the complete gp150 gene from a human placental genomic DNA library. The intact gp150 gene, assembled from three recombinant phages, proved to be biologically active when transfected into NIH 3T3 cells. Molecular probes from the gp150 locus annealed with a 4.0-kb polyadenylated RNA transcript derived from human myeloid cell lines and from tertiary mouse cell transformants. The gp150 gene was assigned to human chromosome 15, and was subchromosomally localized to bands q25-26 by in situ hybridization. The chromosomal location of the gp150 gene coincides cytogenetically with the region assigned to the c-fes proto-oncogene, another human gene specifically expressed by myeloid cells.