Injury Prediction in Competitive Runners With Machine Learning.
Staying injury free is a major factor for success in sports. Although injuries are difficult to forecast, novel technologies and data-science applications could provide important insights. Our purpose was to use machine learning for the prediction of injuries in runners, based on detailed training logs. Prediction of injuries was evaluated on a new data set of 74 high-level middle- and long-distance runners, over a period of 7 years. Two analytic approaches were applied. First, the training load from the previous 7 days was expressed as a time series, with each day's training being described by 10 features. These features were a combination of objective data from a global positioning system watch (eg, duration, distance), together with subjective data about the exertion and success of the training. Second, a training week was summarized by 22 aggregate features, and a time window of 3 weeks before the injury was considered. A predictive system based on bagged XGBoost machine-learning models resulted in receiver operating characteristic curves with average areas under the curves of 0.724 and 0.678 for the day and week approaches, respectively. The results of the day approach especially reflect a reasonably high probability that our system makes correct injury predictions. Our machine-learning-based approach predicts a sizable portion of the injuries, in particular when the model is based on training-load data in the days preceding an injury. Overall, these results demonstrate the possible merits of using machine learning to predict injuries and tailor training programs for athletes.


Expression and transfer of engineered catabolic pathways harbored by Pseudomonas spp. introduced into activated sludge microcosms.
Two genetically engineered microorganisms (GEMs), Pseudomonas sp. strain B13 FR1(pFRC20P) (FR120) and Pseudomonas putida KT2440(pWWO-EB62) (EB62), were introduced into activated sludge microcosms that had the level of aeration, nutrient makeup, and microbial community structure of activated sludge reactors. FR120 contains an experimentally assembled ortho cleavage route for simultaneous degradation of 3-chlorobenzoate (3CB) and 4-methyl benzoate (4MB); EB62 contains a derivative TOL plasmid-encoded degradative pathway for toluene experimentally evolved so that it additionally processes 4-ethyl benzoate (4EB). Experiments assessed survival of the GEMs, their ability to degrade target substrates, and lateral transfer of plasmid-encoded recombinant DNA. GEMs added at initial densities of 10(6) to 10(7) bacteria per ml of activated sludge declined to stable population densities of 10(4) to 10(5) bacteria per ml. FR120 degraded combinations of 3CB and 4MB (1 mM each) following 3 days of adaptation in the microcosms. Indigenous microorganisms required an 8-day adaptation period before degradation of 4MB was observed; 3CB was degraded only after the concentration of 4MB was much reduced. The indigenous microbial community was killed when both compounds were present at concentrations of 4.0 mM. However, in parallel microcosms containing FR120, the microbial community maintained a normal density of viable cells. Indigenous microbes readily degraded 4EB (2 mM), and EB62 did not significantly increase the observed rate of degradation. In filter matings, transfer of pFRC20P, which specifies mobilization but not transfer functions, from FR120 to P. putida UWC1 was not detectable (< 10(-7) transconjugants per donor cell).(ABSTRACT TRUNCATED AT 250 WORDS)


Rubinstein-Taybi syndrome with scoliosis.
Case report. The authors present the case of a 14-year-old boy with Rubinstein-Taybi syndrome (RSTS) presenting scoliosis. There have been no reports on surgery for RSTS presenting scoliosis. The patient was referred to our hospital for evaluation of a progressive spinal curvature. A standing anteroposterior spine radiograph at presentation to our hospital revealed an 84-degree right thoracic curve from T6 to T12, along with a 63-degree left lumbar compensatory curve from T12 to L4. We planned a two-staged surgery and decided to fuse from T4 to L4. The first operation was front-back surgery because of the rigidity of the right thoracic curve. The second operation of lumbar anterior discectomy and fusion was arranged 9 months after the first surgery to prevent the crankshaft phenomenon due to his natural course of adolescent growth. To avoid respiratory complications, the patient was put on a respirator in the ICU for several days after both surgeries. Full-length spine radiographs after the first surgery revealed no instrumentation failure and showed that the right thoracic curve was corrected to 31 degrees and the left lumbar curve was corrected to 34 degrees. No postoperative complications occurred after both surgeries. We succeeded in treating the patient without complications. Full-length spine standing radiographs at one year after the second operation demonstrated a stable bony arthrodesis with no loss of initial correction.


Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2.
Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-receptor type 1 (CRF-R1) antagonist antalarmin (500 ng/side) or CP-376395 (500 ng/side), but not the CRF-R2 antagonist astressin-2B (500 ng or 1 μg/side) or antisauvagine-30 (ASV-30; 500 ng/side) into the VTA. Likewise, intra-VTA antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1-selective agonist cortagine (100 ng/side) but not the CRF-R2-selective agonist rat urocortin II (rUCN II; 250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1-dependent regulation of addiction-related neurocircuitry in the VTA.


Exchanges of short polymorphic DNA segments predating speciation in feline major histocompatibility complex class I genes.
Sequence comparisons of 14 distinct MHC class I cDNA clones isolated from species representing the three major taxonomic lineages of Felidae (domestic cat lineage, ocelot lineage, and pantherine lineage) revealed that feline MHC class I alleles have highly mosaic structures with short polymorphic sequence motifs that are rearranged between alleles of individual MHC loci, between MHC class I genes within cat species, and between homologous MHC loci in different species. The pattern of sequence variation in felids supports the role of the following factors in production and maintenance of MHC variation: (1) gradual spontaneous mutation; (2) selective pressure to conserve certain residues but also to vary in hypervariable regions, notably residues that functionally participate in antigen recognition and presentation; and (3) recombination-mediated gene exchange between alleles and between related genes. The overall amount of genetic variation observed among MHC class I genes in the Felidae family is no greater than the amount of variation within any outbred cat species (i.e., domestic cat, ocelot). The occurrence of equivalent levels of polymorphism plus the simultaneous persistence of the same sequence motifs in divergent feline species suggest that most MHC class I nucleotide site polymorphism predated species divergences. Ancient polymorphisms have been transmitted through the speciation events and modern feline MHC class I alleles were derived by recombinational exchange of polymorphic sequence motifs. Moreover, some of these sequence motifs were found in other mammalian MHC class I genes, such as classical human HLA-B5, nonclassical human HLA-E class I genes, and bovine class I genes. These results raise the prospect of an ancient origin for some motifs, although the possibility of convergence in parallel mammalian radiations cannot be excluded.


TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. impaired B cell maturation in mice lacking BLyS.
BLyS and APRIL have similar but distinct biological roles, mediated through two known TNF receptor family members, TACI and BCMA. We show that mice treated with TACI-Ig and TACI-Ig transgenic mice have fewer transitional T2 and mature B cells and reduced levels of circulating immunoglobulin. TACI-Ig treatment inhibits both the production of collagen-specific Abs and the progression of disease in a mouse model of rheumatoid arthritis. In BLyS-deficient mice, B cell development is blocked at the transitional T1 stage such that virtually no mature B cells are present, while B-1 cell numbers are relatively normal. These findings further elucidate the roles of BLyS and APRIL in modulating B cell development and suggest that BLyS is required for the development of most but not all mature B cell populations found in the periphery.


Folic acid fortification of wheat flour: Chile.
Neural tube defects (open spina bifida, anencephaly, and encephalocele) represent the first congenital malformations to be preventable through public health measures such as supplementation and/or food fortification with folic acid. In Chile, starting in January 2000, the Chilean Ministry of Health legislated to add folic acid to wheat flour (2.2 mg/kg) to reduce the risk of NTDs. This policy resulted in an estimated mean additional supply of 427 microg/d in significant increases in serum folate and red cell folate of 3.8 and 2.4-fold, respectively, in women of fertile age, one year after fortification. The impact on the rate of NTDs is presently being studied in all births, both live births and still births, with birth weight >500 g in the city of Santiago. Preliminary results show a reduction of 40% in the rates on NTDs from the pre-fortification period (1999-2000) to post-fortification period (2001-June 2002). Fortification of wheat flour with folic acid in Chile is effective in preventing NTDs in Chile.


The evolving impact of HIV/AIDS on outpatient health services in Kwazulu-Natal, South Africa.
BACKGROUND AND OBJECTIVE; The high HIV prevalence in KwaZulu-Natal (KZN) places immense pressure on the health system. The burden of HIV/AIDS on health services is evolving as the epidemic progresses and as antiretroviral treatment becomes more widely available. For health policy makers and managers, timely and appropriate information is needed to facilitate adaptive management of health services. Through longitudinal research covering outpatient health services in KZN we examined the dynamics of the evolving HIV/AIDS burden and the resource implications of this burden, necessary for resource allocation decisions. Data were collected between 2004 and 2005 in outpatient services across six health facilities in the province. The burden of HIV/AIDS was measured by assessing the proportion of outpatients presenting as HIV positive, determined by a clinical diagnosis (and test result where available). The burden was also measured by looking at the types of diseases presenting at outpatient facilities. Moreover, the study assessed the burden experienced by health care workers and financial implications for health facilities. The study demonstrates that the burden on outpatient services is significant but has not been increasing over time, suggesting that people are not accessing care if and when they need it. However, in terms of resources, this burden has been increasing and shifting from tertiary services to more primary services. In order to accommodate the demands of HIV/AIDS, our focus therefore needs to turn towards outpatient services, in particular at the primary care level.


Low consumption power variable optical attenuator with sol-gel derived organic/inorganic hybrid materials.
An integrated optical waveguide variable optical attenuator (VOA) made of organic/inorganic hybrid materials was fabricated. At 1550 nm, the VOA showed a very low activation power of about 13 mW, due to the large thermo-optic coefficients of the hybrid materials. The optical power attenuations achieved were more than 25 dB for both TE and TM polarization. The response time of the device was less than 4.7 ms.


Poly(A) polymerase modification and reverse transcriptase PCR amplification of environmental RNA.
We describe a combination of two established techniques for a novel application for constructing full-length cDNA clone libraries from environmental RNA. The cDNA was cloned without the use of prescribed primers that target specific genes, and the procedure did not involve random priming. Purified RNA was first modified by addition of a poly(A) tail and then was amplified by using a commercially available reverse transcriptase PCR (RT-PCR) cDNA synthesis kit. To demonstrate the feasibility of this approach, a cDNA clone library was constructed from size-fractionated RNA (targeting 16S rRNA) purified from a geothermally heated soil in Yellowstone National Park in Wyoming. The resulting cDNA library contained clones representing Bacteria and Eukarya taxa and several mRNAs. There was no exact clone match between this library and a separate cDNA library generated from an RT-PCR performed with unmodified rRNA and Bacteria-specific forward and universal reverse primers that were designed from cultivated organisms; however, both libraries contained representatives of the Firmicutes and the alpha-Proteobacteria. Unexpectedly, there were no Archaea clones in the library generated from poly(A)-modified RNA. Additional RT-PCRs performed with universal and Archaea-biased primers and unmodified RNA demonstrated the presence of novel Archaea in the soil. Experiments with pure cultures of Sulfolobus solfataricus and Halobacterium halobium revealed that some Archaea rRNA may not be a suitable substrate for the poly(A) tail modification step. The protocol described here demonstrates the feasibility of directly accessing prokaryote RNA (rRNA and/or mRNA) in environmental samples, but the results also illustrate potentially important problems.


Non-specialist health worker interventions for the care of mental, neurological and substance-abuse disorders in low- and middle-income countries.
Many people with mental, neurological and substance-use disorders (MNS) do not receive health care. Non-specialist health workers (NSHWs) and other professionals with health roles (OPHRs) are a key strategy for closing the treatment gap. To assess the effect of NSHWs and OPHRs delivering MNS interventions in primary and community health care in low- and middle-income countries. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register) (searched 21 June 2012); MEDLINE, OvidSP; MEDLINE In Process & Other Non-Indexed Citations, OvidSP; EMBASE, OvidSP (searched 15 June 2012); CINAHL, EBSCOhost; PsycINFO, OvidSP (searched 18 and 19 June 2012); World Health Organization (WHO) Global Health Library (searched 29 June 2012); LILACS; the International Clinical Trials Registry Platform (WHO); OpenGrey; the metaRegister of Controlled Trials (searched 8 and 9 August 2012); Science Citation Index and Social Sciences Citation Index (ISI Web of Knowledge) (searched 2 October 2012) and reference lists, without language or date restrictions. We contacted authors for additional studies. Randomised and non-randomised controlled trials, controlled before-and-after studies and interrupted-time-series studies of NSHWs/OPHR-delivered interventions in primary/community health care in low- and middle-income countries, and intended to improve outcomes in people with MNS disorders and in their carers. We defined an NSHW as any professional health worker (e.g. doctors, nurses and social workers) or lay health worker without specialised training in MNS disorders. OPHRs included people outside the health sector (only teachers in this review). Review authors double screened, double data-extracted and assessed risk of bias using standard formats. We grouped studies with similar interventions together. Where feasible, we combined data to obtain an overall estimate of effect. The 38 included studies were from seven low- and 15 middle-income countries. Twenty-two studies used lay health workers, and most addressed depression or post-traumatic stress disorder (PTSD). The review shows that the use of NSHWs, compared with usual healthcare services: 1. may increase the number of adults who recover from depression or anxiety, or both, two to six months after treatment (prevalence of depression: risk ratio (RR) 0.30, 95% confidence interval (CI) 0.14 to 0.64; low-quality evidence); 2. may slightly reduce symptoms for mothers with perinatal depression (severity of depressive symptoms: standardised mean difference (SMD) -0.42, 95% CI -0.58 to -0.26; low-quality evidence); 3. may slightly reduce the symptoms of adults with PTSD (severity of PTSD symptoms: SMD -0.36, 95% CI -0.67 to -0.05; low-quality evidence); 4. probably slightly improves the symptoms of people with dementia (severity of behavioural symptoms: SMD -0.26, 95% CI -0.60 to 0.08; moderate-quality evidence); 5. probably improves/slightly improves the mental well-being, burden and distress of carers of people with dementia (carer burden: SMD -0.50, 95% CI -0.84 to -0.15; moderate-quality evidence); 6. may decrease the amount of alcohol consumed by people with alcohol-use disorders (drinks/drinking day in last 7 to 30 days: mean difference -1.68, 95% CI -2.79 to -0.57); low-quality evidence).It is uncertain whether lay health workers or teachers reduce PTSD symptoms among children. There were insufficient data to draw conclusions about the cost-effectiveness of using NSHWs or teachers, or about their impact on people with other MNS conditions. In addition, very few studies measured adverse effects of NSHW-led care - such effects could impact on the appropriateness and quality of care. Overall, NSHWs and teachers have some promising benefits in improving people's outcomes for general and perinatal depression, PTSD and alcohol-use disorders, and patient- and carer-outcomes for dementia. However, this evidence is mostly low or very low quality, and for some issues no evidence is available. Therefore, we cannot make conclusions about which specific NSHW-led interventions are more effective.


A new species of Paraberrapex Jensen, 2001 (Cestoda: Lecanicephalidea) from Squatina guggenheim Marini (Squatiniformes: Squatinidae) off Argentina.
Paraberrapex atlanticus sp. n. (Cestoda: Lecanicephalidea) is described from the spiral intestine of the angel shark Squatina guggenheim Marini from coastal waters off Buenos Aires Province, Argentina. Paraberrapex atlanticus sp. n. can be distinguished from the only species described in the genus, P. manifestus Jensen, 2001 in having cocoons 5-6 times longer with more eggs per cocoon, the extension of the uterine duct, the distribution of vitelline follicles, and the size and density of microtriches on the bothridial surfaces. The presence of P. atlanticus sp. n. in S. guggenheim confirms the specificity of Paraberrapex Jensen, 2001 for squatiniform sharks.


Endothelium-dependent vasodilation in myogenically active mouse skeletal muscle arterioles: role of EDH and K(+) channels.
As smooth muscle cell (SMC) membrane potential (E(m)) is critical for vascular responsiveness, and arteriolar SMCs are depolarized at physiological intraluminal pressures, we hypothesized that myogenic tone impacts on dilation mediated by endothelium-derived hyperpolarization (EDH). Studies were performed on cannulated mouse cremaster arterioles [diameter, 33+/-2 microm (n=23) at 60 mmHg; SMC Em -34.6+/-1.2 mV (n=7)]. Myogenic activity was assessed as tone developed in response to intraluminal pressure. Functional observations were related to mRNA, protein expression, and anatomy. Acetylcholine concentration-response curves showed a modest shift following indomethacin (10 microM) and L-NAME (100 microM), although maximal vasodilation was achieved. Residual dilation was removed by apamin (1 microM) in combination with TRAM-34 (1 microM) or charybotoxin (0.1 microM), indicating the requirement of small (S) and intermediate (I) calcium-activated potassium channels (K(Ca)). Charybdotoxin, but not TRAM-34, caused vasoconstriction, presumably through the inhibition of SMC BK(Ca). Expression of SK3 and IK1 was confirmed by immunohistochemistry and polymerase chain reaction, while myoendothelial junctions were common, suggesting a high degree of cell coupling. Also consistent with a role for endothelial K(Ca) channels, acetylcholine increased endothelium [Ca(2 +)](i). Apamin and TRAM-34 similarly blocked EDH-mediated dilation at intraluminal pressures of 30 and 90 mmHg, suggesting that in mouse arterioles, SK(Ca -) and IK(Ca -) mediated mechanisms predominate and operate independently of physiological levels of myogenic activation.


Activities of the chaperonin containing TCP-1 (CCT): implications for cell cycle progression and cytoskeletal organisation.
The chaperonin containing TCP-1 (CCT) is required for the production of native actin and tubulin and numerous other proteins, several of which are involved in cell cycle progression. The mechanistic details of how CCT acts upon its folding substrates are intriguing: whilst actin and tubulin bind in a sequence-specific manner, it is possible that some proteins could use CCT as a more general binding interface. Therefore, how CCT accommodates the folding requirements of its substrates, some of which are produced in a cell cycle-specific manner, is of great interest. The reliance of folding substrates upon CCT for the adoption of their native structures results in CCT activity having far-reaching implications for a vast array of cellular processes. For example, the dependency of the major cytoskeletal proteins actin and tubulin upon CCT results in CCT activity being linked to any cellular process that depends on the integrity of the microfilament and microtubule-based cytoskeletal systems.


Double knockdown of prolyl hydroxylase and factor-inhibiting hypoxia-inducible factor with nonviral minicircle gene therapy enhances stem cell mobilization and angiogenesis after myocardial infarction.
Under normoxic conditions, hypoxia-inducible factor (HIF)-1α is rapidly degraded by 2 hydroxylases: prolyl hydroxylase (PHD) and factor-inhibiting HIF-1 (FIH). Because HIF-1α mediates the cardioprotective response to ischemic injury, its upregulation may be an effective therapeutic option for ischemic heart failure. PHD and FIH were cloned from mouse embryonic stem cells. The best candidate short hairpin (sh) sequences for inhibiting PHD isoenzyme 2 and FIH were inserted into novel, nonviral, minicircle vectors. In vitro studies after cell transfection of mouse C2C12 myoblasts, HL-1 atrial myocytes, and c-kit(+) cardiac progenitor cells demonstrated higher expression of angiogenesis factors in the double-knockdown group compared with the single-knockdown and short hairpin scramble control groups. To confirm in vitro data, shRNA minicircle vectors were injected intramyocardially after left anterior descending coronary artery ligation in adult FVB mice (n=60). Functional studies using MRI, echocardiography, and pressure-volume loops showed greater improvement in cardiac function in the double-knockdown group. To assess mechanisms of this functional recovery, we performed a cell trafficking experiment, which demonstrated significantly greater recruitment of bone marrow cells to the ischemic myocardium in the double-knockdown group. Fluorescence-activated cell sorting showed significantly higher activation of endogenous c-kit(+) cardiac progenitor cells. Immunostaining showed increased neovascularization and decreased apoptosis in areas of injured myocardium. Finally, western blots and laser-capture microdissection analysis confirmed upregulation of HIF-1α protein and angiogenesis genes, respectively. We demonstrated that HIF-1α upregulation by double knockdown of PHD and FIH synergistically increases stem cell mobilization and myocardial angiogenesis, leading to improved cardiac function.


The dynamics of chronic gout treatment: medication gaps and return to therapy.
To identify gaps in therapy with urate-lowering drugs for the treatment of gout as well as factors associated with resuming therapy. From 2 integrated delivery systems, we identified patients 18 years or older with a diagnosis of gout who initiated use of a urate-lowering drug from January 1, 2000 through June 30, 2006 and who had a gap in therapy. A gap was defined as a period of over 60 days after the completion of 1 prescription in which no refill for a urate-lowering drug was obtained. Survival curves were used to assess return to therapy of urate-lowering drugs. Cox proportional hazards analysis estimated the association between covariates and return to therapy. There were 4166 new users of urate-lowering drugs (97% received allopurinol), of whom 2929 (70%) had a gap in therapy. Among those with a gap, in 75% it occurred in the first year of therapy. Fifty percent of patients with a gap returned to therapy within 8 months, and by 4 years it was 75%. Age 45-74 years (<45 referent) and greater duration of urate-lowering drug use before the gap was associated with resuming treatment within 1 year. In contrast, receipt of nonsteroidal anti-inflammatory drugs or glucocorticoids in the year before the gap was associated with a reduced likelihood of resuming therapy. The majority of gout patients with gaps in urate-lowering drug use returned to treatment. More investigation is needed to better understand why patients may go for months without refilling prescriptions, given the clinical consequences of nonadherence.


Oral budesonide for induction of remission in ulcerative colitis.
Corticosteroids are first-line therapy for induction of remission in ulcerative colitis. Although corticosteroids may improve symptoms, they have significant adverse effects. Steroids which act topically, with less systemic side-effects may be more desirable. Budesonide is a topically acting corticosteroid with extensive first pass hepatic metabolism. There are currently three formulations of budesonide: two standard formulations including a controlled-ileal release capsule and a pH-dependent capsule both designed to release the drug in the distal small intestine and right colon; and the newer Budesonide-MMX® capsule designed to release the drug throughout the entire colon. The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction of remission in ulcerative colitis. We searched MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Group Specialised Register from inception to April 2015. We also searched reference lists of articles, conference proceedings and ClinicalTrials.gov. Randomised controlled trials comparing oral budesonide to placebo or another active therapy for induction of remission in ulcerative colitis were considered eligible. There were no exclusions based on patient age or the type, dose, duration or formulation of budesonide therapy. Two independent investigators reviewed studies for eligibility, extracted data and assessed study quality. Methodological quality was assessed using the Cochrane risk of bias tool. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. The primary outcome was induction of remission (as defined by the primary studies) at week eight. Secondary outcomes included clinical, endoscopic and histologic improvement, adverse events and early withdrawal. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome and the mean difference (MD) and corresponding 95% CI for each continuous outcome. Data were analysed on an intention-to-treat basis. Six studies (1808 participants) were included. Four studies compared budesonide-MMX® with placebo, one small pilot study looked at clinical remission at week four, and was subsequently followed by three large, studies that assessed combined clinical and endoscopic remission at week eight. Although two placebo-controlled studies had mesalamine and Entocort (standard budesonide) treatment arms, these studies were not sufficiently powered to compare Budesonide-MMX® with these active comparators. One small study compared standard budesonide with prednisolone and one study compared standard budesonide to mesalamine. Four studies were rated as low risk of bias and two studies had an unclear risk of bias. A pooled analysis of three studies (900 participants) showed that budesonide-MMX® 9 mg was significantly superior to placebo for inducing remission (combined clinical and endoscopic remission) at 8 weeks. Fifteen per cent (71/462) of budesonide-MMX® 9 mg patients achieved remission compared to 7% (30/438) of placebo patients (RR 2.25, 95% CI 1.50 to 3.39). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (101 events). A subgroup analysis by concurrent mesalamine use suggests higher efficacy in the 442 patients who were not considered to be mesalamine-refractory (RR 2.89, 95% CI 1.59 to 5.25). A subgroup analysis by disease location suggests budesonide is most effective in patients with left-sided disease (RR 2.98, 95% CI 1.56 to 5.67; 289 patients). A small pilot study reported no statistically significant difference in endoscopic remission between budesonide and prednisolone (RR 0.75, 95% CI 0.23 to 2.42; 72 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to unclear risk of bias and very sparse data (10 events). Standard oral budesonide was significantly less likely to induce clinical remission than oral mesalamine after 8 weeks of therapy (RR 0.72, 95% CI 0.57 to 0.91; 1 study, 343 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (161 events). Another study found no difference in remission rates between budesonide-MMX® 9 mg and mesalamine (RR 1.48, 95% CI 0.81 to 2.71; 247 patients). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (37 events). One study found no difference in remission rates between budesonide-MMX® 9 mg and standard budesonide 9 mg (RR 1.38, 95% CI 0.72 to 2.65; 212 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (32 events). Suppression of plasma cortisol was more common in prednisolone-treated patients (RR 0.02, 95% CI 0.0 to 0.33). While budesonide does appear to suppress morning cortisol to some extent, mean morning cortisol values remained within the normal range in 2 large studies (n = 899) and there was no difference in glucocorticoid-related side-effects across different treatment groups. Further, study withdrawal due to adverse events was not more common in budesonide compared with placebo treated patients (RR 0.85, 95% CI 0.53 to 1.38). Common adverse events included worsening ulcerative colitis, headache, pyrexia, insomnia, back pain, nausea, abdominal pain, diarrhoea, flatulence and nasopharyngitis. Moderate quality evidence to supports the use of oral budesonide-MMX® at a 9 mg daily dose for induction of remission in active ulcerative colitis, particularly in patients with left-sided colitis. Budesonide-MMX® 9 mg daily is effective for induction of remission in the presence or absence of concurrent 5-ASA therapy. Further, budesonide-MMX® appears to be safe, and does not lead to significant impairment of adrenocorticoid function compared to placebo. Moderate quality evidence from a single study suggests that mesalamine may be superior to standard budesonide for the treatment of active ulcerative colitis. Low quality evidence from one study found no difference in remission rates between budesonide MMX® and mesalamine. Very low quality evidence from one small study showed no difference in endoscopic remission rates between standard budesonide and prednisolone. Low quality evidence from one study showed no difference in remission rates between budesonide-MMX® and standard budesonide. Adequately powered studies are needed to allow conclusions regarding the comparative efficacy and safety of budesonide versus prednisolone, budesonide-MMX® versus standard budesonide and budesonide versus mesalamine.


[Profile of parturients and their newborn babies receiving care in a university hospital in northwestern Paraná].
The study had the purpose to outline the profile of parturients and their newborn babies receiving care in a school hospital, based on the Live Birth Information System - Sistema de Informações sobre Nascidos Vivos - SINASC. For so, a descriptive, exploratory study was elaborated, identifying the characteristics of all the parturients and their newborns receiving care at Hospital Universitário de Maringá - HUM in 2006. It was observed that 27.1% of the parturients were adolescents, 68.4% had no partner, 59.3% lived outside Maringá, and 63.6% had seven or more pre-natal appointments. The ratio of cesarian sections was 50.4%. The newborns, mostly, had good vitality at birth, although 25.5% were preterms and 23.6% had low weight at birth. With the results, it was possible to outline the profile of the parturients and their newborns receiving care at the HUM, show the possibility of using the SINASC as an instrument of health evaluation in tertiary units and propose interventions capable of preventing maternal-child morbimortality.


Addition of the long-axis information to short-axis contours reduces interstudy variability of left-ventricular analysis in cardiac magnetic resonance studies.
To reduce interstudy variability using long-axis information for correcting short-axis (SA) contours at basal and apical level for left-ventricular analysis by magnetic resonance imaging. A total of 20 patients with documented heart failure and 20 volunteers underwent magnetic resonance imaging examination twice for measuring endocardial end-diastolic volume, endocardial end-systolic volume, mass, and ejection fraction. The boundary of the left ventricle, the mitral valve plane, and apex were marked manually on the 2- and 4-chamber long-axis images. Automatic epicardial and endocardial contour detection was performed on the SA images using the intersection of the outlines from the long axis as starting positions. The same observer compared the interstudy variability of this method with analysis that was based on the SA images only. The interstudy variability decreased when information from the long axis was included; for end-systolic volume, 9.6% versus 4.7% (P = 0.00014); for end-diastolic volume, 4.9% versus 2.5% (P = 0.0011); for mass, 7.4% versus 5.0% (P = 0.11); and for ejection fraction 12.2% versus 5.6% (P = 0.0017), respectively. Identification of the mitral valve plane and apex on long-axis images to limit the extent of volume at the base and the apex of the heart reduces interstudy variability for left-ventricular functional assessment.


Knowledge, attitude, and practice regarding the screening of cervical cancer among women in New Delhi, India.
Cervical cancer is one of the major concerns of public health importance in today's world. It is a leading cause of mortality in women of reproductive age group worldwide, mainly in developing countries. Reduction in mortality and morbidity due to cervical cancer is possible through early detection and treatment. The major factors influencing the early detection of cervical cancer are knowledge regarding risk factors, screening, Pap smear, and symptoms among women. The present cross-sectional study was carried out to assess the knowledge, attitude, and practice of women about the risk factors, symptoms, and prevention of cervical cancer. Data were obtained from 220 women who visited international trade fair using a pretested self-administered questionnaire. Only 75 study women (50.0%) had ever heard of cervical cancer. The knowledge regarding cervical cancer and its various domains was significantly higher in students and unmarried women. The foul-smelling vaginal discharge was the most common early symptom of cervical cancer according to most of the study women (26, 17.3%). Most of the study women (19, 12.7%) reported tobacco and smoking as the most common risk factor associated with cervical cancer. Only 39 women (26%) had ever heard of cervical cancer screening. Only 27 women (18.0%) ever had Pap smear done in the past and 87 women (58.0%) were willing to undergo cervical cancer screening is offered free of cost. The study demonstrates the lack of awareness in women regarding cervical cancer and its screening modalities. This necessitates spreading awareness regarding early symptoms and risk factors associated with cervical cancer for early detection and treatment initiation.


The training and professional expectations of medical students in Angola, Guinea-Bissau and Mozambique.
The purpose of this paper is to describe and analyze the professional expectations of medical students during the 2007-2008 academic year at the public medical schools of Angola, Guinea-Bissau and Mozambique, and to identify their social and geographical origins, their professional expectations and difficulties relating to their education and professional future. Data were collected through a standardised questionnaire applied to all medical students registered during the 2007-2008 academic year. Students decide to study medicine at an early age. Relatives and friends seem to have an especially important influence in encouraging, reinforcing and promoting the desire to be a doctor.The degree of feminization of the student population differs among the different countries.Although most medical students are from outside the capital cities, expectations of getting into medical school are already associated with migration from the periphery to the capital city, even before entering medical education.Academic performance is poor. This seems to be related to difficulties in accessing materials, finances and insufficient high school preparation.Medical students recognize the public sector demand but their expectations are to combine public sector practice with private work, in order to improve their earnings. Salary expectations of students vary between the three countries.Approximately 75% want to train as hospital specialists and to follow a hospital-based career. A significant proportion is unsure about their future area of specialization, which for many students is equated with migration to study abroad. Medical education is an important national investment, but the returns obtained are not as efficient as expected. Investments in high-school preparation, tutoring, and infrastructure are likely to have a significant impact on the success rate of medical schools. Special attention should be given to the socialization of students and the role model status of their teachers.In countries with scarce medical resources, the hospital orientation of students' expectations is understandable, although it should be associated with the development of skills to coordinate hospital work with the network of peripheral facilities. Developing a local postgraduate training capacity for doctors might be an important strategy to help retain medical doctors in the home country.


Bringing Model-Based Prediction to Oncology Clinical Practice: A Review of Pharmacometrics Principles and Applications.
Despite much investment and progress, oncology is still an area with significant unmet medical needs, with new therapies and more effective use of current therapies needed. The emergent field of pharmacometrics combines principles from pharmacology (pharmacokinetics [PK] and pharmacodynamics [PD]), statistics, and computational modeling to support drug development and optimize the use of already marketed drugs. Although it has gained a role within drug development, its use in clinical practice remains scarce. The aim of the present study was to review the principal pharmacometric concepts and provide some examples of its use in oncology. Integrated population PK/PD/disease progression models as part of the pharmacometrics platform provide a powerful tool to predict outcomes so that the right dose can be given to the right patient to maximize drug efficacy and reduce drug toxicity. Population models often can be developed with routinely collected medical record data; therefore, we encourage the application of such models in the clinical setting by generating close collaborations between physicians and pharmacometricians. The present review details how the emerging field of pharmacometrics can integrate medical record data with predictive pharmacological and statistical models of drug response to optimize and individualize therapies. In order to make this routine practice in the clinic, greater awareness of the potential benefits of the field is required among clinicians, together with closer collaboration between pharmacometricians and clinicians to ensure the requisite data are collected in a suitable format for pharmacometrics analysis.


Factors influencing hospice thromboprophylaxis policy: a qualitative study.
Despite level 1 evidence supporting the use of low-molecular weight heparin thromboprophylaxis in hospitalised cancer patients, only 7% of specialist palliative care units (SCPU) have thromboprophylaxis guidelines. The reasons for this are unclear. To explore specialist palliative care units (SPCU) directors' views on thromboprophylaxis in the inpatient unit, audiotaped semi-structured interviews were conducted with SCPU medical directors to explore factors influencing thromboprophylaxis practice. Purposive sampling of units known not to have thromboprophylaxis guidelines was conducted (as identified from previous research). The hospice directory was used to sample from units in each region of Great Britain and Ireland to ensure representation across the specialty. Interviews were transcribed and analysed using interpretative phenomenological analysis (IPA). Four major and four sub themes were identified. Participants were progressive in their attitudes to palliative care and comfortable with instigating active interventions for patient benefit. Symptomatic venous thromboembolism (VTE) was rarely seen and therefore not considered important enough to warrant guidelines. There was concern that evidence informing thromboprophylaxis guidelines in the general population was not transferable to the advanced cancer population and that the outcome measures from these studies were less meaningful to a palliative care patient. Thromboprophylaxis was considered a life prolonging intervention which may result in a poorer death than one because of VTE. Nevertheless, participants were receptive to change if presented with convincing evidence derived from a representative population. Until the true prevalence and symptomatic burden of VTE is known, the role of thromboprophylaxis in the SPCU setting will remain controversial. There is a need for a well-designed study to explore the utility of thromboprophylaxis in the palliative care inpatient setting. However, this will require meaningful outcome measures to be used within a clinically applicable population.


Childhood Infections and Subsequent School Achievement Among 598,553 Danish Children.
Hospitalizations for infections have been associated with subsequent decreased cognitive ability, but it is uncertain if childhood infections influence subsequent scholastic achievement (SA). We aimed to estimate the association between infections during childhood and SA. Nationwide prospective cohort study including 598,553 children born in Denmark between 1987 and 1997 and their parents. Exposures were hospitalization for infections and treatment with anti-infective agents. Outcomes were completion of ninth grade and ninth grade test scores. Data were analyzed with logistic and linear regression analysis techniques and adjusted for any mental disorder, birthweight, Apgar score, malformations at birth, chronic somatic diseases, first-born child, parental educational level and parental mental disorders. Hospitalization with infections was linked to lower completion of ninth grade with an odds ratio of 0.82 (95% confidence interval: 0.79-0.85) compared with children without prior hospitalizations for infections. Dose-response relationships were observed with respect to number of hospital contacts for infections and a shorter time since last hospitalization (all P < 0.001). Among those who completed the ninth grade test score, we found a dose-response and time-since relationship between number of prior severe infections and subsequent lower grade scores (P < 0.001). Treatment of nonsevere infections with anti-infective agents did not predict lower completion of ninth grade but was associated with lower grade scores (P < 0.001). Infections, particularly those requiring hospitalizations, were associated with subsequent affected cognitive ability as indicated by lower SA. These findings might also be explained by missed school days or socioeconomic factors associated with the susceptibility of acquiring infections.


Association Between More Intensive vs Less Intensive Blood Pressure Lowering and Risk of Mortality in Chronic Kidney Disease Stages 3 to 5: A Systematic Review and Meta-analysis.
Trials in patients with hypertension have demonstrated that intensive blood pressure (BP) lowering reduces the risk of cardiovascular disease and all-cause mortality but may increase the risk of chronic kidney disease (CKD) incidence and progression. Whether intensive BP lowering is associated with a mortality benefit in patients with prevalent CKD remains unknown. To conduct a systematic review and meta-analysis of randomized clinical trials (RCTs) to investigate if more intensive compared with less intensive BP control is associated with reduced mortality risk in persons with CKD stages 3 to 5. Ovid MEDLINE, Cochrane Library, EMBASE, PubMed, Science Citation Index, Google Scholar, and clinicaltrials.gov electronic databases. All RCTs were included that compared 2 defined BP targets (either active BP treatment vs placebo or no treatment, or intensive vs less intensive BP control) and enrolled adults (≥18 years) with CKD stages 3 to 5 (estimated glomerular filtration rate <60 mL/min/1.73 m2) exclusively or that included a CKD subgroup between January 1, 1950, and June 1, 2016. Two of us independently evaluated study quality and extracted characteristics and mortality events among persons with CKD within the intervention phase for each trial. When outcomes within the CKD group had not previously been published, trial investigators were contacted to request data within the CKD subset of their original trials. All-cause mortality during the active treatment phase of each trial. This study identified 30 RCTs that potentially met the inclusion criteria. The CKD subset mortality data were extracted in 18 trials, among which there were 1293 deaths in 15 924 participants with CKD. The mean (SD) baseline systolic BP (SBP) was 148 (16) mm Hg in both the more intensive and less intensive arms. The mean SBP dropped by 16 mm Hg to 132 mm Hg in the more intensive arm and by 8 mm Hg to 140 mm Hg in the less intensive arm. More intensive vs less intensive BP control resulted in 14.0% lower risk of all-cause mortality (odds ratio, 0.86; 95% CI, 0.76-0.97; P = .01), a finding that was without significant heterogeneity and appeared consistent across multiple subgroups. Randomization to more intensive BP control is associated with lower mortality risk among trial participants with hypertension and CKD. Further studies are required to define absolute BP targets for maximal benefit and minimal harm.


Moving beyond prevalence studies: screening and interventions for children with disabilities in low-income and middle-income countries.
Research understanding the lives of children with disabilities in low-income and middle-income countries has predominantly focused on prevalence studies with little progress on evidence-based service development. At the same time, global attention in child health has shifted from child survival strategies to those that bring child survival and development together. This review examines whether intervention research can be better aligned with current theoretical constructs of disability and international guidelines that advocate for the realisation of rights for children with disabilities and inclusive early childhood development.


Aerobic Exercise as a Warm-up for Singing: Acoustic Impacts.
In a previous work, it was found that a 30-minute aerobic workout significantly increased singers' sound pressure level and airflow during voicing, suggesting a shift to flow phonation. This companion study was designed to assess the impact of the same workout on pitch accuracy, vibrato rate, extent and regularity, and the singing power ratio. This study is a cohort experimental study. Twenty-two students in an academic vocal performance program participated. They performed an aerobic workout for 30 minutes. Before and after the workout, they sang the first seven notes of the "Star-Spangled Banner" on /pa/, producing seven /pa/s on the last note. The students then sang an ascending and descending scale to the ninth on "ah." The following measures were obtained from the "Star-Spangled Banner": pitch accuracy calculated on the seventh note ("by"); and vibrato rate, regularity, and extent, calculated on the most sustained sixth note ("see"). For the scale, the following measures were calculated from each note: pitch accuracy; vibrato rate, regularity, and extent; and the singing power ratio. There were no significant differences from pre- to postworkout across any measures. It appears that an aerobic workout positively impacts the respiratory driving force for voice production but does little for phonation. Critical for performance is the fine tuning and balancing across the respiratory, laryngeal, and resonance systems. It appears that this can only be achieved with vocalization exercises, facilitating coordination within and across the physiological systems involved in the complex art of bel canto.


Setting up home noninvasive ventilation.
Home noninvasive ventilation (NIV) is widely used to correct nocturnal alveolar hypoventilation in patients with chronic respiratory failure of various etiologies. The most commonly used ventilation mode is pressure support with a backup respiratory rate. This mode requires six main settings, as well as some additional settings that should be adjusted according to the individual patient. This review details the effect of each setting, how the settings should be adjusted according to each patient, and the risks if they are not adjusted correctly. The examples described here are based on real patient cases and bench simulations. Optimizing the settings for home NIV may improve the quality and tolerance of the treatment.


Driving with a forearm plaster cast: patients' perspective.
Forearm plaster casts are commonly used in orthopaedic practice for the treatment of fractures of the wrist and carpal bones. A common question put by patients seeks to clarify suitability to drive a motor vehicle. DVLA guidelines do not specifically comment about temporary immobilisation in a cast. A questionnaire was sent to 248 adult patients who had recently been treated in Colles' or scaphoid-type casts to determine the driving habits of the patients and their attitudes to the legality and safety of driving with a cast. Of those who responded, 87% considered it unsafe to drive a car with a plaster cast. 79% thought it should be illegal. Only 9% of patients reported driving while immobilised, and these tended to be young men who did not inform any authority. Previous literature is confusing and there appears to be little consensus among orthopaedic surgeons about letting these patients drive. Clarification is reported from the Medical Advisory Group at the DVLA and the Head of Road Policing Business Area for the Association of Chief Police Officers. It is recommended that all medical professionals advise their patients that they should not drive while immobilised in an upper limb plaster cast.


Dynamic Nuclear Polarization NMR as a new tool to investigate the nature of organic compounds occluded in plant silica particles.
The determination of the chemical nature of the organic matter associated with phytoliths remains a challenge. This difficulty mainly stems from amounts of organic carbon (C) that are often well below the detection limit of traditional spectroscopic tools. Conventional solid-state 13C Nuclear Magnetic Resonance (NMR) is widely used to examine the nature and structure of organic molecules, but its inherent low sensitivity prohibits the observation of diluted samples. The recent advent of commercial microwave source in the terahertz range triggered a renewed interest in the Dynamic Nuclear Polarization (DNP) technique to improve the signal to noise ratio of solid-state NMR experiments. With this technique, the 13C spectrum of a phytolith sample containing 0.1% w/w C was obtained overnight with sufficient quality to permit a semi-quantitative analysis of the organic matter, showing the presence of peptides and carbohydrates as predominant compounds. Considering the natural abundance of the 13C isotope, this experiment demonstrates that DNP NMR is sufficiently sensitive to observe spin systems present in amounts as low as a few tens of ppm.


Importance of radio-guided minimally invasive parathyroidectomy using hand-held gamma probe and low (99m)Tc-MIBI dose. Technical considerations and long-term clinical results.
(99m)Tc-MIBI radio-guided surgery results, obtained in a group of 141 patients with primary hyperparathyroidism (HPT), are reported. All patients were preoperatively evaluated by a single day protocol based on double-tracer parathyroid scintigraphy and neck ultrasound, and then operated by the same surgical team. In 102 patients (72.3%) with a high scan/ultrasound probability of solitary parathyroid adenoma and normal thyroid gland, a minimally invasive radio-guided surgery was planned. In the other 39 patients (27.7%) with scan/ultrasound evidence of multi-glandular disease (n=8) or concomitant nodular goiter (n=31), the intraoperative gamma probe was used during a standard bilateral neck exploration. Intraoperative quick parathyroid hormone (PTH) levels were routinely measured. The minimally invasive radio-guided surgery technique we developed, consisted of: a) injection of a low 37 MBq (99m)Tc-MIBI dose in the operative theatre during anaesthesia induction, b) patient's neck scan with a hand-held gamma probe just before the surgical cut to localize the cutaneous projection of the parathyroid adenoma, c) intraoperative probe detection of the parathyroid adenoma and its removal through a small 2-2.5 cm skin incision. Minimally invasive radio-guided surgery was successfully performed in 99/102 patients (97.0%). The gamma probe was particularly useful in patients with an ectopic parathyroid adenoma in the upper mediastinum (n=11) or to the carotid bifurcation (n=1) or located deep in the neck (n=8). Minimally invasive radio-guided surgery was also obtained in 18/23 patients who had previously undergone thyroid/parathyroid surgery. The mean operative time for minimally invasive radio-guided surgery was 38 min. No major surgical complication was recorded. Conversion to bilateral neck exploration was required in only 3 cases because of intra-operative diagnosis of parathyroid carcinoma (n=2), and persistence of elevated quick PTH levels after removal of the preoperatively visualized parathyroid adenoma (n=1). Among patients treated by standard bilateral neck exploration, the gamma probe was useful in localizing a thymical enlarged parathyroid gland in 1 patient with multi-glandular disease, a parathyroid adenoma located deep in the neck in 4 patients with concomitant nodular goiter and an ectopic parathyroid adenoma to the carotid bifurcation in another. However, in some other patients with a parathyroid adenoma located near to the thyroid, it was difficult to intraoperatively distinguish the parathyroid adenoma from a MIBI avid thyroid nodule. It can be concluded that: (a) in primary HPT patients with high scan/ultrasound probability of solitary parathyroid adenoma and normal thyroid gland, the gamma probe appears to be an effective, rapid and safe technique to perform minimally invasive radio-guided surgery; b) a (99m)Tc-MIBI dose as low as 37 MBq appears to be adequate to successfully perform radio-guided surgery; c) the measurement of quick PTH is recommended during minimally invasive radio-guided surgery; d) minimally invasive radio-guided surgery can be performed also in HPT patients with previous parathyroid/thyroid surgery thus limiting surgical trauma; e) with the possible exception of parathyroid adenoma located in ectopic sites or deep in the neck, the gamma probe technique does not seem recommendable in HPT patients with concomitant nodular goiter.


Application of long single-stranded DNA donors in genome editing: generation and validation of mouse mutants.
Recent advances in clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome editing have led to the use of long single-stranded DNA (lssDNA) molecules for generating conditional mutations. However, there is still limited available data on the efficiency and reliability of this method. We generated conditional mouse alleles using lssDNA donor templates and performed extensive characterization of the resulting mutations. We observed that the use of lssDNA molecules as donors efficiently yielded founders bearing the conditional allele, with seven out of nine projects giving rise to modified alleles. However, rearranged alleles including nucleotide changes, indels, local rearrangements and additional integrations were also frequently generated by this method. Specifically, we found that alleles containing unexpected point mutations were found in three of the nine projects analyzed. Alleles originating from illegitimate repairs or partial integration of the donor were detected in eight projects. Furthermore, additional integrations of donor molecules were identified in four out of the seven projects analyzed by copy counting. This highlighted the requirement for a thorough allele validation by polymerase chain reaction, sequencing and copy counting of the mice generated through this method. We also demonstrated the feasibility of using lssDNA donors to generate thus far problematic point mutations distant from active CRISPR cutting sites by targeting two distinct genes (Gckr and Rims1). We propose a strategy to perform extensive quality control and validation of both types of mouse models generated using lssDNA donors. lssDNA donors reproducibly generate conditional alleles and can be used to introduce point mutations away from CRISPR/Cas9 cutting sites in mice. However, our work demonstrates that thorough quality control of new models is essential prior to reliably experimenting with mice generated by this method. These advances in genome editing techniques shift the challenge of mutagenesis from generation to the validation of new mutant models.


The Maudsley bipolar disorder project. A survey of psychotropic prescribing patterns in bipolar I disorder.
The outcome of Bipolar 1 Disorder (BD1) is greatly dependent on the adequacy and appropriateness of its treatment. As the treatment choices in BD1 disorder are increasing the aim of this study was to examine the current use of the pharmacological agents in BD1 patients and its association with clinical characteristics. Case note review of the pharmacotherapy of a sample of BD1 patients from a specified South London sector of a National Health Service Trust. Half of the patients were on mood-stabilizers (usually lithium) and their use was associated with female gender and multiple admissions. Antipsychotics were more commonly used in patients with psychotic features and multiple manic episodes. Antidepressants were rarely prescribed alone and were not associated with increased number of manic episodes. Combination treatments were mostly used in patients in acute episodes and with multiple hospitalizations. In ordinary care, the treatment of BD1 is often driven by symptoms and falls short of the existing practice guidelines.


Anterior cruciate ligament reconstruction and determination of tunnel size and graft obliquity.
Increase in ACL (anterior cruciate ligament) reconstructions has led to a higher prevalence of patients with postoperative symptoms which require investigation. We aimed to investigate the utility of magnetic resonance imaging (MRI) and computer tomography (CT) in determining tunnel size and graft obliquity after single bundle ACL reconstruction. A retrospective comparison was made on 29 symptomatic knees after anatomic single bundle (trans AM) and transtibial ACL reconstructions which had both MRI and CT scans at an average of 1.3 years postoperatively (2 months-5.7 years). We compared CT and MRI (T2 sequence) tunnel size and graft obliquity estimates using Pearson correlation and t-test. We also compared MRI's of ACL reconstructed knees with hamstrings or patellar autografts, which were confirmed by operative protocol as either antero-medial (AM) technique (n=21) or trans-tibial (TT) technique (n=19). The surgeries were performed for an average of 6.29 (4-10) years for the TT group and 1.3 (0-3) years for the AM group, respectively. The graft inclination was measured relative to the tibial plateau using DICOM software. Statistical analysis used the mean value for each case and the data were processed using the non-parametric Kruskal-Wallis test to determine the difference in graft obliquity and tunnel placement. Tunnel size estimates correlate well between CT and MRI on axial scans: R2=0.795 and 0.630 for femur and tibia respectively. The position of the tunnels and graft obliquity were found to differ on MRI images in both coronal and sagittal planes. Coronal graft obliquity averaged 72.38° (ranging from 69° to 76°) using the AM technique and 75.47° (ranging from 72° to 78°) with TT technique. Sagittal graft inclination angle was 54.5 (51-58.5) and 63.68 (59-69.5) respectively. MRI proves to be the most useful imaging method in determining outcome after ACL reconstruction. However, for a better revision of the ACL reconstructions, CT can offer a clearer image of tunnels and bone stock. A more anatomical graft positioning increases obliquity in coronal and sagittal planes and, thus, becomes difficult to assess both tunnels in a single slice. The anatomic single bundle reconstruction technique has been found to more accurately reproduce the femoral footprint and the orientation of the graft compared to the TT technique where the appropriate tibial tunnel placement resulted in a more vertical graft.


Andrographolide enhances cisplatin-mediated anticancer effects in lung cancer cells through blockade of autophagy.
Lung cancer is the most common cause of cancer-related death worldwide and the platinum-based drugs such as cisplatin have been used as the first line of the treatment. However, the clinical effectiveness of such chemotherapy is limited by intrinsic or acquired resistance. In this study, we found that cisplatin induced autophagy that attenuated the sensitivity of both A549 and Lewis lung cancer (LLC) cells to cisplatin. In contrast, the clinical drug andrographolide (Andro) suppressed autophagy and enhanced cisplatin-mediated apoptosis in these cells. Using two murine lung cancer models, including a subcutaneously inoculated LLC model and an orthotopic LLC implantation model, we investigated the therapeutic efficacy of the combined treatment of cisplatin and Andro. Compared with the sole cisplatin treatment, combining cisplatin with Andro potentially inhibited tumor growth, reduced the incidence of lung metastases, and relieved renal tubular damage. Moreover, the combined treatment prolonged the life span of tumor-bearing mice. TUNEL and immunohistochemistry assays showed the increase in apoptotic cells and the decrease in both conversion of LC3B-I to LC3B-II and Atg5 protein expression in the tumor tissues from mice with the combined treatment. These results suggest that Andro offers an ideal candidate of autophagy inhibitors in clinical application, and combination of cisplatin with Andro could be a promising strategy for the treatment of lung cancer.


Utrophin A is essential in mediating the functional adaptations of mdx mouse muscle following chronic AMPK activation.
Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin along muscle fibers. An attractive therapeutic avenue for DMD consists in the upregulation of utrophin A, a protein with high sequence identity and functional redundancy with dystrophin. Recent work has shown that pharmacological interventions that induce a muscle fiber shift toward a slower, more oxidative phenotype with increased expression of utrophin A confer morphological and functional improvements in mdx mice. Whether such improvements result from the increased expression of utrophin A per se or are linked to other beneficial adaptations associated with the slow, oxidative phenotype remain to be established. To address this central issue, we capitalized on the use of double knockout (dKO) mice, which are mdx mice also deficient in utrophin. We first compared expression of signaling molecules and markers of the slow, oxidative phenotype in muscles of mdx versus dKO mice and found that both strains exhibit similar phenotypes. Chronic activation of 5' adenosine monophosphate-activated protein kinase with 5-amino-4-imidazolecarboxamide riboside (AICAR) resulted in expression of a slower, more oxidative phenotype in both mdx and dKO mice. In mdx mice, this fiber type shift was accompanied by clear functional improvements that included reductions in central nucleation, IgM sarcoplasmic penetration and sarcolemmal damage resulting from eccentric contractions, as well as in increased grip strength. These important morphological and functional adaptations were not seen in AICAR-treated dKO mice. Our findings show the central role of utrophin A in mediating the functional benefits associated with expression of a slower, more oxidative phenotype in dystrophic animals.


Risk factors for developing non-insulin dependent diabetes: a 10 year follow up of men in Uppsala.
To analyse anthropometric and metabolic characteristics as risk factors for development of non-insulin dependent diabetes mellitus in middle aged normoglycaemic men. Prospective population study based on data collected in a health survey and follow up 10 years later. Uppsala, a middle sized city in Sweden. 2322 men aged 47-53, of whom 1860 attended the follow up 7-14 years later, at which time they were aged 56-64. Incidence of non-insulin dependent diabetes. In a multivariate logistic regression analysis, variations of 1 SD from the mean of the group that remained euglycaemic were used to calculate odds ratios and 95% confidence intervals. Blood glucose concentration 60 minutes after the start of an intravenous glucose tolerance test (odds ratio = 5.93, 95% confidence interval 3.05 to 11.5), fasting serum insulin concentration (2.12, 1.54 to 2.93), acute insulin increment at an intravenous glucose tolerance test (1.71, 1.21 to 2.43), body mass index (1.41, 1.01 to 1.97), and systolic blood pressure (1.23, 0.97 to 1.56) were independent predictors of diabetes. In addition, the use of antihypertensive drugs at follow up (selective or unselective beta blocking agents, thiazides, or hydralazine) was an independent risk factor (1.70, 1.11 to 2.60). Metabolic and anthropometric characteristics associated with or reflecting insulin resistance as well as a poor acute insulin response to glucose challenge were important predictors of future diabetes in middle aged men. Antihypertensive drugs were found to constitute a further, iatrogenic risk factor.


M1/70 attenuates blood-borne neutrophil oxidants, activation, and myofiber damage following stretch injury.
The purpose of this study was to determine the role of the CD11b-dependent respiratory burst in neutrophil oxidant generation and activation, interleukin-8 (IL-8) production, and myofiber damage after muscle stretch injury by using the monoclonal antibody M1/70 to block this pathway. Twelve male New Zealand White rabbits were randomly assigned to a treatment group: M1/70 (n = 6), IgG isotype control (n = 3), or saline control (n = 3). After intravenous injection of the assigned agent under gas anesthesia, a standardized single-stretch injury was created in the right tibialis anterior, whereas the left tibialis anterior underwent a sham surgery. Blood-borne neutrophil oxidant generation and CD11b receptor density and plasma IL-8 levels were measured pre- and 24 h postinjury. Damage was assessed histologically at the hematoma site by counting torn myofibers. M1/70 group demonstrated decreased blood-borne neutrophil oxidant generation (P < 0.05) and CD11b receptor density (P < 0.05), an increase in plasma IL-8 concentration (P < 0.01), and less torn myofibers (P < 0.01) compared with IgG isotype or saline control groups. These data indicate that 1). CD11b-dependent respiratory burst is a major source of oxidants produced by the neutrophil, and that treatment with M1/70 2). attenuates neutrophil activation status, 3). increases plasma IL-8 concentration, and 4). minimizes myofiber damage 24 h postmuscle stretch injury.


Recommendations for evaluation of health care improvement initiatives.
Intensive efforts are underway across the world to improve the quality of health care. It is important to use evaluation methods to identify improvement efforts that work well before they are replicated across a broad range of contexts. Evaluation methods need to provide an understanding of why an improvement initiative has or has not worked and how it can be improved in the future. However, improvement initiatives are complex, and evaluation is not always well aligned with the intent and maturity of the intervention, thus limiting the applicability of the results. We describe how initiatives can be grouped into 1 of 3 improvement phases-innovation, testing, and scale-up and spread-depending on the degree of belief in the associated interventions. We describe how many evaluation approaches often lead to a finding of no effect, consistent with what has been termed Rossi's Iron Law of Evaluation. Alternatively, we recommend that the guiding question of evaluation in health care improvement be, "How and in what contexts does a new model work or can be amended to work?" To answer this, we argue for the adoption of formative, theory-driven evaluation. Specifically, evaluations start by identifying a program theory that comprises execution and content theories. These theories should be revised as the initiative develops by applying a rapid-cycle evaluation approach, in which evaluation findings are fed back to the initiative leaders on a regular basis. We describe such evaluation strategies, accounting for the phase of improvement as well as the context and setting in which the improvement concept is being deployed. Finally, we challenge the improvement and evaluation communities to come together to refine the specific methods required so as to avoid the trap of Rossi's Iron Law.


Use of near-infrared imaging using indocyanine green associates with the lower incidence of postoperative complications for intestinal and mesenteric injury.
Anastomotic leakage after intestinal resection is one of the most serious complications of surgical intervention for hollow viscus injury. Adequate vascular perfusion of the anastomotic site is essential to prevent anastomotic leakage. Near-infrared imaging using indocyanine green (NIR-ICG) is useful for the objective assessment of vascular perfusion. The aim of this study was to evaluate the association of NIR-ICG with intestinal and mesenteric injuries. This was a retrospective, single-center study of patients undergoing surgery for intestinal and mesenteric injuries. NIR-ICG was used to evaluate vascular perfusion. Postoperative complications were assessed between NIR-ICG and non-NIR-ICG groups.The use of NIR-ICG was associated with a lower incidence of Clavien-Dindo grade ≥ III complications with a statistical tendency (p = 0.076). When limited to patients that underwent intestinal resection, the use of NIR-ICG was significantly associated with a lower risk of perioperative complications (p = 0.009). The use of NIR-ICG tended to associate with the lower incidence of postoperative complications after intestinal and mesenteric trauma surgery. NIR-ICG was associated with a significantly lower risk of complications in patients undergoing intestinal resection. The NIR-ICG procedure is simple and quick and is expected to be useful for intestinal and mesenteric trauma.


Design and Evaluation of Data Annotation Workflows for CAVE-like Virtual Environments.
Data annotation finds increasing use in Virtual Reality applications with the goal to support the data analysis process, such as architectural reviews. In this context, a variety of different annotation systems for application to immersive virtual environments have been presented. While many interesting interaction designs for the data annotation workflow have emerged from them, important details and evaluations are often omitted. In particular, we observe that the process of handling metadata to interactively create and manage complex annotations is often not covered in detail. In this paper, we strive to improve this situation by focusing on the design of data annotation workflows and their evaluation. We propose a workflow design that facilitates the most important annotation operations, i.e., annotation creation, review, and modification. Our workflow design is easily extensible in terms of supported annotation and metadata types as well as interaction techniques, which makes it suitable for a variety of application scenarios. To evaluate it, we have conducted a user study in a CAVE-like virtual environment in which we compared our design to two alternatives in terms of a realistic annotation creation task. Our design obtained good results in terms of task performance and user experience.


Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings.
Merkel cell polyomavirus (MCPyV) is thought to be the etiological agent of Merkel cell carcinoma, but little is known about its distribution and modes of transmission. We conducted seroepidemiological surveys in more than 1000 individuals, from two populations from Cameroon. Overall MCPyV seroprevalence was high in both populations (>75% in adults). Data from the first population, comprising mainly children, indicated that MCPyV infections mostly occurred during early childhood, after the disappearance of specific maternal antibodies. Results from the second family-based population provided evidence for familial aggregation of MCPyV infection status. We observed significant sib-sib correlation (odds ratio=3.42 [95% CI 1.27-9.19], p=0.014), particularly for siblings close together in age, and a trend for mother-child correlation (OR=2.71 [0.86-8.44], p=0.08). Overall, our results suggest that MCPyV infection is acquired through close contact, possibly involving saliva and/or the skin, especially between young siblings and between mothers and their children.


[Do generic drugs help control expenditure on hypertension? Apropos of a case].
In this article we analyze the influence of generic drugs on pharmaceutical expenditure on hypertension from the payer's perspective (the public health service), by examining the most widely used drugs: angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs). Based on billing data to the public health service from all the pharmacies in the Health Area of Malaga, we studied the utilization (containers and cost) of ACEi (generic drugs ACEi+G and brand name) and ARBs (brand name only) (subgroup C09 ATC index) from 1999 to 2002. The mean price (weighted according to sales) and the percentage of deviation of prescriptions from one group of drugs to another was also studied. The increase in consumption of packages in subgroup C09 was 20.79%; the increase was greater for ARBs (136%) and for ACEi+G (177%). The total amount spent during the study period increased by more than 42%. Expenditure on ACEis decreased by almost 7%, despite the increase in expenditure on ACEi+G, whereas expenditure on ARBs increased by more than 154%. The mean price of this subgroup, weighted according to sales, increased by nearly 18%. The mean weighted price of the generic drugs, captopril and enalapril, and that of the brand name, trandolapril, decreased. Notable among ARBs was the increase in mean price weighted according to sales of irbesartan (9%) and valsartan (16%). The use of generic drugs has reduced expenditure on ACEi and the mean weighted price of the subgroup. However, the increased use of generic drugs has not produced the expected savings for the Department of Health. This could be due to deviation of prescription scores toward drugs not affected by substitution by the pharmacy.


Prosthetic joint infection diagnosed postoperatively by intraoperative culture.
The purpose of this study was to assess the outcome of prosthetic joint infection initially diagnosed by multiple positive intraoperative cultures after revision arthroplasty and treated by strategies that include less than 6 weeks of intravenous antimicrobial therapy. Between January 1995 and December 1999, 16 of 509 (3%) episodes of prosthetic joint infection in 16 patients initially were diagnosed by positive intraoperative cultures after revision arthroplasty. Patients were followed up for a median of 1057 days (range, 731-1969 days). The median age of the patients was 65 years, and 65% of patients had revision total hip arthroplasty. Coagulase-negative staphylococci and Propionibacterium spp were the main pathogens identified. Intravenous antimicrobial therapy was used in 81% of patients and chronic oral suppression was used in 56% of patients. Three patients received no antimicrobial therapy. The median duration of intravenous antimicrobial therapy was 28 days (range, 2-42 days). The 5-year survival free of treatment failure for the 16 episodes was 89%. These results suggest a favorable outcome of prosthetic joint infections because of low virulence pathogens initially diagnosed as positive intraoperative cultures after revision arthroplasty with a variety of medical treatment strategies, including strategies that contain less than 6 weeks intravenous antimicrobial therapy.


Digital vs face-to-face information provision in patient counselling for prenatal screening: A noninferiority randomized controlled trial.
To evaluate face-to-face information provision in patient counselling for prenatal screening compared with two forms of digital information provision, namely, noninteractive instructional video or interactive video. We performed a prospective, noninferiority, cluster-randomized controlled trial comparing face-to-face (usual care) with two forms of digital information provision (intervention) in counselling for prenatal screening. This study was performed in the Amsterdam UMC, the Netherlands, in 2017, and included women in the first trimester of pregnancy. Main outcomes were knowledge gained by the patient and counselling duration. We performed a noninferiority analysis. One hundred forty-one women were included, randomized, and analysed. The baseline characteristics were comparable. The intervention group was noninferior compared with the control group regarding the level of satisfaction. The knowledge grade difference was higher after using intervention, and the duration was significantly longer in the face-to-face group at 23 minutes versus 16 minutes. The addition of interaction with the video made no difference in any of the outcomes. Adding an instructional video to patient counselling is of added value to improve patient's knowledge and shorten time consumption of the counsellor, therefore possibly saving costs. But this form of counselling maintains the same level of satisfaction.


Terahertz filter based on refractive properties of metallic photonic crystal.
We propose a new type of pass-band filter, in this case designed to operate in the terahertz frequency regime, possessing two separate passbands utilizing the distinction between positive and negative refraction in a photonic crystal prism. The prism is formed from a two-dimensional hexagonal arrangement of metallic rods. In order to understand the operation of the filter we both consider the photonic bandstructure of the associated infinite photonic structure and carry out simulations of the refraction properties of the prism using finite-difference time-domain software.


Disease surveillance methods used in the 8-site MAL-ED cohort study.
Describing the early life associations between infectious disease episodes and growth, cognitive development, and vaccine response in the first 2 years of life is one of the primary goals of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. To collect high-resolution data during a critical early period of development, field staff visit each study participant at their house twice weekly from birth to 2 years of age to collect daily reported illness and treatment data from caregivers. Detailed infectious disease histories will not only allow us to relate the overall burden of infectious disease with the primary outcomes of the study, but will also allow us to describe the ages at which infectious diseases have the greatest effect on child health. In addition, twice-weekly visits allow for sample collection when diarrhea episodes are identified. This article describes the methods used to collect illness and treatment history data and discusses the a priori definitions of diarrhea and acute lower respiratory illness episodes.


Black carbon lofts wildfire smoke high into the stratosphere to form a persistent plume.
In 2017, western Canadian wildfires injected smoke into the stratosphere that was detectable by satellites for more than 8 months. The smoke plume rose from 12 to 23 kilometers within 2 months owing to solar heating of black carbon, extending the lifetime and latitudinal spread. Comparisons of model simulations to the rate of observed lofting indicate that 2% of the smoke mass was black carbon. The observed smoke lifetime in the stratosphere was 40% shorter than calculated with a standard model that does not consider photochemical loss of organic carbon. Photochemistry is represented by using an empirical ozone-organics reaction probability that matches the observed smoke decay. The observed rapid plume rise, latitudinal spread, and photochemical reactions provide new insights into potential global climate impacts from nuclear war.


Potential antimalarials from African natural products: A reviw.
Malaria remains an overwhelming infectious disease with significant health challenges in African and other endemic countries globally. Resistance to antimalarial drugs has become one of the most momentous challenges to human health, and thus has necessitated the hunt for new and effective drugs. Consequently, few decades have witnessed a surfeit of research geared to validate the effectiveness of commonly used traditionally medicines against malaria fever. The present review work focuses on documenting natural products from African whose activity has been reported in vivo or in vitro against malaria parasite. Literature was collected using electronic search of published articles (Google Scholar, PubMed, Medline, Sciencedirect, and Science domain) that report on antiplasmodial activity of natural products from differernts Africa region. A total of 652 plant taxa from 146 families, 134 isolated antimalarial compounds from 39 plants species, 2 herbal formulations and 4 insect/products were found to be reported in literature from 1996 to 2015. Plants species from family Asteraceae (11.04%), Fababceae (8.128%), Euphorbiaceae (5.52%), Rubiaceas (5.52%), and Apocyanaceae (5.214%), have received more scientific validation than others. African natural products possess remarkable healing properties as revealed in the various citations as promising antimalarial agents. Some of these natural products from Africa demonstrate high, promising or low activities against Plasmodium parasite. This study also shows that natural products from Africa have a huge amount of novel antimalarial compounds that could serve as a leads for the development of new and effective antiplasmodial drugs. However, in a view of bridging the gap in knowledge, clinical validation of these natural products are of paramount importance.


Improvement of intestinal stem cells and barrier function via energy restriction in middle-aged C57BL/6 mice.
This study aimed to reveal the impact of energy restriction on the intestine via structural and molecular changes in terms of intestinal stem cell (ISC) function, ISC niche, intestinal epithelial barrier function, and intestinal immune function. Female C57BL/6J mice, aged 12 months, fed a commercial chow were used in this study. The ISC function, ISC niche, intestinal epithelial barrier function, and intestinal immune function were assessed. Energy restriction reversed aging-induced intestinal shortening and made the crypts shallower. The intestinal epithelial cells isolated from the intestine showed a significant increase in the expression levels of stem cell-associated genes in small intestinal epithelial cells as detected by flow cytometry. Despite the increase in the number of stem cells and the expression levels of markers, no increase or decrease was found in the enteroid complexity of the small intestine and colonic enteroid formation in vitro. The colonic mucous layer was measured in mice of the energy restricted (ER)-treated group to investigate the epithelial barrier function in the colon. The results revealed that the barrier was more complete. The fluorescence intensity of tight junction markers claudin-2 and zonula occludens-1 increased and the mRNA expression profiles of monocyte chemotactic protein 1 and interleukin-6 decreased in the colon of mice in the ER-treated group. The beneficial effects of ER on the colon in terms of the integrity of the mucosal barrier and alleviation of inflammation were confirmed, thus highlighting the importance of modulating the intestinal function in developing effective antiaging dietary interventions.


Gene expression changes in human cells after exposure to mobile phone microwaves.
Possible biological effects of mobile phone microwaves were investigated in vitro. In this study, which was part of the 5FP EU project REFLEX (Risk Evaluation of Potential Environmental Hazards From Low-Energy Electromagnetic Field Exposure Using Sensitive in vitro Methods), six human cell types, immortalized cell lines and primary cells, were exposed to 900 and 1800 MHz. RNA was isolated from exposed and sham-exposed cells and labeled for transcriptome analysis on whole-genome cDNA arrays. The results were evaluated statistically using bioinformatics techniques and examined for biological relevance with the help of different databases. NB69 neuroblastoma cells, T lymphocytes, and CHME5 microglial cells did not show significant changes in gene expression. In EA.hy926 endothelial cells, U937 lymphoblastoma cells, and HL-60 leukemia cells we found between 12 and 34 up- or down-regulated genes. Analysis of the affected gene families does not point towards a stress response. However, following microwave exposure, some but not all human cells might react with an increase in expression of genes encoding ribosomal proteins and therefore up-regulating the cellular metabolism.


Recycling Carbon Dioxide during Xylose Fermentation by Engineered Saccharomyces cerevisiae.
Global climate change caused by the emission of anthropogenic greenhouse gases (GHGs) is a grand challenge to humanity. To alleviate the trend, the consumption of fossil fuels needs to be largely reduced and alternative energy technologies capable of controlling GHG emissions are anticipated. In this study, we introduced a synthetic reductive pentose phosphate pathway (rPPP) into a xylose-fermenting Saccharomyces cerevisiae strain SR8 to achieve simultaneous lignocellulosic bioethanol production and carbon dioxide recycling. Specifically, ribulose-1,5-bisphosphate carboxylase/oxygenase from Rhodospirillum rubrum and phosphoribulokinase from Spinacia oleracea were introduced into the SR8 strain. The resulting strain with the synthetic rPPP was able to exhibit a higher yield of ethanol and lower yields of byproducts (xylitol and glycerol) than a control strain. In addition, the reduced release of carbon dioxide by the engineered strain was observed during xylose fermentation, suggesting that the carbon dioxide generated by pyruvate decarboxylase was partially reassimilated through the synthetic rPPP. These results demonstrated that recycling of carbon dioxide from the ethanol fermentation pathway in yeast can be achieved during lignocellulosic bioethanol production through a synthetic carbon conservative metabolic pathway. This strategy has a great potential to alleviate GHG emissions during the production of second-generation ethanol.


A case of allergic bronchopulmonary aspergillosis with marked peripheral blood eosinophilia successfully treated with benralizumab.
We herein report a case of allergic bronchopulmonary aspergillosis (ABPA) with marked eosinophilia and high attenuation mucus (HAM) on chest computed tomography (CT), which demonstrated a rapid and remarkable improvement with benralizumab treatment. A 67-year-old Japanese woman, who was diagnosed with asthma at the age of 64 years, was admitted with dyspnea. Her blood test results showed marked eosinophilia (peripheral blood eosinophil count 24403/μL) and elevated serum IgE levels. Chest CT also revealed ground-glass opacity. Sputum cytology detected filamentous fungi, suggesting an infection with Aspergillus spp. Based on these findings, ABPA was diagnosed. Following systemic corticosteroid treatment, her respiratory symptoms and chest radiography findings showed improvements. However, with the gradual tapering and eventual discontinuance of the corticosteroid therapy, a concomitant increase in the peripheral blood eosinophils and a recurrence of the clinical symptoms, was observed. In addition, her pulmonary function decreased and chest CT revealed worsened bronchial mucus plugs. To control the asthma with ABPA exacerbation, benralizumab was administered. Following treatment with benralizumab, the patient's asthmatic symptoms improved, together with a decrease in her peripheral eosinophil count. Mucus plugs were no longer visible on chest CT. Pulmonary function test result also showed a remarkable improvement. There was no relapse of dyspnea and no reappearance of the mucus plugs. This case suggests that benralizumab may be a suitable treatment option for patients with ABPA with marked eosinophilia and HAM on chest CT.


Dynamics of branched tissue assembly.
The assembly of cells into tissues is a complex process controlled by numerous signaling pathways to ensure the fidelity of the final structure. Tissue assembly is also very dynamic, as exemplified by the formation of branched organs. Here we present two examples of tissue assembly in branched systems that highlight this dynamic nature: formation of the tracheal network in Drosophila melanogaster and the ducts of the mammary gland in mice. Extension of the branches during tracheal development is a stereotyped process that produces identical organ geometries across individuals, whereas elongation of the ducts of the pubertal mammary gland is a non-stereotyped process that produces unique patterns. By studying these two organs, we can begin to understand the dynamic nature of development of other stereotyped and non-stereotyped branching systems, including the lung, kidney, and salivary gland.


Variants of the microsomal triglyceride transfer protein gene are associated with plasma cholesterol levels and body mass index.
The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins from liver and intestine. We set out to study the phenotypic modulation of all common genetic variants in the MTP gene. In addition, we aimed at characterizing the association between the various polymorphisms. A total of 564 healthy men were genotyped for the MTP -493 G/T, -400 A/T, and -164 T/C promoter polymorphisms, as well as the Q/H 95, I/T 128, Q/E 244, and H/Q 297 missense polymorphisms. The -493 G/T, -164 T/C, and I/T 128 polymorphisms showed to be in almost complete linkage disequilibrium. Subjects homozygous for the less common -493 T, -164 C, and T 128 alleles showed significantly lower plasma total and LDL cholesterol levels and plasma LDL apoB levels, and also significantly higher body mass index (BMI) and plasma insulin levels compared with carriers of the common alleles. The associations between plasma total cholesterol and MTP -493 genotype was verified in a cohort consisting of 1,117 disease-free control subjects of the West of Scotland Coronary Prevention Study (WOSCOPS). None of the other polymorphisms showed any significant change in either lipid and lipoprotein levels or anthropometric variables. In summary, two promoter polymorphisms and one missense polymorphism in the MTP gene alter plasma total and LDL cholesterol levels, plasma LDL apoB levels, BMI, and insulin levels. This may, in turn, have implications for genetic regulation of cardiovascular risk factors.


Representing Sudden Shifts in Intensive Dyadic Interaction Data Using Differential Equation Models with Regime Switching.
A growing number of social scientists have turned to differential equations as a tool for capturing the dynamic interdependence among a system of variables. Current tools for fitting differential equation models do not provide a straightforward mechanism for diagnosing evidence for qualitative shifts in dynamics, nor do they provide ways of identifying the timing and possible determinants of such shifts. In this paper, we discuss regime-switching differential equation models, a novel modeling framework for representing abrupt changes in a system of differential equation models. Estimation was performed by combining the Kim filter (Kim and Nelson State-space models with regime switching: classical and Gibbs-sampling approaches with applications, MIT Press, Cambridge, 1999) and a numerical differential equation solver that can handle both ordinary and stochastic differential equations. The proposed approach was motivated by the need to represent discrete shifts in the movement dynamics of [Formula: see text] mother-infant dyads during the Strange Situation Procedure (SSP), a behavioral assessment where the infant is separated from and reunited with the mother twice. We illustrate the utility of a novel regime-switching differential equation model in representing children's tendency to exhibit shifts between the goal of staying close to their mothers and intermittent interest in moving away from their mothers to explore the room during the SSP. Results from empirical model fitting were supplemented with a Monte Carlo simulation study to evaluate the use of information criterion measures to diagnose sudden shifts in dynamics.


Compliance or non-compliance of hypertensive adults to hypertension management at three primary healthcare day clinics in Tshwane.
The objective of this article was to report on the rate of compliance to medication, sodium use and appointment keeping of hypertensive adults who are attending primary healthcare clinics in Tshwane. Despite the availability of effective management of hypertension globally, non-compliance to management still exists. This article reports on the hypertensive adult's compliance to medication, sodium use and appointment keeping. The design was a cross-sectional descriptive study. The sample was n=101 hypertensive patients from three primary healthcare clinics. Structured interviews were used to gather the data. The results indicated a variation in compliance rate depending on the question asked. When investigating whether the participants received enough medication on their last visit to the clinic, 98% said that they received enough medication to last them a month (Nkosi 2008:130). However, the appointment-keeping scale revealed that 23% of the participants reported that they left the clinic without prescribed medication or missed an appointment. When, using the Hill-Bone Compliance Scale, individuals were asked a question using the verb forgetting, 9 out of 10 would answer 'no', but when the verb decide was used to determine compliance, 6 out of 10 would admit to deciding not to take their medication sometimes. In terms of sodium use, 33% showed good compliance and 44% low compliance (Nkosi 2008:138). Compliance with regard to taking hypertension medication was 70%, which is good. This study recommends that compliance to hypertension management be assessed by asking questions specifically for sodium use, medication and appointment keeping as it was clear from the findings of this study that a person would comply with appointment keeping but not take medication daily as prescribed or not use sodium as recommended.