Growth in the care of older patients by hospitalists in the United States.
National and population-based information on the increase in patient care by hospitalists in the United States is lacking. Using a 5% sample of Medicare beneficiaries in 1995, 1997, 1999, and the period from 2001 through 2006, we identified 120,226 physicians in general internal medicine who were providing care to older patients in 5800 U.S. hospitals. We defined hospitalists as general internists who derived 90% or more of their Medicare claims for evaluation-and-management services from the care of hospitalized patients. We then calculated the percentage of all inpatient Medicare services provided by hospitalists and identified patient and hospital characteristics associated with the receipt of hospitalist services. The percentage of physicians in general internal medicine who were identified as hospitalists increased from 5.9% in 1995 to 19.0% in 2006, and the percentage of all claims for inpatient evaluation-and-management services by general internists that were attributed to hospitalists increased from 9.1% to 37.1% during this same period. Accompanying the increase in care by hospitalists was an increase in the percentage of all hospitalized Medicare patients who were treated by general internists (both hospitalists and traditional, non-hospital-based general internists), from 46.4% in 1995 to 61.0% in 2006. In a multilevel, multivariable analysis controlling for patient and hospital characteristics, the odds of receiving care from a hospitalist increased by 29.2% per year from 1997 through 2006. In 2006, there was marked geographic variation in the rates of care provided by hospitalists, with rates of more than 70% in some hospital-referral regions. These analyses of data from Medicare claims showed a substantial increase in the care of hospitalized patients by hospitalist physicians from 1995 to 2006.


Monkey median nerve repaired by nerve graft or collagen nerve guide tube.
Nerve regeneration was followed in 15 median and 1 ulnar nerve of eight Macaca fascicularis monkeys by serial electrophysiological assessments over a period of three and a half years. Nerve gaps of 5 mm at the wrist were bridged by collagen-based nerve guides, nerve autografts, or direct suture repairs. Thenar muscle reinnervation occurred between 50 and 70 d for all groups, indicating axonal elongation rates of approximately 1 mm/d. The recovery rates of the compound muscle action potential (CMAP) and the compound sensory action potential (CSAP) amplitudes were significantly slower after direct suture repair compared to the other two procedures, although the final levels of recovery were all comparable. Similar results were achieved in one median and one ulnar nerve following nerve guide repair of a 15 mm nerve gap. The functional reinnervation of Pacinian corpuscles was detected in all cases following either nerve graft or nerve guide repair, with similar amplitudes and latencies of the tactile evoked CSAP for both types of repair. Histological analysis demonstrated a significant increase in the number of myelinated axons in the median nerve distal to the nerve lesions following both nerve graft and nerve guide repairs compared to proximal and normal controls, with significant reductions of fiber diameter and corresponding increases in g-ratio. The return of a bimodal frequency distribution of myelinated axon fiber diameter was confirmed by three-dimensional surface plots which illustrate the frequency distribution of the relationship between fiber diameter and g-ratio. These combined results demonstrate that nerve regeneration after repair of a 5 mm nerve gap with a collagen nerve guide in the nonhuman primate is similar to that after graft repair, and the final level of physiological recovery for both repair procedures is comparable to direct suture repair of the median nerve.


Influence of supplemental magnesium, tryptophan, vitamin C, and vitamin E on stress responses of pigs to vibration.
Our objectives were to investigate and compare the effects of supplemental Mg, Trp, vitamin E (vit E), and vitamin C (vit C) on stress responses of pigs undergoing transport simulation. In this study, 126 pigs (25.1 +/- 4.4 kg BW) were allocated to one of the six following treatments: 1) negative control (no supplementation); 2) positive control (i.m. injection with 0.5 mg of carazolol/20 kg BW 12 h before vibration, beta-blocker); 3) Trp (additional amount of 6 g/kg of feed for 5 d, as-fed basis); 4) Mg (3 g/L drinking water for 2 d); 5) vit E (additional amount of 150 mg/kg of feed for 21 d, as-fed basis); 6) or vit C (additional amount of 300 mg/kg of feed for 21 d, as-fed basis). Pigs were treated in groups of three, and each treatment was replicated seven times. Feed and water intake were not different among treatments. Heart rate variables (mean, peak, and minimum heart rate, ventricular ectopic beats, and ST elevation of Channels A and B) and heart rate variability were registered from the night before vibration. Pigs were subjected to vibration in a transport simulator (8 Hz, 3 m/s) for 2 h and allowed to recover for 2 h. Generally, the positive control pigs had the lowest heart rate values (mean, peak, minimum heart rate, ST elevation of Channel A; P < 0.05), whereas Mg and Trp decreased ventricular ectopic beats and ST elevation of Channel B, respectively. The effect of vit C and E as vagal stimulators was clearly visible, whereas carazolol and Mg clearly blocked the sympathetic pathways of the autonomic nervous system. During vibration, the negative control pigs lay the least, and Mg pigs the most (P < 0.05). Salivary cortisol concentrations (taken before and after vibration and after recovery) showed that vit E pigs produced the least cortisol during stress periods. Intermediary metabolites (glucose, lactate, creatine kinase, and NEFA) were analyzed in plasma from blood taken before and after vibration. At the two sampling points, the vit E and Mg pigs had the lowest NEFA concentrations (P < 0.05), and the vit E pigs also had the lowest lactate concentrations before vibration. Urine samples were collected before and after vibration to determine catecholamine concentrations; only negative control pigs had an increase (P = 0.04) in epinephrine concentration, despite large individual variation. In general, these results indicate that the supplementation of Trp, Mg, vit E, or vit C improved coping ability of pigs during vibration comparison with the negative control treatment. A muscular injection of carazolol influenced only the heart rate variables.


Postnatal depression: a global public health perspective.
The aim of this paper is to discuss whether or not postnatal depression is a global public health concern. Public health is the study of the morbidity, mortality and the cause and course of disease, at a population rather than an individual level. Public health is also concerned with examining factors that cause health inequalities. Postnatal depression is a mental and emotional condition that can affect women during the first postnatal year. Since the effects of postnatal depression are known to go beyond the mother in that it also affects the partner and the child, it can be deemed a public health problem. Additionally, severe postnatal depression can lead to infanticide as well as maternal death, often by suicide. Furthermore, evidence demonstrates that all countries are faced with the challenge of postnatal depression, but low- to middle-income countries face the greatest burden. The literature revealed various treatment options for this complex condition. However, it also uncovered that not all women are assessed for postnatal depression, nor do all women receive treatment. The emerging picture is that postnatal depression is indeed a public health problem, particularly as the incidence is much higher than the quoted rate of 10%-15%. This paper recommends direction for public health-orientated perinatal mental health research and suggests that service providers should consider the routine assessment of all postnatal women.


Protein-protein interactions: methods for detection and analysis.
The function and activity of a protein are often modulated by other proteins with which it interacts. This review is intended as a practical guide to the analysis of such protein-protein interactions. We discuss biochemical methods such as protein affinity chromatography, affinity blotting, coimmunoprecipitation, and cross-linking; molecular biological methods such as protein probing, the two-hybrid system, and phage display: and genetic methods such as the isolation of extragenic suppressors, synthetic mutants, and unlinked noncomplementing mutants. We next describe how binding affinities can be evaluated by techniques including protein affinity chromatography, sedimentation, gel filtration, fluorescence methods, solid-phase sampling of equilibrium solutions, and surface plasmon resonance. Finally, three examples of well-characterized domains involved in multiple protein-protein interactions are examined. The emphasis of the discussion is on variations in the approaches, concerns in evaluating the results, and advantages and disadvantages of the techniques.


Efficient light harvesting of a luminescent solar concentrator using excitation energy transfer from an aggregation-induced emitter.
The compromise between light absorption and reabsorption losses limits the potential light conversion efficiency of luminescent solar concentrators (LSCs). Current approaches do not fully address both issues. By using the excitation energy transfer (EET) strategy with a donor chromophore that exhibits aggregation-induced emission (AIE) behaviour, it is shown that both transmission and reabsorption losses can be minimized in a LSC device achieving high light collection and concentration efficiencies. The light harvesting performance of the LSC developed has been characterized using fluorescence quantum yield measurements and Monte Carlo ray tracing simulations. Comparative incident photon conversion efficiency and short-circuit current data based on the LSC coupled to a silicon solar cell provide additional evidence for improved performance.


Sustained improvement in clinical preventive service delivery among independent primary care practices after implementing electronic health record systems.
Studies showing sustained improvements in the delivery of clinical preventive services are limited. Fewer studies demonstrate sustained improvements among independent practices that are not affiliated with hospitals or integrated health systems. This study examines the continued improvement in clinical quality measures for a group of independent primary care practices using electronic health records (EHRs) and receiving technical support from a local public health agency. We analyzed clinical quality measure performance data from a cohort of primary care practices that implemented an EHR at least 3 months before October 2009, the study baseline. We assessed trends for 4 key quality measures: antithrombotic therapy, blood pressure control, smoking cessation intervention, and hemoglobin A1c (HbA1c) testing based on monthly summary data transmitted by the practices. Of the 151 practices, 140 were small practices and 11 were community health centers; average time using an EHR was 13.7 months at baseline. From October 2009 through October 2011, average rates increased for antithrombotic therapy (from 58.4% to 74.8%), blood pressure control (from 55.3% to 64.1%), HbA1c testing (from 46.4% to 57.7%), and smoking cessation intervention (from 29.3% to 46.2%). All improvements were significant. During 2 years, practices showed significant improvement in the delivery of several key clinical preventive services after implementing EHRs and receiving support services from a public health agency.


Febrile seizures impair memory and cAMP response-element binding protein activation.
The long-term effects of brief but repetitive febrile seizures (FS) on memory have not been as thoroughly investigated as the impact of single and prolonged seizure in the developing brain. Using a heated-air FS paradigm, we subjected male rat pups to one, three, or nine episodes of brief FS on days 10 to 12 postpartum. Neither hippocampal neuronal damage nor apoptosis was noted within 72 hours after FS, nor was there significant hippocampal neuronal loss, aberrant mossy fiber sprouting, or altered seizure threshold to pentylenetetrazol in any FS group at adulthood. The adult rats subjected to nine episodes of early-life FS, however, showed long-term memory deficits as assessed by the Morris water maze. They also exhibited impaired intermediate and long-term memory but spared short-term memory in the inhibitory avoidance task. Three hours after inhibitory avoidance training, phosphorylation of cAMP response-element binding (CREB) protein in the hippocampus was significantly lower in nine-FS-group rats than in controls. Furthermore, rolipram administration, which activated the cAMP-CREB signaling pathway by inhibiting phosphodiesterase type IV, reversed the long-term memory deficits in nine-FS-group rats by enhancing hippocampal CREB phosphorylation. These results raise concerns about the long-term cognitive consequences of even brief frequently repetitive FS during early brain development.


Transcriptomic diversification of developing cumulus and mural granulosa cells in mouse ovarian follicles.
Cumulus cells and mural granulosa cells (MGCs) have functionally distinct roles in antral follicles, and comparison of their transcriptomes at a global and systems level can propel future studies on mechanisms underlying their functional diversity. These cells were isolated from small and large antral follicles before and after stimulation of immature mice with gonadotropins, respectively. Both cell types underwent dramatic transcriptomic changes, and differences between them increased with follicular growth. Although cumulus cells of both stages of follicular development are competent to undergo expansion in vitro, they were otherwise remarkably dissimilar with transcriptomic changes quantitatively equivalent to those of MGCs. Gene ontology analysis revealed that cumulus cells of small follicles were enriched in transcripts generally associated with catalytic components of metabolic processes, while those from large follicles were involved in regulation of metabolism, cell differentiation, and adhesion. Contrast of cumulus cells versus MGCs revealed that cumulus cells were enriched in transcripts associated with metabolism and cell proliferation while MGCs were enriched for transcripts involved in cell signaling and differentiation. In vitro and in vivo models were used to test the hypothesis that higher levels of transcripts in cumulus cells versus MGCs is the result of stimulation by oocyte-derived paracrine factors (ODPFs). Surprisingly ∼48% of transcripts higher in cumulus cells than MGCs were not stimulated by ODPFs. Those stimulated by ODPFs were mainly associated with cell division, mRNA processing, or the catalytic pathways of metabolism, while those not stimulated by ODPFs were associated with regulatory processes such as signaling, transcription, phosphorylation, or the regulation of metabolism.


Retention and loss of immunoglobulin heavy chain alleles in helper T cell hybridoma clones.
Retention or loss of immunoglobulin heavy chain genes was studied in 20 functional T cell hybridoma clones. DNA probes representing C mu, C alpha and JH genes, as well as VH subgroups II and III were hybridized with restriction enzyme fragments of hybridoma DNA by the Southern filter hybridization technique. Parental alleles of the hybridoma cells were distinguished on the basis of polymorphism of the lengths of restriction enzyme fragments. All clones retained the alleles of the lymphoma parent cell BW-5147 at all four loci. Thirteen clones lost both CH and VH alleles of the immune partner cell, whereas seven retained both VH alleles, and at least C alpha of the antigen-specific partner. Hence, T cell function in these cells is compatible with the loss of most immunoglobulin heavy chain alleles. This is interpreted to indicate either gene rearrangement and deletion, or chromosome loss. Accordingly, the T cell receptor is either controlled by two split gene loci in chromosome 12, at the two respective (5' and 3') ends of the mouse heavy chain gene family, or by a gene(s) outside chromosome 12.


Treating inflammatory bowel disease by adsorptive leucocytapheresis: a desire to treat without drugs.
Ulcerative colitis and Crohn's disease are the major phenotypes of the idiopathic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms, impairing function and quality of life. Current medications are aimed at reducing the symptoms or suppressing exacerbations. However, patients require life-long medications, and this can lead to drug dependency, loss of response together with adverse side effects. Indeed, drug side effects become additional morbidity factor in many patients on long-term medications. Nonetheless, the efficacy of anti-tumour necrosis factors (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation of IBD. However, inflammatory cytokines are released by patients' own cellular elements including myeloid lineage leucocytes, which in patients with IBD are elevated with activation behaviour and prolonged survival. Accordingly, these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn. Based on this background, recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries. Efficacy rates have been impressive as well as disappointing. In fact the clinical response to GMA seems to define the patients' disease course, response to medications, duration of active disease, and severity at entry. The best responders have been first episode cases (up to 100%) followed by steroid naïve and patients with a short duration of active disease prior to GMA. Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA. It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD. Additionally, GMA is very much favoured by patients for its good safety profile. GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates. However, in patients with IBD, there is a scope for removing from the body the sources of pro-inflammatory cytokines and achieve disease remission. The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications, many patients should respond to GMA and avoid pharmacologics. This should fulfill the desire to treat without drugs.


A retrospective, observational study of medicolegal cases against obstetricians and gynaecologists in South Africa's private sector.
The viability of obstetric practice in the private sector has been threatened as a result of steep increases in professional indemnity fees over the past 10 years. Despite this, empirical research investigating key aetiological factors to target risk management interventions has been lacking. To explore private practice medicolegal data linked to obstetricians and gynaecologists (O&Gs) to identify factors in clinical practice associated with claims, for the purposes of guiding future research and risk management solutions. This was a retrospective, observational study of private sector O&Gs' medicolegal case histories. All incidents declared to a prominent local professional indemnity insurer were categorised in terms of medicolegal case type, as well as clinical parameters. To allow for risk-adjusted calculations of case incidence, year of entry into private practice was estimated for all practitioners. Steep increases in medicolegal investigations and demands were demonstrated for both obstetrics- and gynaecology-related cases from about 2003 to 2012. Whereas the total numbers of claims, regulatory complaints and requests for records were similar for obstetrics and gynaecology in recent years (accounting for 52% v. 48% of known cases, respectively), a significantly greater percentage of demands and paid settlements related to gynaecology rather than obstetrics (58% and 76% v. 42% and 24% of cases, respectively). In obstetrics, about half of all cases on record with a paid settlement were in the context of severe neonatal birth-related neurological injury (n=9). For gynaecology, procedure-related complications accounted for 92% of settlements, of which at least 41% were for intraoperative injuries to internal organs and vessels. Laparoscopic procedures were most frequently associated with such intraoperative injuries, followed by vaginal and abdominal hysterectomies/oophorectomies and caesarean sections. For O&Gs in private practice for >2 years, 50/458 (11%) accounted for 138/228 (61%) of demands over a 10-year period. The higher number of gynaecological demands and settlements in comparison with obstetric cases was unexpected and is contrary to international experiences and public sector findings, calling for more research to identify reasons for this finding. Other than further exploring surgical outcomes in private sector gynaecological patients, aspects of surgical training and accreditation standards in gynaecology may need review. Regarding birth-related injuries, the contribution of system failures needs quantification and further interrogation. The high contribution towards the medicolegal burden by a small group of practitioners suggests a need for doctor-focused interventions, including strengthening of peer review and regulatory oversight.


Associations between subspecialty fellowship interest and knowledge of internal medicine: a hypothesis-generating study of internal medicine residents.
Little is known about whether and how medical knowledge relates to interest in subspecialty fellowship training. The purpose of this study was to examine the relationships between residents' interest in subspecialty fellowship training and their knowledge of internal medicine (IM). A questionnaire was emailed to 48 categorical postgraduate-year (PGY) two and three residents at a New York university-affiliated IM residency program in 2007 using the Survey Monkey online survey instrument. Overall and content area-specific percentile scores from the IM in-training examination (IM-ITE) for the same year was used to determine objective knowledge. Forty-five of 48 residents (response rate was 93.8%) completed the survey. Twenty-two (49%) were PG2 residents and 23(51%) were PGY3 residents. Sixty percent of respondents were male. Six (13%) residents were graduates of U.S. medical schools. Eight (18%) reported formal clinical training prior to starting internal medicine residency in the U.S. Of this latter group, 6 (75%) had training in IM and 6 (75) % reported a training length of 3 years or less. Thirty-seven of 45 (82%) residents had a subspecialty fellowship interest. Residents with a fellowship interest had a greater mean overall objective knowledge percentile score (56.44 vs. 31.67; p = 0.04) as well as greater mean percentile scores in all content areas of IM. The adjusted mean difference was statistically significant (p < 0.02) across three content areas. More than half of surveyed residents indicated interest in pursuing a subspecialty fellowship. Fellowship interest appears positively associated with general medical knowledge in this study population. Further work is needed to explore motivation and study patterns among internal medicine residents.


ESR, zero-field splitting, and magnetic exchange of exchange-coupled copper(II)-copper(II) pairs in copper(II) tetraphenylporphyrin N-oxide.
The crystal structures of the dimer form of copper(II) tetraphenylporphyrin N-oxide, [Cu(tpp-N-O)]2 (3-dimer), and zinc(II) tetraphenylporphyrin N-oxide, [Zn(tpp-N-O)]2 (4-dimer), were established. The geometry at the copper ion in 3-dimer is essentially square-pyramidal with one oxygen bridge [O(1A)] occupying the apical site, giving a much larger Cu-O bond distance compared to those at the basal plane. The respective Cu...Cu distance and Cu-O-Cu angle in the core of 3-dimer are 3.987(4) A and 148.1(3) degrees. The Zn(1) atom in 4-dimer has a distorted square-pyramidal [4 + 1] coordination geometry that gives a tau-value of 0.19. The respective Zn...Zn distance and Zn-O-Zn angle in the dimeric unit of 4-dimer are 4.025(3) A and 148.1(2) degrees. The 3-dimer displays axial X-band electron paramagnetic resonance spectral features (Es = 0) in the powder state at 4 K, giving g parallel = 2.51 (A(parallel,s) = (9.6 +/- 0.2) x 10-3 cm(-1)) and g(perpendicular) = 2.11 and in the same powder state at 293 K giving Ds = 0.0731 cm(-1) (as derived from DeltaMs = 1 lines) or 0.0743 cm(-1) (as derived from the DeltaMs = 2 lines). In addition, 3-dimer displays a DeltaMs = 2 transition at g = 4.17 indicating the presence of spin-exchange coupling. The anisotropic exchange interaction (Ds(ex)= 0.132 cm(-1)) gives the main contribution to Ds in 3-dimer. The theoretical fit of the susceptibility and effective magnetic moment data of 3-dimer in the temperature range of 5-300 K gives 2J = 68 cm(-1), g = 2.01, p = 0.06, and a temperature-independent paramagnetism of 10(-6) cm3 mol(-1). This magnetic susceptibility data indicates that the copper(II) ions in 3-dimer are coupled in a ferromagnetic manner with the ground-spin triplet stabilized by 68 cm(-1) with regard to the singlet.


Bovine cysticercosis--development of a real-time PCR to enhance classification of suspect cysts identified at meat inspection.
Laboratory confirmation methods are important in bovine cysticerosis diagnosis as other pathologies can result in morphologically similar lesions resulting in false identifications. We developed a probe-based real-time PCR assay to identify Taenia saginata in suspect cysts encountered at meat inspection and compared its use with the traditional method of identification, histology, as well as a published nested PCR. The assay simultaneously detects T. saginata DNA and a bovine internal control using the cytochrome c oxidase subunit 1 gene of each species and shows specificity against parasites causing lesions morphologically similar to those of T. saginata. The assay was sufficiently sensitive to detect 1 fg (Ct 35.09 ± 0.95) of target DNA using serially-diluted plasmid DNA in reactions spiked with bovine DNA as well as in all viable and caseated positive control cysts. A loss in PCR sensitivity was observed with increasing cyst degeneration as seen in other molecular methods. In comparison to histology, the assay offered greater sensitivity and accuracy with 10/19 (53%) T. saginata positives detected by real-time PCR and none by histology. When the results were compared with the reference PCR, the assay was less sensitive but offered advantages of faster turnaround times and reduced contamination risk. Estimates of the assay's repeatability and reproducibility showed the assay is highly reliable with reliability coefficients greater than 0.94.


Bartonella clarridgeiae, a newly recognized zoonotic pathogen causing inoculation papules, fever, and lymphadenopathy (cat scratch disease).
Shortly after adopting a 6-week-old cat, a veterinarian was bitten on the left index finger. Within 3 weeks, he developed headache, fever, and left axillary lymphadenopathy. Initial blood cultures from the cat and veterinarian were sterile. Repeat cultures from the cat grew Bartonella-like organisms with lophotrichous flagella. Sera from the veterinarian were not reactive against Bartonella henselae, B. quintana, or B. elizabethae antigens but were seroreactive (reciprocal titer, 1,024) against the feline isolate. Sequential serum samples from the cat were reactive against antigens of B. henselae (titer, 1,024), B. quintana (titer, 128), and the feline isolate (titer, 2,048). Phenotypic and genotypic characterization of this and six additional feline isolates, including microscopic evaluation, biochemical analysis, 16S rRNA gene sequencing, DNA-DNA hybridization, and PCR-restriction fragment length polymorphism of the 16S gene, 16S-23S intergenic spacer region, and citrate synthase gene identified the isolates as B. clarridgeiae. This is the first report of cat scratch disease associated with B. clarridgeiae.


A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome.
To determine the effectiveness of oral micronized progesterone, alprazolam, and placebo in premenstrual syndrome (PMS) treatment and the effect of clinical contact on treatment responses. Randomized, double-blind, placebo-controlled 3-month parallel treatment arms with flexible dosage and with the length of clinical contact randomized within each treatment group. University hospital PMS medical treatment outpatient program in obstetrics/gynecology department. Among volunteers for PMS treatment, 444 were evaluated and 185 meeting defined PMS criteria were randomized to treatment; treatment data are available for 170. There were no medical withdrawals for adverse events. A double-blinded protocol in which 300 mg of oral micronized progesterone, 0.25 mg of alprazolam, or placebo was administered four times a day from day 18 of the menstrual cycle through day 2 of the next cycle, including taper. The mean daily dose at the third treatment was 1760 mg of progesterone or 1.5 mg of alprazolam. Subjects were randomized to brief (< 20 minutes) or extended (50 minutes) visits. Daily symptom report (DSR) scored for total DSR symptoms, four DSR factors. Alprazolam was significantly better than placebo or progesterone for total premenstrual symptoms and DSR factors of mental function, pain, and mood. Thirty-seven percent of the alprazolam group experienced a 50% reduction in total DSR scores. There were no clinically significant withdrawal symptoms when alprazolam administration was restricted to the luteal phase. Oral micronized progesterone therapy was no better than placebo. Brief vs extended visits had no effect on treatment outcome. Treatment response was associated with severity of premenstrual symptoms at baseline but with no other diagnostic variables. Alprazolam has a role in PMS treatment and offers a therapy limited to the luteal phase. Oral micronized progesterone is ineffective for PMS.


Predictors of hypertension awareness, treatment, and control among Mexican American women and men.
The burden of hypertension and related health care needs among Mexican Americans will likely increase substantially in the near future. In a nationally representative sample of U.S. Mexican American adults we examined: 1) the full range of blood pressure categories, from normal to severe; 2) predictors of hypertension awareness, treatment and control and; 3) prevalence of comorbidities among those with hypertension. Cross-sectional analysis of pooled data from the National Health and Nutrition Examination Surveys (NHANES), 1999-2004. The group of participants encompassed 1,359 Mexican American women and 1,421 Mexican American men, aged 25-84 years, who underwent a standardized physical examination. Physiologic measures of blood pressure, body mass index, and diabetes. Questionnaire assessment of blood pressure awareness and treatment. Prevalence of Stage 1 hypertension was low and similar between women and men ( approximately 10%). Among hypertensives, awareness and treatment were suboptimal, particularly among younger adults (65% unaware, 71% untreated) and those without health insurance (51% unaware, 62% untreated). Among treated hypertensives, control was suboptimal for 56%; of these, 23% had stage >/=2 hypertension. Clustering of CVD risk factors was common; among hypertensive adults, 51% of women and 55% of men were also overweight or obese; 24% of women and 23% of men had all three chronic conditions-hypertension, overweight/obesity and diabetes. Management of hypertension in Mexican American adults fails at multiple critical points along an optimal treatment pathway. Tailored strategies to improve hypertension awareness, treatment and control rates must be a public health priority.


Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia.
Dasatinib is effective therapy for chronic myeloid leukemia (CML) after imatinib failure. In this study, we investigate the efficacy of dasatinib as initial therapy for patients with CML in early chronic phase. Patients with newly diagnosed CML in early chronic phase were randomly assigned to receive dasatinib 100 mg once daily or 50 mg twice daily as initial therapy. Among 50 patients observed for at least 3 months, 49 patients (98%) achieved a complete cytogenetic response (CCyR), and 41 patients (82%) achieved a major molecular response (MMR). Responses occurred rapidly, with 94% of patients achieving CCyR by 6 months. There was no difference in response rate by treatment arm. The projected event-free survival rate at 24 months is 88%, and all patients are alive after a median follow-up time of 24 months. Grade >or= 3 neutropenia and thrombocytopenia occurred in 21% and 10% of patients, respectively. Nonhematologic toxicity was usually grade 1 to 2. There was no significant difference in toxicity between the two arms, and the actual median dose at 12 months was 100 mg (range, 20 to 100 mg). Dasatinib is an effective agent for the initial management of CML in early chronic phase, producing high rates of CCyR and MMR.


Biological insights from 108 schizophrenia-associated genetic loci.
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.


Crossmodal representation of a functional robotic hand arises after extensive training in healthy participants.
The way in which humans represent their own bodies is critical in guiding their interactions with the environment. To achieve successful body-space interactions, the body representation is strictly connected with that of the space immediately surrounding it through efficient visuo-tactile crossmodal integration. Such a body-space integrated representation is not fixed, but can be dynamically modulated by the use of external tools. Our study aims to explore the effect of using a complex tool, namely a functional prosthesis, on crossmodal visuo-tactile spatial interactions in healthy participants. By using the crossmodal visuo-tactile congruency paradigm, we found that prolonged training with a mechanical hand capable of distal hand movements and providing sensory feedback induces a pattern of interference, which is not observed after a brief training, between visual stimuli close to the prosthesis and touches on the body. These results suggest that after extensive, but not short, training the functional prosthesis acquires a visuo-tactile crossmodal representation akin to real limbs. This finding adds to previous evidence for the embodiment of functional prostheses in amputees, and shows that their use may also improve the crossmodal combination of somatosensory feedback delivered by the prosthesis with visual stimuli in the space around it, thus effectively augmenting the patients' visuomotor abilities.


15q13.3 microdeletions increase risk of idiopathic generalized epilepsy.
We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.


Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers.
Dabrafenib plus trametinib has demonstrated clinical benefit across multiple BRAF-mutant tumours, leading to approval for resected stage III and metastatic melanoma, non-small-cell lung cancer (NSCLC) and anaplastic thyroid cancer. Pyrexia is a common adverse event in patients treated with dabrafenib plus trametinib. Here, we characterise the incidence, patterns and management of pyrexia in patients receiving dabrafenib plus trametinib in clinical trials. Patients (N = 1076) included in the analysis received dabrafenib plus trametinib in the following clinical trials: phase II registration trial in advanced NSCLC (N = 82), phase III COMBI-AD study in resectable stage III melanoma (N = 435) and phase III COMBI-d and COMBI-v studies in unresectable or metastatic melanoma (N = 209 and N = 350, respectively). Among the 1076 patients enrolled in the clinical trials, 61.3% developed pyrexia, 5.7% developed grade 3/4 pyrexia and 15.6% developed a protocol-defined serious pyrexia event. Among the 660 patients with pyrexia, 33.0% had 1 occurrence, 19.8% had 2 occurrences and 47.1% had ≥3 occurrences. The incidence of pyrexia was highest early in treatment and decreased with time on treatment. Temporary dose interruption of dabrafenib or trametinib was the most common and effective management strategy. Pyrexia is the most common adverse event associated with dabrafenib plus trametinib but is manageable with dose interruption. ClinicalTrials.gov (Phase II NSCLC, NCT01336634; COMBI-AD, NCT01682083; COMBI-d, NCT01584648; COMBI-v, NCT01597908).


Current state and novel approaches of antiplatelet therapy.
An unresolved problem with clinical use of antiplatelet therapy is that a significant number of individuals either still get thrombosis or run the risk of life-threatening bleeding. Antiplatelet drugs are widely used clinically, either chronically for people at risk of athero/thrombotic disease or to prevent thrombus formation during surgery. However, a subpopulation may be resistant to standard doses, while the platelet targets of these drugs are also critical for the normal hemostatic function of platelets. In this review, we will briefly examine current antiplatelet therapy and existing targets while focusing on new potential approaches for antiplatelet therapy and improved monitoring of effects on platelet reactivity in individuals, ultimately to improve antithrombosis with minimal bleeding. Primary platelet adhesion-signaling receptors, glycoprotein (GP)Ib-IX-V and GPVI, that bind von Willebrand factor/collagen and other prothrombotic factors are not targeted by drugs in clinical use, but they are of particular interest because of their key role in thrombus formation at pathological shear.


Large breasts and narrow waists indicate high reproductive potential in women.
Physical characteristics, such as breast size and waist-to-hip ratio (WHR), function as important features used by human males to assess female attractiveness. Males supposedly pay attention to these features because they serve as cues to fecundity and health. Here, we document that women with higher breast-to-underbreast ratio (large breasts) and women with relatively low WHR (narrow waists) have higher fecundity as assessed by precise measurements of daily levels of 17-beta-oestradiol (E2) and progesterone. Furthermore, women who are characterized by both narrow waists and large breasts have 26% higher mean E2 and 37% higher mean mid-cycle E2 levels than women from three groups with other combinations of body-shape variables, i.e. low WHR with small breasts and high WHR with either large or small breasts. Such gains in hormone levels among the preferred mates may lead to a substantial rise in the probability of conception, thus providing a significant fitness benefit.


Exploring Variation in the Receipt of Recommended Active Surveillance for Men with Favorable-Risk Prostate Cancer.
Men on active surveillance for favorable-risk prostate cancer do not receive all the recommended testing. Reasons for variation in receipt are unknown. We combined prospective registry data from the Michigan Urological Surgery Improvement Collaborative, a collaborative of 46 academic and community urology practices across Michigan, with insurance claims from 2014 to 2018 for men on active surveillance for favorable-risk prostate cancer. We defined receipt of recommended surveillance according to the collaborative's low-intensity criteria as: annual prostate specific antigen testing and either magnetic resonance imaging or prostate biopsy every 3 years. We assessed receipt of recommended surveillance among men with ≥36 months of followup (246). We conducted multilevel analyses to examine the influence of the urologist, urologist and primary care provider visits, and patient demographic and clinical factors on variation in receipt. During 3 years of active surveillance, just over half of men (56.5%) received all recommended surveillance testing (69.9% annual prostate specific antigen testing, 72.8% magnetic resonance imaging/biopsy). We found 19% of the variation in receipt was attributed to individual urologists. While increasing provider visits were not significantly associated with receipt, older men were less likely to receive magnetic resonance imaging/biopsy (≥75 vs <55 years, adjusted odds ratio 0.07; 95% confidence interval 0.01-0.81). Nearly half of men on active surveillance for favorable-risk prostate cancer did not receive all recommended surveillance. While urologists substantially influenced receipt of recommended testing, exploring how to leverage patients and their visits with their primary care providers to positively influence receipt appears warranted.


Accelerator-based boron neutron capture therapy for malignant glioma: a pilot neutron irradiation study using boron phenylalanine, sodium borocaptate and liposomal borocaptate with a heterotopic U87 glioblastoma model in SCID mice.
Purpose: To evaluate the efficacy of boron neutron capture therapy (BNCT) for a heterotopic U87 glioblastoma model in SCID mice using boron phenylalanine (BPA), sodium borocaptate (BSH) and liposomal BSH as boron compounds at a unique, accelerator-based neutron source.Materials and methods: Glioblastoma models were obtained by subcutaneous implantation of U87 cells in the right thighs of SCID mice before administration of 350 mg/kg of BPA (BPA-group), 100 mg/kg of BSH (BSH-group) or 100 mg/kg of BSH in PEGylated liposomes (liposomal BSH-group) into the retroorbital sinus. Liposomes were prepared by reverse-phase evaporation. Neutron irradiation was carried out at a proton accelerator with a lithium target developed for BNCT at the Budker Institute of Nuclear Physics, Novosibirsk, Russian Federation. A proton beam current integral of 3 mA/h and energy of 2.05 MeV were used for neutron generation.Results: Boron compound accumulation in tumor tissues at the beginning of irradiation was higher in the BPA group, followed by the Liposomal BSH and BSH groups. Tumor growth was significantly slower in all irradiated mice from the 7th day after BNCT compared to untreated controls (p < .05). Tumor growth in all treated groups showed no large variation, apart from the Irradiation only group and the BPA group on the 7th day after BNCT. The overall trend of tumor growth was clear and the differences between treatment groups became significant from the 50th day after BNCT. Tumor growth was significantly slower in the Liposomal BSH group compared to the Irradiation only group on the 50th (p = .012), 53rd (p = .005), and the 57th (p = .021) days after treatment. Tumor growth in the Liposomal BSH group was significantly different from that in the BPA group on the 53rd day after BNCT (p = .021) and in the BSH group on the 50th (p = .024), 53rd (p = .015), and 57th (p = .038) days after BNCT. Skin reactions in the form of erosions and ulcers in the tumor area developed in treated as well as untreated animals with further formation of fistulas and necrotic decay cavities in most irradiated mice.Conclusions: We observed a tendency of BNCT at the accelerator-based neutron source to reduce or suspend the growth of human glioblastoma in immunodeficient animals. Liposomal BSH showed better long-term results compared to BPA and non-liposomal BSH. Further modifications in liposomal boron delivery are being studied to improve treatment outcomes.


A treelet transform analysis to relate nutrient patterns to the risk of hormonal receptor-defined breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).
Pattern analysis has emerged as a tool to depict the role of multiple nutrients/foods in relation to health outcomes. The present study aimed at extracting nutrient patterns with respect to breast cancer (BC) aetiology. Nutrient patterns were derived with treelet transform (TT) and related to BC risk. TT was applied to twenty-three log-transformed nutrient densities from dietary questionnaires. Hazard ratios (HR) and 95 % confidence intervals computed using Cox proportional hazards models quantified the association between quintiles of nutrient pattern scores and risk of overall BC, and by hormonal receptor and menopausal status. Principal component analysis was applied for comparison. The European Prospective Investigation into Cancer and Nutrition (EPIC). Women (n 334 850) from the EPIC study. The first TT component (TC1) highlighted a pattern rich in nutrients found in animal foods loading on cholesterol, protein, retinol, vitamins B12 and D, while the second TT component (TC2) reflected a diet rich in β-carotene, riboflavin, thiamin, vitamins C and B6, fibre, Fe, Ca, K, Mg, P and folate. While TC1 was not associated with BC risk, TC2 was inversely associated with BC risk overall (HRQ5 v. Q1=0·89, 95 % CI 0·83, 0·95, P trend<0·01) and showed a significantly lower risk in oestrogen receptor-positive (HRQ5 v. Q1=0·89, 95 % CI 0·81, 0·98, P trend=0·02) and progesterone receptor-positive tumours (HRQ5 v. Q1=0·87, 95 % CI 0·77, 0·98, P trend<0·01). TT produces readily interpretable sparse components explaining similar amounts of variation as principal component analysis. Our results suggest that participants with a nutrient pattern high in micronutrients found in vegetables, fruits and cereals had a lower risk of BC.


Single-shot measurement of the amplitude and phase of ultrashort laser pulses in the violet.
Using single-shot, self-diffraction, frequency-resolved optical gating, we measure the complete electric field amplitude and phase of 405-nm second-harmonic pulses from an amplified Ti:sapphire system. The single-shot frequency-resolved optical gating device gives both qualitative and quantitative information, which is useful for analyzing and optimizing the grating compressor in the chirped-pulse amplification system.


A graph-based evolutionary algorithm: Genetic Network Programming (GNP) and its extension using reinforcement learning.
This paper proposes a graph-based evolutionary algorithm called Genetic Network Programming (GNP). Our goal is to develop GNP, which can deal with dynamic environments efficiently and effectively, based on the distinguished expression ability of the graph (network) structure. The characteristics of GNP are as follows. 1) GNP programs are composed of a number of nodes which execute simple judgment/processing, and these nodes are connected by directed links to each other. 2) The graph structure enables GNP to re-use nodes, thus the structure can be very compact. 3) The node transition of GNP is executed according to its node connections without any terminal nodes, thus the past history of the node transition affects the current node to be used and this characteristic works as an implicit memory function. These structural characteristics are useful for dealing with dynamic environments. Furthermore, we propose an extended algorithm, "GNP with Reinforcement Learning (GNPRL)" which combines evolution and reinforcement learning in order to create effective graph structures and obtain better results in dynamic environments. In this paper, we applied GNP to the problem of determining agents' behavior to evaluate its effectiveness. Tileworld was used as the simulation environment. The results show some advantages for GNP over conventional methods.


Myosin-7b Promotes Distal Tip Localization of the Intermicrovillar Adhesion Complex.
Transporting epithelial cells interact with the luminal environment using a tightly packed array of microvilli known as the brush border. During intestinal epithelial differentiation, microvillar packing and organization are driven by cadherin-dependent adhesion complexes that localize to the distal tips of microvilli, where they drive physical interactions between neighboring protrusions. Although enrichment of the "intermicrovillar adhesion complex" (IMAC) at distal tips is required for proper function, the mechanism driving tip accumulation of these factors remains unclear. Here, we report that the actin-based motor myosin-7b (Myo7b) promotes the accumulation of IMAC components at microvillar tips. Myo7b is highly enriched at the tips of microvilli in both kidney and intestinal brush borders, and loss of Myo7b in differentiating intestinal epithelial cells disrupts intermicrovillar adhesion and, thus, brush border assembly. Analysis of cells lacking Myo7b revealed that IMAC components and the resulting intermicrovillar adhesion links are mislocalized along the microvillar axis rather than enriched at the distal tips. We also found that Myo7b motor domains are capable of supporting tip-directed transport. However, motor activity is supplemented by other passive targeting mechanisms that together drive highly efficient IMAC accumulation at the tips. These findings illuminate the molecular basis of IMAC enrichment at microvillar tips and hold important implications for understanding apical morphogenesis in transporting and sensory epithelial tissues.


Interest in providing multiple sclerosis care and subspecializing in multiple sclerosis among neurology residents.
Although detailed knowledge regarding treatment options for multiple sclerosis (MS) patients is largely limited to neurologists, shortages in the neurologist workforce, including MS subspecialists, are predicted. Thus, MS patients may have difficulties in gaining access to appropriate care. No systematic evaluation has yet been performed of the number of neurology residents planning to pursue MS subspecialization. This study identifies factors affecting interest in providing MS patient care or MS subspecialization among current neurology residents. We randomly selected half of all Accreditation Council of Graduate Medical Education-certified neurology residency programs in the continental United States to receive the neurology resident survey. Completed surveys were received from 218 residents. Residents were significantly more likely to have increased interest in MS care when they participated in MS research, were interested in teaching, and indicated that the "ability to improve patient outcomes and quality of life" was a positive factor influencing their desire to provide MS patient care. Residents who were interested in providing MS care, interested in teaching, and indicated that "research opportunities" was a positive factor for providing MS patient care were significantly more likely to express interest in MS subspecialization. Increasing opportunities to interact with MS patients, learn about MS care, and participate in MS research may increase interest in MS care and subspecialization among neurology residents. Opportunities to educate residents regarding MS patient care may affect residents' attitudes.


Marijuana consumption and tolerance to physiological and subjective effects.
The relation between marijuana consumption and the development of tolerance was investigated during a 31-day study. Volunteers with a history of moderate or heavy marijuana use were given access to one-gram (2.1% delta9 tetrahydrocannabinol [THC]) marijuana cigarettes during a 21-day smoking period. Both groups tended to increase consumption during this time. Heavy users averaged 5.7 cigarettes per day and indicated a progressive decline in ratings of intoxication and duration of pulse rate effect. Moderate users averaged 3.2 cigarettes per day but showed no changes in either of these reactions during this time. Results suggested that tolerance does not develop to the two most reliable indexes of marijuana intoxication unless heavy doses of delta9 THC are self-administered repeatedly. Also, the tendency to increase consumption during this time is not necessarily associated with the development of tolerance.


Caffeine consumption, toxicity, tolerance and withdrawal; shared genetic influences with normative personality and personality disorder traits.
Our main aim was to estimate the extent of overlapping etiology between caffeine consumption and response and normative and pathological personality. Linear mixed-effects models were used to identify normative personality domains and personality disorder (PD) traits for inclusion in multivariate twin analyses together with individual caffeine related measures. Data were obtained from Norwegian adult twins in a face-to-face interview conducted in 1999-2004 as part of a population-based study of mental health and through self-report in 2010-2011 and 2015-2017. Personality disorder data was available for 2,793 twins, normative personality for 3,889 twins, and caffeine for 3,862 twins (mean age 43.0 years). Normative personality was assessed using the self-reported Big Five Inventory, PD traits were assessed by the Structured Interview for DSM-IV Personality, and caffeine consumption, toxicity, tolerance, and withdrawal were assessed through a self-report questionnaire developed at the Norwegian Institute of Public Health. Caffeine measures were found to be moderately heritable, h2 = 30.1%-45.0%. All normative personality domains and four PD traits, antisocial, borderline, dependent and paranoid, were significantly associated with at least one caffeine variable. A small proportion of variance in caffeine consumption was attributable to genetic factors shared with normative personality (1.3%) and personality disorders (11.4%). A modest proportion of variance in caffeine tolerance and toxicity was attributable to genetic factors shared with both normative personality (26.9%, 24.8%) and personality disorders (21.0%, 36.0%). The present study found caffeine consumption and response to be heritable and provides evidence that a small to-modest proportion of this genetic etiology is shared with both normative and pathological personality. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


A guide to aid the selection of diagnostic tests.
In recent years, a wide range of diagnostic tests has become available for use in resource-constrained settings. Accordingly, a huge number of guidelines, performance evaluations and implementation reports have been produced. However, this wealth of information is unstructured and of uneven quality, which has made it difficult for end-users, such as clinics, laboratories and health ministries, to determine which test would be best for improving clinical care and patient outcomes in a specific context. This paper outlines a six-step guide to the selection and implementation of in vitro diagnostic tests based on Médecins Sans Frontières' practical experience: (i) define the test's purpose; (ii) review the market; (iii) ascertain regulatory approval; (iv) determine the test's diagnostic accuracy under ideal conditions; (v) determine the test's diagnostic accuracy in clinical practice; and (vi) monitor the test's performance in routine use. Gaps in the information needed to complete these six steps and gaps in regulatory systems are highlighted. Finally, ways of improving the quality of diagnostic tests are suggested, such as establishing a model list of essential diagnostics, establishing a repository of information on the design of diagnostic studies and improving quality control and postmarketing surveillance.


[Cannabis affects driving skills].
Delta (9)-tetrahydrocannabinol (THC), the most important psychoactive substance in cannabis, is frequently detected in blood from apprehended drivers suspected for drugged driving. Both experimental and epidemiological studies have demonstrated the negative effects of THC upon cognitive functions and psychomotor skills. These effects could last longer than a measurable concentration of THC in blood. Culpability studies have recently demonstrated an increased risk of becoming responsible in fatal or injurious traffic accidents, even with low blood concentrations of THC. It has also been demonstrated that there is a correlation between the degree of impairment, the drug dose and the THC blood concentration. It is very important to focus on the negative effect of cannabis on fitness to drive in order to prevent injuries and loss of human life and to avoid large economic consequences to the society.


Adsorption of diclofenac onto different biochar microparticles: Dataset - Characterization and dosage of biochar.
Due to its wide occurrence in water resources and toxicity, pharmaceuticals and personal care products are becoming an emerging concern throughout the world. Application of residual/waste materials for water remediation can be a good strategy in waste management as well as in waste valorization. Herein, this dataset provides information on biochar application for the removal of emerging contaminant, diclofenac from water matrices. The data presented here is an extension of the research article explaining the mechanisms of adsorption diclofenac on biochars (Lonappan et al., 2017 [1]). This data article provides general information on the surface features of pine wood and pig manure biochar with the help of SEM and FTIR data. This dataset also provides information on XRD profiles of pine wood and pig manure biochars. In addition, different amounts of biochars were used to study the removal of a fixed concentration of diclofenac and the data is provided with this data set.


Neurobehavioral evaluation of soil and structural fumigators using methyl bromide and sulfuryl fluoride.
Neurobehavioral functions affected by methyl bromide exposure were evaluated in California structural and soil fumigators using methyl bromide and sulfuryl fluoride. Sampling data revealed that structural fumigators are exposed for up to 1.5 hrs/day to 0-2.2 ppm methyl bromide and/or 10-200 ppm sulfuryl fluoride, and soil fumigators can be exposed to 2.3 ppm methyl bromide over an 8-hr day. Subjects were grouped for statistical analysis on the basis of exposure history: Those exposed primarily (80% or more of the work period with exposure potential) to methyl bromide (N = 32), primarily to sulfuryl fluoride (24), or to a combination of methyl bromide and sulfuryl fluoride (40-60% of each) for a minimum of one year (18), and those not exposed to high concentrations of any chemicals (29 Referents). Fumigators using methyl bromide reported a significantly higher prevalence of 18 symptoms consistent with methyl bromide toxicity than did Referents. Methyl bromide fumigators did not perform as well as Referents on 23 of 27 behavioral tests (chosen to reflect methyl bromide effects), and were significantly lower on one test of finger sensitivity and one of cognitive performance. These consistent differences suggest that even the low levels of methyl bromide found in fumigation today may produce slight neurotoxic effects. found in fumigation today may produce slight neurotoxic effects. The greater number of symptoms and reduced performance on all cognitive tests in sulfuryl fluoride fumigators compared to the Reference Group plus the absence of published research on this compound suggest that the data base for sulfuryl fluoride is inadequate.


Asymmetric line shapes of the instrumental function found in two-étalon systems with a finite field of view.
The instrumental functions of the two-étalon system with a finite field of view have been examined in cases in which both étalons are inclined against the optical axis. The average transmittances of the rays in the finite field of view are obtained by numerical integration. It is shown that the line shape of the instrumental function becomes asymmetric, varying not only with the zenith angles of the symmetry axes of the two étalons but also with their azimuth angles. Experimental measurements of line shapes with the He-Ne laser show the asymmetric feature predicted by the calculation. The simulation calculations for the two-pass étalon system are also carried out and show a drastic discrepancy in transmittances between azimuth angle differences of 0° and 180°.


Free radical scavenging effects of melatonin and serotonin: possible mechanism.
Melatonin has been reported to be a potent free radical scavenger, but the mechanism by which it protects membranes from lipid peroxidation is poorly understood. The present study addresses this problem by comparing the free radical scavenging properties of melatonin and serotonin, two indoles with similar structure, but differing solubilities. Both serotonin and melatonin significantly prevented lipid peroxidation of platelet membranes. Additionally, melatonin significantly decreased the microviscosity (increased the fluidity) of platelet membranes, while serotonin had the opposite effect. These data led us to postulate that serotonin exerts its free radical scavenging action in the aqueous phase, or at the water-membrane interface, while melatonin positions itself within the lipid bilayer where it protects membrane phospholipids against free radical attack.


Holder-Pasteurized Human Donor Milk: How Long Can It Be Preserved?
When own mother's milk falls short, pasteurized human donor milk is recommended as alternative feeding for preterm infants. Donor milk has to meet the highest safety standards, but its processing and storage is expensive. The recommended storage time of pasteurized donor milk is 3 months. The objective of the present study was to determine whether the frozen storage time of pasteurized donor milk can be extended beyond 3 months without compromising its safety and quality. For this prospective observational study breast milk samples of 34 unique women, collected between November 2014 and June 2015, were provided by the Dutch Human Milk Bank. Samples were Holder pasteurized within 3 months after expression and stored at -20°C. Analysis of both bacterial growth (by inoculation of milk on a blood and a cysteine-, lactose-, and electrolyte-deficient agar) and fat, crude protein, carbohydrate and energy content of milk (analyzed by infrared spectroscopy) was done monthly during the first 6 months and every 2 months thereafter, up to 1 year postpasteurization. Thirty of 306 (9.8%) follow-up samples showed bacterial growth when cultured. None of the samples showed sequential contamination with the same strain up to 8 months of frozen storage. No significant decreases in macronutrients and energy content were observed over 8 months. Pasteurized human donor milk can be stored safely for 8 months at -20°C, without compromising its macronutrient and energy content. This longer storage time will reduce disposal of expired donor milk and subsequently reduce costs.


Membrane deformable mirror for adaptive optics: performance limits in visual optics.
The performance of a membrane deformable mirror with 37 electrodes (OKO Technologies) is studied in order to characterize its utility as an adaptive optics element. The control procedure is based on knowledge of the membrane's response under the action of each isolate electrode, i.e., the influence functions. The analysis of the mathematical techniques to obtain the control matrix gives useful information about the surfaces that are within the device's range of production, thus predicting the best performance of the mirror. We used a straightforward iterative algorithm to control the deformable membrane that permits the induction of surfaces in approximately four iterations, with an acceptable level of stability. The mirror and the control procedure are tested by means of generating Zernike polynomials and other surfaces. The mirror was incorporated in an adaptive optics prototype to compensate the eye's aberration in real time and in a closed loop. Double-pass retinal images with and without aberration correction were directly recorded in a real eye in order to evaluate the actual performance of the adaptive optics prototype.


Functional screening yields a new beta-1,4-endoglucanase gene from Heterodera glycines that may be the product of recent gene duplication.
Clones with secreted cellulolytic activity were identified when a cDNA library constructed from poly A(+) RNA of preparasitic second-stage juveniles of Heterodera glycines, the soybean cyst nematode, was expressed in the Escherichia coli SOLR strain and overlaid with a carboxymethylcellulose (CMC) substrate. Twenty CMC-degrading clones were analyzed, and all were either identical or strongly similar to a beta-1,4-endoglucanase gene (HG-eng-2), previously isolated from H. glycines. A subgroup of identical "HG-eng-2-like" clones had considerable differences in the 5' untranslated region compared with HG-eng-2 and were designated HG-eng-3. One H. glycines genomic clone contained HG-eng-2 and HG-eng-3 full-length genes, separated by a distance of approximately 8 kb, and a second genomic clone contained two copies of HG-eng-2, separated by approximately 6.5 kb, suggesting the presence of endoglucanase gene clusters in H. glycines. The HG-eng-2 and HG-eng-3 genes were in opposite transcriptional orientation, with considerable nucleotide differences in their 5' flanking regions. The highly conserved nucleotide sequence in the introns and exons and their close proximity within the genome suggest that HG-eng-2 and HG-eng-3 are the products of recent gene duplication and inversion.


In Vitro Activities of the Novel Investigational Tetrazoles VT-1161 and VT-1598 Compared to the Triazole Antifungals against Azole-Resistant Strains and Clinical Isolates of Candida albicans.
The fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new therapies to combat fungal infections, including Candida spp. To evaluate their in vitro activities compared to other azoles, MICs were determined by Clinical and Laboratory Standards Institute (CLSI) method for VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and posaconazole against 68 C. albicans clinical isolates well characterized for azole resistance mechanisms and mutant strains representing individual azole resistance mechanisms. VT-1161 and VT-1598 demonstrated potent activity (geometric mean MICs ≤0.15 μg/ml) against predominantly fluconazole-resistant (≥8 μg/ml) isolates. However, five of 68 isolates exhibited MICs greater than six dilutions (>2 μg/ml) to both tetrazoles compared to fluconazole-susceptible isolates. Four of these isolates likewise exhibited high MICs beyond the upper limit of the assay for all triazoles tested. A premature stop codon in ERG3 likely explained the high-level resistance in one isolate. VT-1598 was effective against strains with hyperactive Tac1, Mrr1, and Upc2 transcription factors and against most ERG11 mutant strains. VT-1161 MICs were elevated compared to the control strain SC5314 for hyperactive Tac1 strains and two strains with Erg11 substitutions (Y132F and Y132F&K143R) but showed activity against hyperactive Mrr1 and Upc2 strains. While mutations affecting Erg3 activity appear to greatly reduce susceptibility to VT-1161 and VT-1598, the elevated MICs of both tetrazoles for four isolates could not be explained by known azole resistance mechanisms, suggesting the presence of undescribed resistance mechanisms to triazole- and tetrazole-based sterol demethylase inhibitors.


Functional Dissociation of Confident and Not-Confident Errors in the Spatial Delayed Response Task Demonstrates Impairments in Working Memory Encoding and Maintenance in Schizophrenia.
Even though extensively investigated, the nature of working memory (WM) deficits in patients with schizophrenia (PSZ) is not yet fully understood. In particular, the contribution of different WM sub-processes to the severe WM deficit observed in PSZ is a matter of debate. So far, most research has focused on impaired WM maintenance. By analyzing different types of errors in a spatial delayed response task (DRT), we have recently demonstrated that incorrect yet confident responses (which we labeled as false memory errors) rather than incorrect/not-confident responses reflect failures of WM encoding, which was also impaired in PSZ. In the present study, we provide further evidence for a functional dissociation between confident and not-confident errors by manipulating the demands on WM maintenance, i.e., the length over which information has to be maintained in WM. Furthermore, we investigate whether these functionally distinguishable WM processes are impaired in PSZ. Twenty-four PSZ and 24 demographically matched healthy controls (HC) performed a spatial DRT in which the length of the delay period was varied between 1, 2, 4, and 6 s. In each trial, participants also rated their level of response confidence. Across both groups, longer delays led to increased rates of incorrect/not-confident responses, while incorrect/confident responses were not affected by delay length. This functional dissociation provides additional support for our proposal that false memory errors (i.e., confident errors) reflect problems at the level of WM encoding, while not-confident errors reflect failures of WM maintenance. Schizophrenic patients showed increased numbers of both confident and not-confident errors, suggesting that both sub-processes of WM-encoding and maintenance-are impaired in schizophrenia. Combined with the delay length-dependent functional dissociation, we propose that these impairments in schizophrenic patients are functionally distinguishable.


Differentiation of nonperforated from perforated appendicitis: accuracy of CT diagnosis and relationship of CT findings to length of hospital stay.
To determine retrospectively the sensitivity and specificity of computed tomographic (CT) signs in differentiating acute nonperforated appendicitis from perforated appendicitis and to compare CT findings with the length of hospital stay. Institutional Review Board approval was obtained for this study, and patient informed consent was obtained for record review for research purposes. Two radiologists were blinded to patient identification but were informed that all patients presented to the emergency department with abdominal pain and underwent appendectomy. Radiologists independently reviewed CT images of 86 consecutive patients (45 males, 41 females; mean age, 33.7 years; age range, 8.2-87.1 years) who presented to the emergency department with acute abdominal pain, who underwent CT after initial emergency department assessment, and who underwent appendectomy within the subsequent 24 hours. Individual findings and confidence level for the diagnosis of perforated appendicitis were noted. Consensus interpretation was performed with a third radiologist. The consensus CT findings were correlated with the surgical and pathologic findings by using chi(2) or Fisher exact tests for univariate analysis and logistic regression for multiple variable analysis. Wilcoxon rank sum tests were used to assess the association between consensus CT findings and length of hospital stay. Twenty-one (24%) of the 86 patients had appendiceal perforation. Extraluminal air and either moderate or severe periappendiceal inflammatory stranding were statistically significant independent predictors for perforation (P < .001). A focal defect in enhancing appendiceal wall was significantly associated with perforation (P < .001) and had a sensitivity of 58.8% and specificity of 85.7% on consensus review, with eight false-positive results. There was a strong association between the degree of periappendiceal inflammatory stranding and the length of hospital stay (P < .001). Extraluminal air and moderate or severe periappendiceal inflammatory stranding are statistically significant independent predictors for appendiceal perforation and are associated with increased hospital stay.


Quantum-classical modeling of nonlinear pulse propagation in a dissolved two-photon active chromophore.
In the present work we outline the implications of a quantum-classical approach for modeling two-photon absorption of organic chromophores in solution. The approach joins many-photon absorption dynamic simulations with quantum chemical first principles calculations of corresponding excitation energies and transition matrix elements. Among a number of conclusions of the study, we highlight three: (i) The use of either short- or long-pulse excitation is demonstrated to switch the absorptive capacity of the nonlinear medium owing to enhancement of the nonlinear stepwise processes; (ii) The two-photon cross section strongly depends on the way in which the dephasing rate decays when the laser frequency is tuned off-resonant with the corresponding molecular transition; (iii) The results of the pulse propagation simulations based on electronic structure data obtained with a new Coulomb attenuated functional is shown to be in much better agreement with the experimental results than those based on data received with traditional density functionals.


Acoustic and foraging behavior of a Baird's beaked whale, Berardius bairdii, exposed to simulated sonar.
Beaked whales are hypothesized to be particularly sensitive to anthropogenic noise, based on previous strandings and limited experimental and observational data. However, few species have been studied in detail. We describe the underwater behavior of a Baird's beaked whale (Berardius bairdii) from the first deployment of a multi-sensor acoustic tag on this species. The animal exhibited shallow (23 ± 15 m max depth), intermediate (324 ± 49 m), and deep (1138 ± 243 m) dives. Echolocation clicks were produced with a mean inter-click interval of approximately 300 ms and peak frequency of 25 kHz. Two deep dives included presumed foraging behavior, with echolocation pulsed sounds (presumed prey capture attempts) associated with increased maneuvering, and sustained inverted swimming during the bottom phase of the dive. A controlled exposure to simulated mid-frequency active sonar (3.5-4 kHz) was conducted 4 hours after tag deployment, and within 3 minutes of exposure onset, the tagged whale increased swim speed and body movement, and continued to show unusual dive behavior for each of its next three dives, one of each type. These are the first data on the acoustic foraging behavior in this largest beaked whale species, and the first experimental demonstration of a response to simulated sonar.


Inhibition of ATP-regulated K+ channels precedes depolarization-induced increase in cytoplasmic free Ca2+ concentration in pancreatic beta-cells.
The effects of glucose, diazoxide, K+, and tolbutamide on the activity of K+ channels, membrane potential, and cytoplasmic free Ca2+ concentration were investigated in beta-cells from the Uppsala colony of obese hyperglycemic mice. With [K+]e = [K+]i = 146 mM, it was demonstrated that the dominating channel at the resting potential is a K+ channel with a single-channel conductance of about 65 picosiemens and a reversal potential of about +70 mV (pipette potential). This channel is characterized by complex kinetics with openings grouped in bursts. The channel was completely inhibited by 20 mM glucose in intact cells or by intracellularly applied Mg-ATP (1 mM). The number of active channels was markedly reduced already by 5 mM glucose. However, the single channel current of the channels remaining active was unaffected, indicating no major depolarization. To evoke a substantial depolarization of the membrane and thereby action potentials, a total block in channel activity was necessary. This could be achieved either by increasing the concentration of glucose to 20 mM or by combining 5 mM glucose with 100 microM tolbutamide. In both cases, the effect was counteracted by the hyperglycemic sulfonamide diazoxide. The effects on single channel activity were paralleled by changes in membrane potential and cytoplasmic free Ca2+ concentration, also when the latter measurements were performed at room temperature. The transient increase in the number of active channels and the resulting hyperpolarization observed after raising the glucose concentration to 20 mM probably reflected a drop in cytoplasmic ATP concentration. It is suggested that ATP works as a key regulator of the beta-cell membrane potential and thereby the opening of voltage-activated Ca2+ channels.


A comparison of management practices, farmer-perceived disease incidence and winter housing on organic and non-organic dairy farms in the UK.
There have been increases in the number of organic dairy farms in the UK in recent years. However, there is little information on the impact of organic regulations on cow welfare. As part of a larger study, we aimed to investigate differences between organic and non-organic farms in management practices and winter housing quality. Forty organic and 40 non-organic farms throughout the UK were visited. Organic and non-organic farms were paired for housing type, and as far as possible for herd size, genetic merit and location. A detailed questionnaire covering key aspects of dairy management was carried out with each farmer. On a subset of twenty pairs, an assessment of the quality of the winter housing for both lactating and dry cows was undertaken, covering the parlour, bedding, loafing and feeding areas. Management practices and building conditions varied greatly within farm types and there was considerable overlap between organic and non-organic farms. Milk yield, level and composition of concentrate feed, management of heifers and calving, and use of 'alternative treatments' to prevent and treat mastitis differed between organic and non-organic farms. In all other respects there were no differences between farm types. Building dimensions per cow did not differ, even though organic recommendations advise greater space per cow than recommended for non-organic farms. The similarity between organic and non-organic farms in most respects indicates that cow housing and health, based on both the described management regimes and the farmers' perceptions of disease incidence, on organic dairy farms is neither compromised by the regulations, nor considerably better than on non-organic farms.


Automaticity and control in prospective memory: a computational model.
Prospective memory (PM) refers to our ability to realize delayed intentions. In event-based PM paradigms, participants must act on an intention when they detect the occurrence of a pre-established cue. Some theorists propose that in such paradigms PM responding can only occur when participants deliberately initiate processes for monitoring their environment for appropriate cues. Others propose that perceptual processing of PM cues can directly trigger PM responding in the absence of strategic monitoring, at least under some circumstances. In order to address this debate, we present a computational model implementing the latter account, using a parallel distributed processing (interactive activation) framework. In this model PM responses can be triggered directly as a result of spreading activation from units representing perceptual inputs. PM responding can also be promoted by top-down monitoring for PM targets. The model fits a wide variety of empirical findings from PM paradigms, including the effect of maintaining PM intentions on ongoing response time and the intention superiority effect. The model also makes novel predictions concerning the effect of stimulus degradation on PM performance, the shape of response time distributions on ongoing and prospective memory trials, and the effects of instructing participants to make PM responses instead of ongoing responses or alongside them. These predictions were confirmed in two empirical experiments. We therefore suggest that PM should be considered to result from the interplay between bottom-up triggering of PM responses by perceptual input, and top-down monitoring for appropriate cues. We also show how the model can be extended to simulate encoding new intentions and subsequently deactivating them, and consider links between the model's performance and results from neuroimaging.


Syndrome-Related Stigma in the General Social Environment as Reported by Women with Classical Congenital Adrenal Hyperplasia.
Stigma defined as "undesired differentness" (Goffman, 1963) and subtyped as "experienced" or "enacted," "anticipated," and "internalized" has been documented for patients with diverse chronic diseases. However, no systematic data exist on the association of stigma with somatic intersexuality. The current report concerns women with classical congenital adrenal hyperplasia (CAH), the most prevalent intersex syndrome, and provides descriptive data on CAH-related stigma as experienced in the general social environment (excluding medical settings and romantic/sexual partners) during childhood, adolescence, and adulthood. A total of 62 adult women with classical CAH [41 with the salt-wasting (SW) variant and 21 with the simple-virilizing (SV) variant] underwent a qualitative retrospective interview, which focused on the impact of CAH and its medical treatment on many aspects of women's lives. Deductive content analysis was performed on the transcribed texts. The women's accounts of CAH-related stigma were identified and excerpted as vignettes, and the vignettes categorized according to social context, stigma type, and the associated features of the CAH condition. Nearly two-thirds of women with either variant of CAH provided stigma vignettes. The vignettes included all three stigma types, and most involved some somatic or behavioral feature related to sex or gender. Stigma situations were reported for all ages and all social contexts of everyday life: family, peers, colleagues at work, strangers, and the media. We conclude that there is a need for systematic documentation of stigma in intersexuality as a basis for the development of improved approaches to prevention and intervention.


Randomised controlled trial of an innovative hypoglycaemia pathway for self-care at home and admission avoidance: a partnership approach with a regional ambulance trust.
Hypoglycaemia is a common and potentially life-threatening condition in people with diabetes, commonly caused by medications such as insulin. Hypoglycaemic events often require in-patient treatment and/or follow-up with a diabetes specialist nurse (DSN) or GP to make adjustments to medication. This referral pathway commonly relies on patient self-referral to primary care, and as a result many patients are not actively followed up and go on to experience repeat hypoglycaemic events. Randomised controlled trial in partnership with East Midlands Ambulance Service NHS Trust. People with diabetes calling out an ambulance for a severe hypoglycaemic episode and meeting the eligibility criteria were randomised to either a novel DSN-led pathway or to their general practice for routine follow-up. Primary outcome was proportion of participants with a documented consultation with a healthcare professional to discuss the management of their diabetes within 28 days of call-out. 162 people were randomised to one of the pathways (73 DSN arm, 89 GP arm) with 81 (50%, 35 DSN, 46 GP) providing full consent to be followed up. Due to lower than anticipated randomisation and consent rates, the recruitment target was not met. In the 81 participants who provided full consent, there were higher rates of consultation following the call-out when referred to a DSN compared to primary care (90% vs. 65%). Of the 81 participants, 26 (32%) had a second call-out within 12 months. Consultation rates following the call-out were high in the DSN-led arm, but there was insufficient power to complete the planned comparative analysis. The study highlighted the difficulty in recruitment and delivery of research in pre-hospital emergency care. Further work is needed to provide more feasible study designs and consent procedures balancing demands on ambulance staff time with the need for robust well-designed evaluation of referral pathways.


Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2.
To evaluate the efficacy and safety of eptinezumab, a humanized anti-calcitonin gene-related peptide monoclonal antibody, in the preventive treatment of chronic migraine (CM). The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-2 (PROMISE-2) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Adults with CM were randomly assigned to receive IV eptinezumab 100 mg, eptinezumab 300 mg, or placebo administered on day 0 and week 12. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) over weeks 1 to 12. Among treated participants (n = 1,072), baseline mean number of MMDs was ≈16.1 across groups. Treatment with eptinezumab 100 and 300 mg was associated with significant reductions in MMDs across weeks 1 to 12 compared with placebo (placebo -5.6, 100 mg -7.7, p < 0.0001 vs placebo; 300 mg -8.2, p < 0.0001 vs placebo). Treatment-emergent adverse events (TEAEs) were reported by 43.5% (100 mg), 52.0% (300 mg), and 46.7% (placebo) of patients. Nasopharyngitis was the only TEAE reported for >2% of eptinezumab-treated patients at an incidence of >2% over placebo; it occurred in the 300 mg eptinezumab arm (eptinezumab 9.4%, placebo 6.0%). In patients with CM, eptinezumab 100 and 300 mg was associated with a significant reduction in MMDs from the day after IV administration through week 12, was well tolerated, and demonstrated an acceptable safety profile. This study provides Class I evidence that for patients with CM, a single dose of eptinezumab reduces MMDs over 12 weeks of treatment. NCT02974153.


DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes.
Abnormal epigenetic marking is well documented in gene promoters of cancer cells, but the study of distal regulatory siteshas lagged behind.We performed a systematic analysis of DNA methylation sites connected with gene expression profilesacross normal and cancerous human genomes. Utilizing methylation and expression data in 58 cell types, we developed a model for methylation-expression relationships in gene promoters and extrapolated it to the genome. We mapped numerous sites at which DNA methylation was associated with expression of distal genes. These sites bind transcription factors in a methylation-dependent manner, and carry the chromatin marks of a particular class of transcriptional enhancers. In contrast to the traditional model of one enhancer site per cell type, we found that single enhancer sites may define gradients of expression levels across many different cell types. Strikingly, the identified sites were drastically altered in cancers: hypomethylated enhancer sites associated with upregulation of cancer-related genes and hypermethylated sites with downregulation. Moreover, the association between enhancer methylation and gene deregulation in cancerwas significantly stronger than the association of promoter methylationwith gene deregulation. Methylation of distal regulatory sites is closely related to gene expression levels across the genome. Single enhancers may modulate ranges of cell-specific transcription levels, from constantlyopen promoters. In contrast to the remote relationships between promoter methylation and gene dysregulation in cancer, altered methylation of enhancer sites is closely related to gene expression profiles of transformed cells.


Nutritional support for liver disease.
Weight loss and muscle wasting are commonly found in patients with end-stage liver disease. Since there is an association between malnutrition and poor clinical outcome, such patients (or those at risk of becoming malnourished) are often given parenteral nutrition, enteral nutrition, or oral nutritional supplements. These interventions have costs and adverse effects, so it is important to prove that their use results in improved morbidity or mortality, or both. To assess the beneficial and harmful effects of parenteral nutrition, enteral nutrition, and oral nutritional supplements on the mortality and morbidity of patients with underlying liver disease. The following computerised databases were searched: the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, and Science Citation Index Expanded (January 2012). In addition, reference lists of identified trials and review articles and Clinicaltrials.gov were searched. Trials identified in a previous systematic handsearch of Index Medicus were also considered. Handsearches of a number of medical journals, including abstracts from annual meetings, were done. Experts in the field and manufacturers of nutrient formulations were contacted for potential references. Randomised clinical trials (parallel or cross-over design) comparing groups of patients with any underlying liver disease who received, or did not receive, enteral or parenteral nutrition or oral nutritional supplements were identified without restriction on date, language, or publication status. Six categories of trials were separately considered: medical or surgical patients receiving parenteral nutrition, enteral nutrition, or supplements. The following data were sought in each report: date of publication; geographical location; inclusion and exclusion criteria; the type of nutritional support and constitution of the nutrient formulation; duration of treatment; any nutrition provided to the controls; other interventions provided to the patients; number, sex, age of the study participants; hospital or outpatient status; underlying liver disease; risks of bias (sequence generation, allocation concealment, blinding, incomplete outcome reporting, intention-to-treat analysis, selective outcome reporting, others (vested interests, baseline imbalance, early stopping)); mortality; hepatic morbidity (development or resolution of ascites or hepatic encephalopathy, occurrence of gastrointestinal bleeding); quality of life scores; adverse events; infections; lengths of stay in the hospital or intensive care unit; costs; serum bilirubin; postoperative complications (surgical trials only); and nutritional outcomes (nitrogen balance, anthropometric measurements, body weight). The primary outcomes of this review were mortality, hepatic morbidity, quality of life, and adverse events. Data were extracted in duplicate; differences were resolved by consensus.Data for each outcome were combined in a meta-analysis (RevMan 5.1). Estimates were reported using risk ratios or mean differences, along with the 95% confidence intervals (CI). Both fixed-effect and random-effects models were employed; fixed-effect models were reported unless one model, but not the other, found a significant difference (in which case both were reported). Heterogeneity was assessed by the Chi(2) test and I(2) statistic. Subgroup analyses were planned to assess specific liver diseases (alcoholic hepatitis, cirrhosis, hepatocellular carcinoma), acute or chronic liver diseases, and trials employing standard or branched-chain amino acid formulations (for the hepatic encephalopathy outcomes). Sensitivity analyses were planned to compare trials at low and high risk of bias and trials reported as full papers. The following exploratory analyses were undertaken: 1) medical and surgical trials were combined for each nutritional intervention; 2) intention-to-treat analyses in which missing dichotomous data were imputed as best- and worst-case scenarios; 3) all trials were combined to assess mortality; 4) effects were estimated by absolute risk reductions. Thirty-seven trials were identified; only one was at low risk of bias. Most of the analyses failed to find any significant differences. The significant findings that were found were the following: 1) icteric medical patients receiving parenteral nutrition had a reduced serum bilirubin (mean difference (MD) -2.86 mg%, 95% CI -3.82 mg% to -1.89 mg%, 3 trials) and better nitrogen balance (MD 3.60 g/day, 95% CI 0.86 g/day to 6.34 g/day, 1 trial); 2) surgical patients receiving parenteral nutrition had a reduced incidence of postoperative ascites only in the fixed-effect model (RR 0.65, 95% CI 0.48 to 0.87, 2 trials, I(2) = 70%) and one trial demonstrated a reduction in postoperative complications, especially infections (pneumonia in particular); 3) enteral nutrition may have improved nitrogen balance in medical patients (although a combination of the three trials was not possible); 4) one surgical trial of enteral nutrition found a reduction in postoperative complications; and 5) oral nutritional supplements had several effects in medical patients (reduced occurrence of ascites (RR 0.57, 95% CI 0.37 to 0.88, 3 trials), possibly (significant differences only seen in the fixed-effect model) reduced rates of infection (RR 0.49, 95% CI 0.24 to 0.99, 3 trials, I(2) = 14%), and improved resolution of hepatic encephalopathy (RR 3.75, 95% CI 1.15 to 12.18, 2 trials, I(2) = 79%). While there was no overall effect of the supplements on mortality in medical patients, the one low risk of bias trial found an increased risk of death in the recipients of the supplements. Three trials of supplements in surgical patients failed to show any significant differences. No new information was derived from the various subgroup or sensitivity analyses. The exploratory analyses were also unrevealing except for a logical conundrum. There was no difference in mortality when all of the trials were combined, but the trials of parenteral nutrition found that those recipients had better survival (RR 0.53, 95% CI 0.29 to 0.98, 10 trials). Either the former observation represents a type II error or the latter one a type I error. The data do not compellingly justify the routine use of parenteral nutrition, enteral nutrition, or oral nutritional supplements in patients with liver disease. The fact that all but one of these trials were at high risks of bias even casts doubt on the few benefits that were demonstrated. Data from well-designed and executed randomised trials that include an untreated control group are needed before any such recommendation can be made. Future trials have to be powered adequately to see small, but clinically important, differences.


An intron in the genes for U3 small nucleolar RNAs of the yeast Saccharomyces cerevisiae.
The origin of the intervening sequences (introns), which are removed during RNA maturation, is currently unknown. They are found in most genes encoding messenger RNAs, but are lacking in almost all small nuclear (sn)RNAs. One exceptional snRNA (U6) is part of the spliceosomal machinery that is involved in messenger RNA maturation. It has been suggested that its intron arose as a result of incorrect splicing of a messenger RNA precursor. This study revealed the presence of an intron, with the characteristic features of nuclear introns from precursors to messenger RNA, in the two genes coding for Saccharomyces cerevisiae U3 snRNA. The branch point was GACTAAC instead of the TACTAAC sequence found in all yeast introns examined so far. As U3 is a nucleolar snRNA required for maturation of ribosomal RNA, its intron could not have been acquired from aberrant messenger RNA processing in a spliceosome.


Bioengineering and semisynthesis of an optimized cyclophilin inhibitor for treatment of chronic viral infection.
Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance.