Product definition for healthcare contracting: an overview of approaches to measuring hospital output with reference to the UK internal market.
In many industrialised countries, health care third party payers are moving towards contracted provision arrangements with suppliers of hospital care. Essential to such a process is a standard approach to quantifying the care provided. This paper aims to outline the possible approaches to hospital product definition for the UK National Health Service, and recommends appropriate further research. All published and unpublished studies on hospital output measurement in the NHS since 1980 were sought for the purposes of the review. This included both discursive and empirical work, and no exclusion criteria were applied. Most empirical reports on this topic, however, come from the United States. Consequently, the published reports since 1980 from the USA, accessed from the Medline and Healthplan CD-ROM databases, have also been included in the overview. Where data are sufficient, the true casemix approach offers advantages over other methods of output measurement. In the UK NHS, two systems--diagnosis-related groups (DRGs) and healthcare resource groups (HRGs)--are the only casemix measures that have achieved any significant degree of attention. DRGs have been extensively evaluated internationally, and explain variations in resource use in the UK slightly better than do HRGs. As a local product, HRGs can be more easily adapted to the specific needs of the NHS internal market, however, and will thus probably emerge as a better measure for the UK in the long term. In both cases, locally derived cost weights are unavailable, and their development constitutes a major requirement for use in contracting. Adaptations for long stay and outpatient hospital episodes would enhance the usefulness of hospital casemix systems in the NHS. Existing approaches, such as specialty based classifications, are neither standardised nor predictive of resource use, and would be better replaced by casemix systems. Other countries facing similar choices between casemix measurement approaches will need to consider the "trade off" between the adaptability of locally derived systems on the one hand and the low cost, rapidly accessible results, and availability of international comparative data of an imported approach on the other.


[Socioeconomic indicators and oral health services in an underprivileged area of Brazil].
To evaluate the association between the proportion of tooth extractions, socioeconomic indicators, and the availability of oral health services in an underprivileged area of Brazil. An ecological study was carried out in 52 municipalities in the state of Minas Gerais, Brazil. The socioeconomic indicators employed were criteria for health care resources allocation, municipal human development index, Theil index, Gini coefficient, and sanitation conditions. Concerning the availability of oral health services, the following were considered: number of inhabitants, number of dental surgeons living in the city, number of dentists working in the public services, and number of municipal oral health care teams. The utilization of oral health services was evaluated using the indicators recommended by the Health Ministry's Basic Care Package (Pacto da Atencão Básica in Portuguese) and the number of procedures carried out in the primary care setting. The 17 variables assessed were grouped into factorial components, which were then analyzed in terms of their relationship with the dependent variable, tooth extractions. The following six components explained 73.5% of the overall variance: socioeconomic conditions, social inequality, Basic Care Package indicators, number of procedures carried out, ratio of dentists to inhabitants, and coverage of the Family Health Strategy. Inequalities in income distribution (P = 0.031) and coverage by the Family Health Strategy (P = 0.015) contributed significantly to explain the difference in the proportion of tooth extractions in the different municipalities under study. The dental loss observed in the region is largely explained by socioeconomic factors and aspects related to the organization of oral health services.


Gun ownership and firearm-related deaths.
A variety of claims about possible associations between gun ownership rates, mental illness burden, and the risk of firearm-related deaths have been put forward. However, systematic data on this issue among various countries remain scant. Our objective was to assess whether the popular notion "guns make a nation safer" has any merits. Data on gun ownership were obtained from the Small Arms Survey, and for firearm-related deaths from a European detailed mortality database (World Health Organization), the National Center for Health Statistics, and others. Crime rate was used as an indicator of safety of the nation and was obtained from the United Nations Surveys of Crime Trends. Age-standardized disability-adjusted life-year rates due to major depressive disorder per 100,000 inhabitants with data obtained from the World Health Organization database were used as a putative indicator for mental illness burden in a given country. Among the 27 developed countries, there was a significant positive correlation between guns per capita per country and the rate of firearm-related deaths (r = 0.80; P <.0001). In addition, there was a positive correlation (r = 0.52; P = .005) between mental illness burden in a country and firearm-related deaths. However, there was no significant correlation (P = .10) between guns per capita per country and crime rate (r = .33), or between mental illness and crime rate (r = 0.32; P = .11). In a linear regression model with firearm-related deaths as the dependent variable with gun ownership and mental illness as independent covariates, gun ownership was a significant predictor (P <.0001) of firearm-related deaths, whereas mental illness was of borderline significance (P = .05) only. The number of guns per capita per country was a strong and independent predictor of firearm-related death in a given country, whereas the predictive power of the mental illness burden was of borderline significance in a multivariable model. Regardless of exact cause and effect, however, the current study debunks the widely quoted hypothesis that guns make a nation safer.


Accurate Imputation-Based Screening of Gln368Ter Myocilin Variant in Primary Open-Angle Glaucoma.
Myocilin (MYOC) is a well-established primary open-angle glaucoma (POAG) risk gene, with rare variants known to have high penetrance. The most common clinically relevant risk variant, Gln368Ter, has an allele frequency of 0.1% to 0.3% in populations of European ancestry. Detection of rare MYOC variants has traditionally been conducted using Sanger sequencing. Here we report the use of genotyping arrays and imputation to assess whether rare variants including Gln368Ter can be reliably detected. A total of 1155 cases with advanced POAG and 1992 unscreened controls genotyped on common variant arrays participated in this study. Accuracy of imputation of Gln368Ter variants was compared with direct sequencing. A genome-wide association study was performed using additive model adjusted for sex and the first six principal components. We found that although the arrays we used were designed to tag common variants, we could reliably impute the Gln368Ter variant (rs74315329). When tested in 1155 POAG cases and 1992 controls, rs74315329 was strongly associated with risk (odds ratio = 15.53, P = 1.07 × 10-9). All POAG samples underwent full sequencing of the MYOC gene, and we found a sensitivity of 100%, specificity of 99.91%, positive predictive value of 95.65%, and negative predictive value of 100% between imputation and sequencing. Gln368Ter was also accurately imputed in a further set of 1801 individuals without POAG. Among the total set of 3793 (1992 + 1801) individuals without POAG, six were predicted (probability > 95%) to carry the risk variant. We demonstrate that some clinically important rare variants can be reliably detected using arrays and imputation. These results have important implications for the detection of clinically relevant incidental findings in ongoing and future studies using arrays.


The dual loop model: its relation to language and other modalities.
The current neurobiological consensus of a general dual loop system scaffolding human and primate brains gives evidence that the dorsal and ventral connections subserve similar functions, independent of the modality and species. However, most current commentators agree that although bees dance and chimpanzees grunt, these systems of communication differ qualitatively from human language. So why is language unique to humans? We discuss anatomical differences between humans and other animals, the meaning of lesion studies in patients, the role of inner speech, and compare functional imaging studies in language with other modalities in respect to the dual loop model. These aspects might be helpful for understanding what kind of biological system the language faculty is, and how it relates to other systems in our own species and others.


The oculomotor resonance effect in spatial-numerical mapping.
We investigated automatic Spatial-Numerical Association of Response Codes (SNARC) effect in auditory number processing. Two experiments continually measured spatial characteristics of ocular drift at central fixation during and after auditory number presentation. Consistent with the notion of a spatially oriented mental number line, we found spontaneous magnitude-dependent gaze adjustments, both with and without a concurrent saccadic task. This fixation adjustment (1) had a small-number/left-lateralized bias and (2) it was biphasic as it emerged for a short time around the point of lexical access and it received later robust representation around following number onset. This pattern suggests a two-step mechanism of sensorimotor mapping between numbers and space - a first-pass bottom-up activation followed by a top-down and more robust horizontal SNARC. Our results inform theories of number processing as well as simulation-based approaches to cognition by identifying the characteristics of an oculomotor resonance phenomenon.


Radionuclide carriers for targeting of cancer.
This review describes strategies for the delivery of therapeutic radionuclides to tumor sites. Therapeutic approaches are summarized in terms of tumor location in the body, and tumor morphology. These determine the radionuclides of choice for suggested targeting ligands, and the type of delivery carriers. This review is not exhaustive in examples of radionuclide carriers for targeted cancer therapy. Our purpose is two-fold: to give an integrated picture of the general strategies and molecular constructs currently explored for the delivery of therapeutic radionuclides, and to identify challenges that need to be addressed. Internal radiotherapies for targeting of cancer are at a very exciting and creative stage. It is expected that the current emphasis on multidisciplinary approaches for exploring such therapeutic directions should enable internal radiotherapy to reach its full potential.


Umbilical cord levels of macrophage migration inhibitory factor in neonatal respiratory distress syndrome
We aimed to evaluate the association of the umbilical cord macrophage migration inhibitory factor (MIF) with the respiratory distress syndrome (RDS) in preterm infants. A total of eighty six preterm infants (38 with RDS and 48 without RDS) were involved in the study. ELISA is the technique assaying MIF values. The mean of the infants' gestational ages and birth weights were significantly different (P = 0.0001). There were no significant differences in sex, delivery mode or exposure to antenatal steroid among the groups (P > 0.05). Umbilical cord MIF levels of the infants were not correlated with gestational age and birth weight (Spearman's rho = –0.22 and 0.28 respectively, P > 0.05). There was no statistically significant difference in umbilical cord MIF levels of infants whether or not they were administered antenatal steroid (median:17.88 vs. median:17.60, Mann–Whitney U test, P = 0.42). Cord serum MIF levels were higher (mean, 17.09 ± 5.86 ng/mL) in the RDS group than in the non-RDS group (mean, 14.72 ± 4.18 ng/mL) (P = 0.005). This study shows that, MIF level is higher in the cord blood of the infants with RDS than of the infants without RDS. This supports that MIF expression begins in prior to the birth of the preterm infants and MIF has enhancing impact on the lung development of premature babies. With future studies, the assessment of the cord MIF levels at the bedside may be beneficial for the diagnosis and treatment of RDS, and taking actions to prevent long-term consequences.


Genetic Interaction with Plasma Lipids on Alzheimer's Disease in the Framingham Heart Study.
Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer's disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40-60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p = 0.006), but no interaction of the GRS with HDL-C (p = 0.458) or LDL-C (p = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOEɛ4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings.


Sleep restriction masks the influence of the circadian process on sleep propensity.
Previous forced desynchrony studies have highlighted the close relationship between the circadian rhythms of core body temperature (CBT) and sleep propensity. In particular, these studies have shown that a "forbidden zone" for sleep exists on the rising limb of the CBT rhythm. In these previous studies, the length of the experimental day was either ultrashort (90 min), short (20 h), or long (28 h), and the ratio of sleep to wake was normal (i.e., 1:2). The aim of the current study was to examine the relative effects of the circadian and homeostatic processes on sleep propensity using a 28-h forced desynchrony protocol in which the ratio of sleep to wake was substantially lower than normal (i.e., 1:5). Twenty-seven healthy males lived in a time-isolation sleep laboratory for 11 consecutive days. Participants completed either a control (n = 13) or sleep restriction (n = 14) condition. In both conditions, the protocol consisted of 2 × 24-h baseline days followed by 8 × 28-h forced desynchrony days. On forced desynchrony days, the control group had 9.3 h in bed and 18.7 h of wake, and the sleep restriction group had 4.7 h in bed and 23.3 h of wake. For all participants, each 30-s epoch of time in bed was scored as sleep or wake based on standard polysomnography recordings, and was also assigned a circadian phase (360° = 24 h) based on a cosine equation fitted to continuously recorded CBT data. For each circadian phase (i.e., 72 × 5° bins), sleep propensity was calculated as the percentage of epochs spent in bed scored as sleep. For the control group, there was a clear circadian rhythm in sleep propensity, with a peak of 98.5% at 5° (~05:20 h), a trough of 64.9% at 245° (~21:20 h), and an average of 82.3%. In contrast, sleep propensity for the sleep restriction group was relatively high at all circadian phases, with an average of 96.7%. For this group, the highest sleep propensity (99.0%) occurred at 60° (~09:00 h), and the lowest sleep propensity (91.3%) occurred at 265° (~22:40 h). As has been shown previously, these current data indicate that with a normal sleep-to-wake ratio, the effect of the circadian process on sleep propensity is pronounced, such that a forbidden zone for sleep exists at a phase equivalent to evening time for a normally entrained individual. However, these current data also indicate that when the ratio of sleep to wake is substantially lower than normal, this circadian effect is masked. In particular, sleep propensity is very high at all circadian phases, including those that coincide with the forbidden zone for sleep. This finding suggests that if the homeostatic pressure for sleep is sufficiently high, then the circadian drive for wakefulness can be overridden. In future studies, it will be important to determine whether or not this masking effect occurs with less severe sleep restriction, e.g., with a sleep-to-wake ratio of 1:3.


DNA identification of skeletal remains from the World War II mass graves uncovered in Slovenia.
To present the joint effort of three institutions in the identification of human remains from the World War II found in two mass graves in the area of Skofja Loka, Slovenia. The remains of 27 individuals were found in two small and closely located mass graves. The DNA was isolated from bone and teeth samples using either standard phenol/chloroform alcohol extraction or optimized Qiagen DNA extraction procedure. Some recovered samples required the employment of additional DNA purification methods, such as N-buthanol treatment. Quantifiler Human DNA Quantification Kit was used for DNA quantification. PowerPlex 16 kit was used to simultaneously amplify 15 short tandem repeat (STR) loci. Matching probabilities were estimated using the DNA View program. Out of all processed samples, 15 remains were fully profiled at all 15 STR loci. The other 12 profiles were partial. The least successful profile included 13 loci. Also, 69 referent samples (buccal swabs) from potential living relatives were collected and profiled. Comparison of victims' profile against referent samples database resulted in 4 strong matches. In addition, 5 other profiles were matched to certain referent samples with lower probability. Our results show that more than 6 decades after the end of the World War II, DNA analysis may significantly contribute to the identification of the remains from that period. Additional analysis of Y-STRs and mitochondrial DNA (mtDNA) markers will be performed in the second phase of the identification project.


Antifungal activity of acetone extracts from Punica granatum L., Quercus suber L. and Vicia faba L.
Human and animal mycoses become more frequent and more resistant to traditional treatments. In this work, we tested the in vitro antifungal activity of acetonic extracts of Punica granatum L., Quercus suber L. and Vicia faba L. against seven pathogen fungi and the in vivo antifungal activity against Candida albicans and Trichophyton mentagrophytes. The phytochemical screening was also carried out and showed that the extracts contained mainly proanthocyanidins. Other polyphenols were also present but in low quantity. The acetone extract of V. faba L. gave a good in vitro inhibition of yeasts and was the most active for treating candidiasis in mice. It decreased the percentage of mortality with only 20μg. But the in vivo antifungal activity of this extract on T. mentagrophytes was low. It only showed a small diminution of crusting and erythema after the administration of 100μg. On the contrary, the acetone extracts of P. granatum L. had a poor activity against yeasts and a better one against moulds. It gave the best in vivo antifungal activity against T. mentagrophytes by healing animals with 40μg. The extract of P. granatum L. gave also an interesting in vivo antifungal activity against T. mentagrophytes with an active dose of 80μg.


Noninvasive PK11195-PET Image Analysis Techniques Can Detect Abnormal Cerebral Microglial Activation in Parkinson's Disease.
Neuroinflammation has been implicated in the pathophysiology of Parkinson's disease (PD), which might be influenced by successful neuroprotective drugs. The uptake of [11 C](R)-PK11195 (PK) is often considered to be a proxy for neuroinflammation, and can be quantified using the Logan graphical method with an image-derived blood input function, or the Logan reference tissue model using automated reference region extraction. The purposes of this study were (1) to assess whether these noninvasive image analysis methods can discriminate between patients with PD and healthy volunteers (HVs), and (2) to establish the effect size that would be required to distinguish true drug-induced changes from system variance in longitudinal trials. The sample consisted of 20 participants with PD and 19 HVs. Two independent teams analyzed the data to compare the volume of distribution calculated using image-derived input functions (IDIFs), and binding potentials calculated using the Logan reference region model. With all methods, the higher signal-to-background in patients resulted in lower variability and better repeatability than in controls. We were able to use noninvasive techniques showing significantly increased uptake of PK in multiple brain regions of participants with PD compared to HVs. Although not necessarily reflecting absolute values, these noninvasive image analysis methods can discriminate between PD patients and HVs. We see a difference of 24% in the substantia nigra between PD and HV with a repeatability coefficient of 13%, showing that it will be possible to estimate responses in longitudinal, within subject trials of novel neuroprotective drugs.


Hypoxia-inducible factor 1α modulates metabolic activity and cytokine release in anti-Aspergillus fumigatus immune responses initiated by human dendritic cells.
The mold Aspergillus fumigatus causes life-threatening infections in immunocompromised patients. Over the past decade, new findings in research have improved our understanding of A. fumigatus-host interactions, including the recent identification of myeloid-expressed hypoxia-inducible factor 1α (HIF-1α) as a relevant immune-modulating transcription factor and potential therapeutic target in anti-fungal defense. However, the function of HIF-1α signaling for human anti-A. fumigatus immunity is still poorly understood, including its role in dendritic cells (DCs), which are important regulators of anti-fungal immunity. This study investigated the functional relevance of HIF-1α in the anti-A. fumigatus immune response initiated by human DCs. Hypoxic cell culture conditions were included because hypoxic microenvironments occur during A. fumigatus infections and may influence the host immune response. HIF-1α was stabilized in DCs following stimulation with A. fumigatus under normoxic and hypoxic conditions. This stabilization was partially dependent on dectin-1, the major receptor for A. fumigatus on human DCs. Using siRNA-based HIF-1α silencing combined with genome-wide transcriptional analysis, a modulatory effect of HIF-1α on the anti-fungal immune response of human DCs was identified. Specifically, the difference in the transcriptomes of HIF-1α silenced and non-silenced DCs indicated that HIF-1α contributes to DC metabolism and cytokine release in response to A. fumigatus under normoxic as well as hypoxic conditions. This was confirmed by further down-stream analyses that included metabolite analysis and cytokine profiling of a time-course infection experiment. Thereby, this study revealed a so far undescribed functional relevance of HIF-1α in human DC responses against A. fumigatus.


Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells.
Pancreatic stellate cells (PSC), which are implicated in desmoplasia in pancreatic cancer, enhance the malignancy of cancer cells and confer resistance to established treatments. We investigated whether the antifibrotic agent pirfenidone can suppress desmoplasia and exert antitumor effects against pancreatic cancer. Primary PSCs were established from pancreatic cancer tissue obtained during surgery. In vitro, pirfenidone inhibited the proliferation, invasiveness, and migration of PSCs in a dose-dependent manner. Although supernatants of untreated PSCs increased the proliferation, invasiveness, and migration of pancreatic cancer cells (PCC), supernatants of pirfenidone-treated PSCs decreased these effects. Exposure to PCC supernatant increased the production of platelet-derived growth factor-A, hepatic growth factor, collagen type I, fibronectin, and periostin in PSCs, which was significantly reduced by pirfenidone. Mice were subcutaneously implanted with PCCs (SUIT-2 cells) and PSCs into the right flank and PCCs alone into the left flank. Oral administration of pirfenidone to these mice significantly reduced tumor growth of co-implanted PCCs and PSCs, but not of PCCs alone. Pirfenidone also decreased the proliferation of PSCs and the deposition of collagen type I and periostin in tumors. In mice with orthotopic tumors consisting of PCCs co-implanted with PSCs, pirfenidone suppressed tumor growth, reduced the number of peritoneal disseminated nodules, and reduced the incidence of liver metastasis. Pirfenidone in combination with gemcitabine more effectively suppressed orthotopic tumor growth compared with pirfenidone or gemcitabine alone. In conclusion, our findings indicate that pirfenidone is a promising antitumor agent for pancreatic cancer, owing to its suppression of desmoplasia through regulating PSCs.


Evaluation of heart rate reserve and high-sensitivity C-reactive protein in individuals with and without metabolic syndrome in Isfahan, Iran.
Lack of heart rate increase proportionate to exercise causes poor prognosis. Moreover, inflammatory factors such as C-reactive protein (CRP) are associated with atherosclerosis. The current study compared these two indices in individuals with and without metabolic syndrome in Isfahan, Iran. This study was performed on 203 people without and 123 patients with metabolic syndrome who were randomly selected from the participants of the Isfahan Cohort Study. The demographic data, waist circumference, blood pressure, height, and weight of the participants were recorded. Moreover, serum tr`viglyceride (TG), fasting blood sugar (FBS), total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and high-sensitivity CRP (hs-CRP) levels were measured. Exercise test was carried out according to the Bruce standard protocol and heart rate reserve (HRR) was determined and recorded. The age-adjusted data was analyzed using generalized linear regression and student's t-test in SPSS(15). The mean ages of participants without and with metabolic syndrome were 54.16 ± 8.61 and 54.29 ± 7.6 years, respectively. The corresponding values for mean LDL levels were 116.17 ± 24.04 and 120.12 ± 29.55 mg/dl. TG levels were 140.38 ± 61.65 and 259.99 ± 184.49 mg/dl for subjects without and with the metabolic syndrome, respectively. The mean FBS levels were 81.81 ± 9.90 mg/dl in the participants without the syndrome and 107.13 ± 48.46 mg/dl in those with metabolic syndrome. The mean systolic blood pressure was 116.06 ± 13.69 mmHg in persons without metabolic syndrome and 130.73 ± 15.15 mmHg in patients with the syndrome. The values for mean diastolic levels in the two groups were 76.52 ± 6.69 and 82.84 ± 8.7 mmHg, respectively. While the two groups were not significantly different in terms of HRR (P = 0.27), hs-CRP levels in the metabolic syndrome group was significantly higher than the other group (P = 0.02). We failed to establish a relationship between HRR and the metabolic syndrome. However, the observed relationship between metabolic syndrome and hs-CRP level, which is an inflammatory factor, indicates elevated levels of hs-CRP in patients with metabolic syndrome.


Dynamic in prescribing antipsychotic drugs during five year period (2001-2005) in the Psychiatric Hospital Vrapce, Zagreb, Croatia.
Aim of this study was to determine changes in prescribing antipsychotics during 5 year period in Psychiatric Hospital VrapEe. Data about type of antipsychotic medication, ward and gender were collected for all patients receiving antipsychotics on 1st of October. During 5 year period decrease in prescribing classical antipsychotics was observed while prescribing of atypical antipsychotics has shown increase. There was an increase in number of patients treated with combination of antipsychotics, while number of patients treated with clozapine remained the same. It was noticed that female patients were more often treated with atypical antipsychotics. Data for forensic and emergency ward was analyzed separately and trends similar to hospitals were noticed here. Rationalizing use of antipsychotics can decrease cost of treatment, decrease negative effects of antipsychotics and consequently improve the treatment. Through systematic studies of this type positive progress and changes in the prescribing of antipsychotics are possible.


Demonstration of intramolecular energy transfer in asymmetric bimetallic ruthenium(ii) complexes.
A new family of bimetallic Ru(ii) complexes derived from an asymmetric bridging ligand (tpy-Hbzim-dipy) consisting of both bipyridine and terpyridine chelating sites covalently connected via phenyl-imidazole spacer were designed in this work to demonstrate intramolecular energy transfer from one component to the other in asymmetric dyads. To fine tune the photo-redox properties, both bidentate and tridentate terminal ligands in the complexes were varied systematically. Both steady state and time-resolved luminescence spectral results indicated photo-induced intramolecular energy transfer from the excited MLCT state of the [(bpy/phen)2RuII(dipy-Hbzim-tpy)] component to the MLCT state of the tpy-containing unit [(dipy-Hbzim-tpy)RuII(tpy-PhCH3/H2pbbzim)] in dyads with rate constant values on the order of 106-107 s-1. Temperature-dependent luminescence studies indicated an enhancement in the luminescence intensity and excited state lifetimes upon decreasing the temperature.


Assessing psychosocial distress in diabetes: development of the diabetes distress scale.
The purpose of this study was to describe the development of the Diabetes Distress Scale (DDS), a new instrument for the assessment of diabetes-related emotional distress, based on four independent patient samples. In consultation with patients and professionals from multiple disciplines, a preliminary scale of 28 items was developed, based a priori on four distress-related domains: emotional burden subscale, physician-related distress subscale, regimen-related distress subscale, and diabetes-related interpersonal distress. The new instrument was included in a larger battery of questionnaires used in diabetes studies at four diverse sites: waiting room at a primary care clinic (n = 200), waiting room at a diabetes specialty clinic (n = 179), a diabetes management study program (n = 167), and an ongoing diabetes management program (n = 158). Exploratory factor analyses revealed four factors consistent across sites (involving 17 of the 28 items) that matched the critical content domains identified earlier. The correlation between the 28-item and 17-item scales was very high (r = 0.99). The mean correlation between the 17-item total score (DDS) and the four subscales was high (r = 0.82), but the pattern of interscale correlations suggested that the subscales, although not totally independent, tapped into relatively different areas of diabetes-related distress. Internal reliability of the DDS and the four subscales was adequate (alpha > 0.87), and validity coefficients yielded significant linkages with the Center for Epidemiological Studies Depression Scale, meal planning, exercise, and total cholesterol. Insulin users evidenced the highest mean DDS total scores, whereas diet-controlled subjects displayed the lowest scores (P < 0.001). The DDS has a consistent, generalizable factor structure and good internal reliability and validity across four different clinical sites. The new instrument may serve as a valuable measure of diabetes-related emotional distress for use in research and clinical practice.


Update on optimal use of lisdexamfetamine in the treatment of ADHD.
Lisdexamfetamine (LDX) has been a recent addition to the treatment armamentarium for Attention Deficit Hyperactivity Disorder (ADHD). It is unique among stimulants as it is a prodrug, and has been found to be safe and well-tolerated medication in children older than 6 years, adolescents and adults. It has a smooth onset of action, exerts its action up to 13 hours and may have less rebound symptoms. LDX has proven to be effective in the treatment of ADHD in placebo controlled trials, and improved performance in simulated academic and work environments have been noticed. Both stimulant-naïve and stimulant-exposed patients with ADHD appear to benefit from LDX. It has also shown some promise in improving emotional expression and executive function of patients with ADHD. Adverse effects such as decrease in sleep, loss of appetite and others have been reported with LDX use, just as with other stimulant formulations. Since most such studies exclude subjects with preexisting cardiac morbidity, prescribing precautions should be taken with LDX in such subjects, as with any other stimulant. Study subjects on LDX have been reported to have low scores on drug likability scales, even with intravenous use; as a result, LDX may have somewhat less potential for abuse and diversion. There is a need for future studies comparing other long acting stimulants with LDX in ADHD; in fact clinical trials comparing LDX with OROS (osmotic controlled-release oral delivery system) methylphenidate are currently underway. Furthermore, the utility of this medication in other psychiatric disorders and beyond ADHD is being investigated.


Facilitated learning model to teach habits of evidence-based reasoning across an integrated master of science in occupational therapy curriculum.
We describe an integrated master of science in occupational therapy curriculum and a coordinated sequence of evidence-based practice (EBP) courses that incorporate systematic, pragmatic teaching strategies to develop students' EBP skills and habits of reasoning. The EBP courses focus sequentially on the occupational lives of clients and methods for gaining information about occupational performance and needs; appraising the internal, external, and statistical validity of intervention evidence; and generating evidence from one's own practice to answer questions about individual or group client outcomes. All EBP courses use facilitated learning processes that encourage graduate students to take responsibility for their own learning, guided by a carefully structured series of assignments. The integrated curriculum scaffolds the translation and application of previously learned knowledge and skills, including EBP knowledge, into different contexts. Student survey data suggest that graduating students view EBP as an integral part of the clinical process and begin to internalize the habits necessary to be evidence-based practitioners.


Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-Tac mAb: a phase I/II clinical trial.
To evaluate the safety and potential therapeutic activity of humanized anti-IL-2 receptor mAb (Daclizumab) therapy in the treatment of patients with severe, sight-threatening, intermediate and posterior noninfectious uveitis, a nonrandomized, open-label, pilot study was performed. Patients with uveitis were treated with a minimum of 20 mg of prednisone, cyclosporine, antimetabolites, or any combination of these agents were eligible. Patients were weaned off their systemic immunosuppressive agents according to a standardized schedule, while ultimately receiving Daclizumab infusions every 4 weeks. Anti-IL-2 receptor antibody therapy, given intravenously with intervals of up to 4 weeks in lieu of standard immunosuppressive therapy, appeared to prevent the expression of severe sight-threatening intraocular inflammatory disease in 8 of 10 patients treated over a 12-month period, with noted improvements in visual acuity. One patient met a primary endpoint with a loss of vision of 10 letters or more from baseline in one eye and another patient discontinued therapy because of evidence of increased ocular inflammation. All patients were able to tolerate the study medications without the need for dose reduction. We report effective long-term use of anti-IL-2 therapy for an autoimmune indication. These initial findings would suggest that anti-IL-2 receptor therapy may be an effective therapeutic approach for uveitis and, by implication, other disorders with a predominant Th1 profile.


Project USAP 2010: Use of Sedative Agents in Pediatric Dentistry-a 25-year Follow-up Survey.
A 25-year follow-up survey was conducted among members of the American Academy of Pediatric Dentistry (AAPD) to explore changes in the use of sedative agents. The survey was conducted in the winter of 2010 via an email LISTSERV of active members of the AAPD in the United States. The survey targeted demographics of participants and issues related to their use of sedation. A total of 1,642 responded, representing a response rate of 44 percent. The majority was board certified (58 percent) and indicated that nitrous oxide was used for over 50 percent of patients. Restraint (protective stabilization) was used by 72 percent of respondents but had declined compared to previous surveys. The dominant route of sedative administration was oral (93 percent). Benzodiazepines and nitrous oxide represented the most frequently used sedatives. Respondents and their patient pool characteristics are changing (e.g., there are proportionately more diplomates), benzodiazepines are the most frequently used sedative besides nitrous oxide (the use of which appears to be increasing), and protective stabilization among users is declining.


Severe acute malnutrition among under-5 children in low- and middle-income countries: A hierarchical analysis of associated risk factors.
Malnutrition is one of the main reasons for death among children <5 years of age in low- and middle-income countries (LMICs). It accounts for about one-third of preventable deaths among children. Reduction of malnutrition, especially severe acute malnutrition (SAM), is critical, directly or indirectly, to a targeted decrease in child mortality and improvement in maternal health. It would also help achieve sustainable development goal 2 (improvement of nutrition across the board) and sustainable development goal 3 (ensuring healthy lives and well-being promotion for all at all ages). The aim of this study was to develop and test a model of risk factors associated with SAM among under-5 children in LMICs. We used 51 recent demographic and health-surveys, cross-sectional, nationally representative data collected between 2010 and 2018 in LMICs. We used multivariable Bayesian logistic multilevel regression models to analyze the association between individual compositional and contextual risk factors associated with SAM. We analyzed information on 532 680 under-5 children (level 1) nested within 55 823 communities (level 2) from 51 LMICs (level 3). The prevalence of SAM ranged from 0.1% in both Guatemala and Peru to 9.9% in Timor-Leste. Male children, infants, low birth weight children, children whose mothers had no formal education, those from poorer households, and those with no access to any media were more likely to have SAM. Additionally, children from rural areas, neighborhoods with high illiteracy and high unemployment rates, and those from countries with high intensity of deprivation and high rural population percentage were more likely to have SAM. Individual compositional and contextual factors were significantly associated with SAM. Attainment of sustainable development goals 1, 4, and 10 will automatically contribute to the eradication of SAM, which in turn leads to the attainment of sustainable development goals 2 and 3. These findings underscore the need to revitalize existing policies and implement interventions to rescue and prevent children from having SAM at the individual, community, and societal levels in LMICs.


Comparison of nurse practitioner and family physician relative work values.
With the enactment of the Balanced Budget Act of 1997, American nurse practitioners were granted direct Medicare reimbursement for Part B services. Payment structures in fee-for-service and managed care systems are physician-based, leading to difficulties in constructing payments for other health care professionals. The purpose of this pilot study was to examine the feasibility of using nurse practitioner data for specifying relative work values in the Medicare Fee Schedule for three office-visit codes. An exploratory survey was designed to establish relative work values using magnitude-estimation scaling. Nurse practitioners (N = 43) responded to a structured questionnaire in a national mail survey. Physician data (N = 46) were obtained from a computerized database from the American Academy of Family Physicians. The methods used in this study were the same as the process used by the American Medical Association and the Health Care Financing Administration to establish relative work values in the Medicare Fee Schedule. Respondents established relative work values for three Current Procedural Terminology (CPT) codes for office visits (99203, 99213, 99215) commonly billed in primary care practice. Each CPT code descriptor and associated vignette were compared with reference services germane to the practice of nurse practitioners and family physicians, using magnitude-estimation scaling. To establish relative work values for each code, respondents were asked to consider the time to provide the service and intensity of the work involved for each CPT code. No significant differences between nurse practitioners and family physicians were found in the three CPT codes for relative work values and intensity. Nurse practitioners estimated significantly (p < .01) higher intraservice (face to face) time with patients than did family physicians, and family physicians estimated significantly (p < .05) higher pre-service time for two codes and significantly (p < .05) higher postservice times for three codes. Nurse practitioner relative work values did not differ significantly from family physician relative work values. Although the sample sizes were small, the significance of the findings support the need for further research with large data sets and additional CPT codes. Such studies could then be used as a basis for decisions about Medicare payment and public policy.


Effects of nutritional supplementation for HIV patients starting antiretroviral treatment: randomised controlled trial in Ethiopia.
To determine the effects of lipid based nutritional supplements with either whey or soy protein in patients with HIV during the first three months of antiretroviral treatment (ART) and to explore effects of timing by comparing supplementation at the start of ART and after three months delay. Randomised controlled trial. Three public ART facilities in Jimma, Oromia region, Ethiopia. Adults with HIV eligible for ART with body mass index (BMI) >16. Daily supplementation with 200 g (4600 kJ) of supplement containing whey or soy during either the first three or the subsequent three months of ART. Primary: lean body mass assessed with deuterium dilution, grip strength measured with dynamometers, and physical activity measured with accelerometer and heart rate monitors. Secondary: viral load and CD4 counts. Auxiliary: weight and CD3 and CD8 counts. Of 318 patients enrolled, 210 (66%) were women, mean age was 33 (SD 9), and mean BMI was 19.5 (SD 2.4). At three months, participants receiving the supplements containing whey or soy had increased their lean body mass by 0.85 kg (95% confidence interval 0.16 kg to 1.53 kg) and 0.97 kg (0.29 kg to 1.64 kg), respectively, more than controls. This was accompanied by an increased gain of grip strength of 0.68 kg (-0.11 kg to 1.46 kg) for the whey supplement group and 0.93 kg (0.16 kg to 1.70 kg) for the soy supplement group. There were no effects on physical activity. Total weight gain increased by 2.05 kg (1.12 kg to 2.99 kg) and 2.06 kg (1.14 kg to 2.97 kg) for the whey and soy groups, respectively. In addition, in the whey supplement group overall CD3 counts improved by 150 cells/µL (24 to 275 cells/µL), of which 112 cells/µL (15 to 209 cells/µL) were CD8 and 25 cells/µL (-2 to 53 cells/µL) were CD4. Effects of the soy containing supplement on immune recovery were not significant. The effects of the two supplements, however, were not significantly different in direct comparison. Exploratory analysis showed that relatively more lean body mass was gained by patients with undetectable viral load at three months. Patients receiving delayed supplementation had higher weight gain but lower gains in functional outcomes. Lipid based nutritional supplements improved gain of weight, lean body mass, and grip strength in patients with HIV starting ART. Supplements containing whey were associated with improved immune recovery. Trial registration Controlled-trials.com ISRCTN32453477.


Negative feedback regulation of Wnt signaling via N-linked fucosylation in zebrafish.
L-fucose, a monosaccharide widely distributed in eukaryotes and certain bacteria, is a determinant of many functional glycans that play central roles in numerous biological processes. The molecular mechanism, however, by which fucosylation mediates these processes remains largely elusive. To study how changes in fucosylation impact embryonic development, we up-regulated N-linked fucosylation via over-expression of a key GDP-Fucose transporter, Slc35c1, in zebrafish. We show that Slc35c1 overexpression causes elevated N-linked fucosylation and disrupts embryonic patterning in a transporter activity dependent manner. We demonstrate that patterning defects associated with enhanced N-linked fucosylation are due to diminished canonical Wnt signaling. Chimeric analyses demonstrate that elevated Slc35c1 expression in receiving cells decreases the signaling range of Wnt8a during zebrafish embryogenesis. Moreover, we provide biochemical evidence that this decrease is associated with reduced Wnt8 ligand and elevated Lrp6 coreceptor, which we show are both substrates for N-linked fucosylation in zebrafish embryos. Strikingly, slc35c1 expression is regulated by canonical Wnt signaling. These results suggest that Wnt limits its own signaling activity in part via up-regulation of a transporter, slc35c1 that promotes terminal fucosylation and thereby limits Wnt activity.


The clinicopathological significance of NAB2-STAT6 gene fusions in 52 cases of intrathoracic solitary fibrous tumors.
NAB2-STAT6 gene fusion drives STAT6 nuclear expression and is the pathognomonic hallmark of solitary fibrous tumors (SFTs). However, no study has systematically analyzed the clinicopathological features, STAT6 immunoexpression status, or the fusion variants of NAB2-STAT6 in intrathoracic SFTs. Fifty-two intrathoracic SFTs were retrieved to appraise histopathology, assess STAT6 immunoexpression, and determine NAB2-STAT6 fusion variants by RT-PCR. Location-relevant histologic mimics served as controls. Thirty-one pleura-based, 12 mediastinal/pericardial, and nine intrapulmonary lesions were histologically categorized into eight malignant, eight atypical, and 36 conventional or cellular SFTs, including two fat-forming and two giant cell angiofibroma-like SFTs. STAT6 distinctively decorated the tumoral nuclei in 51 (98%) SFTs. However, no nuclear staining was observed in the histological mimics. NAB2-STAT6 fusion was detected in 34 SFTs. Twenty-nine (85.3%) exhibited the major NAB2ex4-STAT6ex2/3 variant and 5 (14.7%) the minor NAB2ex6-STAT6ex16/17. NAB2ex4-STAT6ex2 was significantly associated with older age (P = 0.01) and pleuropulmonary tumors (P = 0.025). After a median follow-up of 33.9 (range, 0.3-174.6) months, adverse outcomes occurred in one atypical and five malignant SFTs, including two local relapses, one intrapulmonary metastasis, and three extrathoracic metastases. Inferior disease-free survival was univariately associated with atypical/malignant histology (P = 0.001) and a mitosis >4/10 HPFs (P = 0.0012) but was unrelated to fusion variants. In conclusion, the majority of intrathoracic SFTs exhibited STAT6 nuclear staining, and NAB2ex4-STAT6ex2/3 was the predominant fusion type. However, clinical aggressiveness is associated with atypical/malignant histology primarily contributed by increased mitosis but was unrelated to the NAB2-STAT6 fusion variants.


Impaired bone formation in ovariectomized mice reduces implant integration as indicated by longitudinal in vivo micro-computed tomography.
Although osteoporotic bone, with low bone mass and deteriorated bone architecture, provides a less favorable mechanical environment than healthy bone for implant fixation, there is no general agreement on the impact of osteoporosis on peri-implant bone (re)modeling, which is ultimately responsible for the long term stability of the bone-implant system. Here, we inserted an implant in a mouse model mimicking estrogen deficiency-induced bone loss and we monitored with longitudinal in vivo micro-computed tomography the spatio-temporal changes in bone (re)modeling and architecture, considering the separate contributions of trabecular, endocortical and periosteal surfaces. Specifically, 12 week-old C57BL/6J mice underwent OVX/SHM surgery; 9 weeks after we inserted special metal-ceramics implants into the 6th caudal vertebra and we measured bone response with in vivo micro-CT weekly for the following 6 weeks. Our results indicated that ovariectomized mice showed a reduced ability to increase the thickness of the cortical shell close to the implant because of impaired peri-implant bone formation, especially at the periosteal surface. Moreover, we observed that healthy mice had a significantly higher loss of trabecular bone far from the implant than estrogen depleted animals. Such behavior suggests that, in healthy mice, the substantial increase in peri-implant bone formation which rapidly thickened the cortex to secure the implant may raise bone resorption elsewhere and, specifically, in the trabecular network of the same bone but far from the implant. Considering the already deteriorated bone structure of estrogen depleted mice, further bone loss seemed to be hindered. The obtained knowledge on the dynamic response of diseased bone following implant insertion should provide useful guidelines to develop advanced treatments for osteoporotic fracture fixation based on local and selective manipulation of bone turnover in the peri-implant region.


Selectivity of neem to Trichogramma pretiosum Riley and Trichogrammatoidea annulata De Santis (Hymenoptera: Trichogrammatidae).
Trichogramma pretiosum Riley and Trichogrammatoidea annulata De Santis are commonly found in avocado and persimmon orchards in northern Parana state. However, their abundance depends on whether insecticides are used or not to control the key lepidopteran pests Stenoma catenifer (Wals.) (Lepidoptera: Elachistidae) and Hypocala andremona (Stoll) (Lepidoptera: Noctuidae), respectively. The aim of this work was to evaluate the effects of an aqueous neem seed extract (ANSE) at 15, 3 and 1.5%, and of an emulsifiable concentrate neem oil (ECNO) at 2.5, 0.5 and 0.25% on lifetime parameters of these trichogrammatids as a way of testing the feasibility of integrating the biological and chemical control methods. Chemicals were applied on Anagasta kuehniella (Zeller) (Lepidoptera: Pyralidae) eggs before or after parasitization (one, three or five days). ANSE was more deleterious to both parasitoid species than ECNO, regardless of the concentration and the time of application. The chemicals acted on a concentration and time dependent manner. Treating the host with neem before parasitism was less deleterious to wasp emergence, especially for T. annulata. Pre-treatments (24h) of the host eggs with ECNO at concentrations varying from 0.5% to 0.25% did not affect T. pretiosum longevity, but 2.5% reduced T. annulata survival. Feeding wasps with honey mixed with 0.25% ECNO negatively affected T. annulata survival.


Delivering a transition programme in literacy from level 4 to level 5 for nursing students: a pilot study.
This paper explores the development, delivery and evaluation of a pilot programme in academic literacy skills to help students make the transition from year 1 of their undergraduate nursing programme (level 4) to year 2 (level 5). Although there is a good deal of literature available about supporting students in year 1 to develop academic literacy skills, there is a dearth of literature on supporting students as they move from level to level during their university programmes. The pilot programme comprised five 1½ hr sessions on different aspects of literacy skills in the transition period between year 1 and year 2. Students from one cohort were invited to participate on a voluntary basis. Students undertook a pre-test before starting the programme and a post-test at the end. However, only a small number chose to sit the post-test making comparative analysis impossible. However, results of the student questionnaires showed that student confidence in their literacy skills increased and their perceptions of their literacy skills were that they were improved as a result of the programme. Importantly, marks on semester 2 written assignments were improved compared with year 1 work for those who had attended the programme. This study is important for both the progression of students from year 1 to year 2 of their nursing programme and for their ability to develop the kinds of literacy skills required for nursing practice.


Characterization of a digital microwave radiometry system for noninvasive thermometry using a temperature-controlled homogeneous test load.
Microwave radiometry has been proposed as a viable noninvasive thermometry approach for monitoring subsurface tissue temperatures and potentially controlling power levels of multielement heat applicators during clinical hyperthermia treatments. With the evolution of technology, several analog microwave radiometry devices have been developed for biomedical applications. In this paper, we describe a digital microwave radiometer with built-in electronics for signal processing and automatic self-calibration. The performance of the radiometer with an Archimedean spiral receive antenna is evaluated over a bandwidth of 3.7-4.2 GHz in homogeneous and layered water test loads. Controlled laboratory experiments over the range of 30-50 degrees C characterize measurement accuracy, stability, repeatability and penetration depth sensitivity. The ability to sense load temperature through an intervening water coupling bolus of 6 mm thickness is also investigated. To assess the clinical utility and sensitivity to electromagnetic interference (EMI), experiments are conducted inside standard clinical hyperthermia treatment rooms with no EM shielding. The digital radiometer provided repeatable measurements with 0.075 degrees C resolution and standard deviation of 0.217 degrees C for homogeneous and layered tissue loads at temperatures between 32-45 degrees C. Within the 3.7-4.2 GHz band, EM noise rejection was good other than some interference from overhead fluorescent lights in the same room as the radiometer. The system response obtained for ideal water loads suggests that this digital radiometer should be useful for estimating subcutaneous tissue temperatures under a 6 mm waterbolus used during clinical hyperthermia treatments. The accuracy and stability data obtained in water test loads of several configurations support our expectation that single band radiometry should be sufficient for sub-surface temperature monitoring and power control of large multielement array superficial hyperthermia applicators.


Collaborative palliative care for advanced heart failure: outcomes and costs from the 'Better Together' pilot study.
Patients with heart failure often receive little supportive or palliative care. 'Better Together' was a 2-year pilot study of a palliative care service for patients with advanced congestive heart failure (CHF). To determine if the intervention made it more likely that patients would be cared for and die in their place of choice, and to investigate its cost-effectiveness. This pragmatic non-randomised pilot evaluation was set in two English primary care trusts (Bradford and Poole). Prospective patient-level data on outcomes and costs were compared with data from a historical control group of clinically comparable patients. Outcomes included death in preferred place of care (available only for the intervention group) and 'hospital admissions averted'. Costs included medical procedures, inpatient care and the direct cost of providing the intervention. 99 patients were referred. Median survival from referral was 48 days in Bradford and 31 days in Poole. Most patients who died did so in their preferred place of death (Bradford 70%, Poole 77%). An estimated 14 and 18 hospital admissions for heart failure were averted in Bradford and Poole, respectively. The average cost-per-heart failure admission averted was £1529 in Bradford, but the intervention was cost saving in Poole. However, there was considerable uncertainty around these cost-effectiveness estimates. This pilot study provides tentative evidence that a collaborative home-based palliative care service for patients with advanced CHF may increase the likelihood of death in place of choice and reduce inpatient admissions. These findings require confirmation using a more robust methodological framework.


Organization of the integrin LFA-1 in nanoclusters regulates its activity.
The beta2-integrin LFA-1 facilitates extravasation of monocytes (MOs) into the underlying tissues, where MOs can differentiate into dendritic cells (DCs). Although DCs express LFA-1, unlike MOs, they cannot bind to ICAM-1. We hypothesized that an altered integrin organization on the DC plasma membrane might cause this effect and investigated the relationship between membrane organization and function of LFA-1 on MOs and DCs. High-resolution mapping of LFA-1 surface distribution revealed that on MOs LFA-1 function is associated with a distribution in well-defined nanoclusters (100-150-nm diameter). Interestingly, a fraction of these nanoclusters contains primed LFA-1 molecules expressing the specific activation-dependent L16-epitope. Live imaging of MO-T-cell conjugates showed that only these primed nanoclusters are dynamically recruited to the cellular interface forming micrometer-sized assemblies engaged in ligand binding and linked to talin. We conclude that besides affinity regulation, LFA-1 function is controlled by at least three different avidity patterns: random distributed inactive molecules, well-defined ligand-independent proactive nanoclusters, and ligand-triggered micrometer-sized macroclusters.


Anterior interosseous nerve syndrome: retrospective analysis of 14 patients.
The anterior interosseous nerve (AIN) is a only motor nerve innervating the deep muscles of the forearm. Its compression is rare. We present a retrospective analysis of 14 patients with an AIN syndrome with a variety of clinical manifestations who underwent operative and conservative treatment. Fourteen patients (six female, eight male, mean age 48 ± 9 years) were included. In six patients, the right limb was affected, and in eight patients the left limb. Conservative treatment was started for every patient. If no signs of recovery appeared within 3 months, operative exploration was performed. Final assessment was performed between 2 and 9 years after the onset of paralysis (mean duration of follow-up 46 ± 11 months). Patients were examined clinically for return of power, range of motion, pinch and grip strengths. Also the disability of the arm, shoulder, and hand (DASH) score was calculated. Seven of our 14 patients had incomplete AIN palsy with isolated total loss of function of flexor pollicis longus (FPL), five of FPL and flexor digitorum profundus (FDP)1 simultaneously, and two of FDP1. Weakness of FDP2 could be seen in four patients. Pronator teres was paralysed in two patients. Pain in the forearm was present in nine patients. Four patients had predisposing factors. Eight patients treated conservatively exhibited spontaneous recovery from their paralysis during 3-12 months after the onset. In six patients, the AIN was explored 12 weeks after the initial symptoms and released from compressing structures. Thirteen patients showed good limb function. In one patient with poor result a tendon transfer was necessary. The DASH score of patients treated conservatively and operatively presented no significant difference. AIN syndrome can have different clinical manifestations. If no signs of spontaneous recovery appear within 12 weeks, operative treatment should be performed.


Early Impacts of the Affordable Care Act on Health Insurance Coverage in Medicaid Expansion and Non-Expansion States.
The Affordable Care Act (ACA) aimed to achieve nearly universal health insurance coverage in the United States through a combination of insurance market reforms, mandates, subsidies, health insurance exchanges, and Medicaid expansions, most of which took effect in 2014. This paper estimates the causal effects of the ACA on health insurance coverage in 2014 using data from the American Community Survey. We utilize difference-in-difference-in-differences models that exploit cross-sectional variation in the intensity of treatment arising from state participation in the Medicaid expansion and local area pre-ACA uninsured rates. This strategy allows us to identify the effects of the ACA in both Medicaid expansion and non-expansion states. Our preferred specification suggests that, at the average pre-treatment uninsured rate, the full ACA increased the proportion of residents with insurance by 5.9 percentage points compared to 2.8 percentage points in states that did not expand Medicaid. Private insurance expansions from the ACA were due to increases in both employer-provided and non-group coverage. The coverage gains from the full ACA were largest for those without a college degree, non-whites, young adults, unmarried individuals, and those without children in the home. We find no evidence that the Medicaid expansion crowded out private coverage.


Apical localization of 1-aminocyclopropane-1-carboxylic acid and its conversion to ethylene in etiolated pea seedlings.
The biosynthetic basis for the high rates of ethylene production by the apical region of etiolated pea (Pisum sativum L.) seedlings was investigated. The ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) was quantified in extracts of various regions of seedlings by measuring isotopic dilution of a (2)H-labelled internal standard using selected-ion-monitoring gas chromatography/mass spectrometry. The ACC levels in the apical hook and leaves were much higher than in the expanded internodes of the epicotyl. The capacity of excised tissue sections to convert exogenous ACC to ethylene was also much greater in the apical region, reflecting the distribution of soluble protein in the epicotyl.


CT and MR in infants with pericerebral collections and macrocephaly: benign enlargement of the subarachnoid spaces versus subdural collections.
To compare CT and MR in the differentiation of benign enlargement of the subarachnoid spaces and subdural collections in infants with macrocephaly. MR was performed in 19 infants with macrocephaly, showing bifrontal enlargement of the subarachnoid spaces on CT. In 11 patients, a single fluid layer could be distinguished on MR of the pericerebral collections, suggesting benign enlargement of the subarachnoid spaces. In eight patients, two separate layers were clearly differentiated, an outer layer that was hyperintense on all sequences and an inner layer with the same intensity as the cerebrospinal fluid. This indicated the presence of subdural collections. These collections were mainly frontal in six and extended over the entire hemisphere in two patients. On CT, these separate lesions were seen only in three patients and missed in three others. In two final patients, CT findings were equivocal with evidence of membrane formation within the hypodense collections. In seven patients with a subdural collection, subdural-external drainage was performed. In three patients, the collection was hemorrhagic. The protein content of the fluid showed a mean of 1381.7 +/- 785.6 mg/dL. The MR and surgical findings of a subdural collection correlated with the absence of a family history of macrocrania, an age under 5 months, and acute clinical signs of vomiting, somnolence, and hypotonia. MR appears essential in the differential diagnosis between benign enlargement of the subarachnoid spaces and subdural collections in infants.


A case-cohort study of lung cancer in poultry and control workers: occupational findings.
We conducted a mortality study of members of the United Food and Commercial Workers International Union who worked in poultry slaughtering/processing plants, and controls. Excess deaths from cancer at 11 different cancer sites including lung cancer were observed in the poultry workers. The study described here is a pilot case-cohort study of lung cancer nested within the cohort to examine if it is possible, in a larger study to be conducted later, to identify specific potentially carcinogenic occupational exposures in poultry workers. Subjects or the next of kin of deceased subjects were interviewed by phone. Logistic regression ORs and Cox proportional HRs were estimated. Elevated risks for poultry exposure were recorded for subjects who (1) killed chickens at work (OR 4.2, 95% CI 1.2 to 14.7; HR 1.8, 95% CI 1.0 to 3.3) and (2) ever had direct contact with chicken blood at work (OR 1.9, 95% CI 1.0 to 3.8; HR 1.3, 95% CI 0.9 to 2.0). These activities are associated with high exposure to oncogenic viruses. These results may have important public health implications, since the general population is also exposed to these viruses. Elevated risks were observed for non-poultry-related occupational exposures such as working in a stockyard, working in a chemical plant, use of chemicals to kill moulds, and working in plants where plastic products were manufactured. These preliminary findings indicate that full scale epidemiological studies of adequate statistical power are needed to examine the role of occupational exposures in cancer occurrence in poultry workers.


A balancing act: the consulting engineers' pragmatic view of process modelling.
Modelling: what do we know, what do we want to know and why? The practical application of models to real projects is often circular because these questions weren't asked prior to making the decision to model the plant under study. Modelling wastewater treatment plants can provide insight into the inner workings of the process that might not be attainable any other way, but is that added process knowledge always needed or necessary and what criteria does one use to determine the level of effort required? These complex modelling decisions require education, communication, and improved understanding amongst both modellers and clients. This submission explores the use of models by consultants for consulting purposes and the balancing acts (time versus knowledge and cost versus benefit) that the consulting engineer must manage when embarking on any modelling project.


Increased risk of high grade cervical squamous intraepithelial lesions in systemic lupus erythematosus: A meta-analysis of the literature.
Conflicting data have been published regarding the risk of cervical lesions among women with systemic lupus erythematosus (SLE). We systematically reviewed the evidence for an association of SLE with cervical precancerous lesions (high-grade squamous intraepithelial lesions, HSIL), and performed a meta-analysis to determine the risk of HSIL in SLE patients. Observational studies identified up to February 2013 from the Medline, Embase and Cochrane databases were selected if they assessed the prevalence of HSIL in female SLE patients versus healthy female controls and included in a meta-analysis with pooled effect estimates obtained using a random-effects model. Of 235 citations retrieved, 7 studies met inclusion criteria. The pooled odds ratio for the risk of HSIL in SLE patients (n=416) versus female controls (n=11,408) was 8.66 (95% CI: 3.75-20.00), without significant heterogeneity across studies. Cumulative meta-analysis according to year of study publication revealed a slight increase in the risk of HSIL in the 2001-2011 period and then a stabilization afterwards. This meta-analysis shows that the risk of HSIL is significantly increased in SLE patients, compared to healthy female controls. This suggests that women with SLE may benefit from HPV vaccines and specific cervical cancer screening.


Burden of Pneumococcal Disease in Northern Togo before the Introduction of Pneumococcal Conjugate Vaccine.
S. pneumoniae is a leading cause of meningitis morbidity and mortality in the African meningitis belt, but little is known of its contribution to the burden of pneumonia in the region. We aimed to estimate the incidence of pneumococcal disease in children and adults in northern Togo, before the introduction of pneumococcal conjugate vaccine (PCV). From May 1st 2010 to April 30th 2013, we systematically enrolled all hospitalized patients meeting a case definition of suspected meningitis or clinical pneumonia, residing in Tone or Cinkasse districts, northern Togo and providing informed consent. We collected clinical data and tested biological specimens according to standardized procedures, including bacteriology and PCR testing of cerebro-spinal fluid for meningitis patients and blood cultures and whole blood lytA PCR for pneumonia patients. Chest X-rays (CXR) were interpreted using the WHO methodology. We included 404 patients with meningitis (104 <5 years of age) and 1550 with pneumonia (251 <5 years) over the study period. Of these, 78 (19%) had pneumococcal meningitis (13 <5 years), 574 (37%) had radiologically-confirmed pneumonia (83 <5 years) and 73 (5%) had culture-confirmed pneumococcal pneumonia (2 <5 years). PCV13 serotypes caused 79% (54/68) of laboratory-confirmed pneumococcal meningitis and 83% (29/35) of culture-confirmed pneumococcal pneumonia. Serotype 1 predominated in meningitis (n = 33) but not in pneumonia patients (n = 1). The incidence of pneumococcal disease was 7.5 per 100,000 among children <5 years of age and 14.8 in persons 5 years of age and above in the study area. When considering CXR-confirmed and blood PCR-positive pneumonia cases as likely pneumococcal, incidence estimates increased to 43.7 and 66.0 per 100,000 in each of these age groups, respectively. Incidence was at least 3-fold higher when we restricted the analysis to the urban area immediately around the study hospitals. Our findings highlight the important role of S. pneumoniae as a meningitis and pneumonia-causing pathogen in the African meningitis belt. Pneumococcal disease incidence in our population was substantially lower than expected from global models; we hypothesize that poor access to hospital care led us to substantially underestimate the burden of disease. Surveillance is ongoing and will enable an evaluation of PCV impact, providing novel, high quality data from the region.


In vitro interaction between amphotericin B and azoles in Candida albicans.
The use of azole prophylaxis as a measure to prevent invasive fungal infections in high-risk patients is increasing and is now the standard of care in many institutions. Previous studies disagree on whether preexposure of Candida albicans to azoles affects their subsequent susceptibility to amphotericin B (AmB). The present in vitro study indicates that azole exposure generates a subpopulation of cells that are not affected by subsequent exposure to AmB. These cells that are phenotypically resistant to AmB tolerated by most cells not exposed to azole. The percentage of cells that convert to phenotypic resistance to AmB varies with the concentration and the azole. Itraconazole is more effective than fluconazole in generating cells that are phenotypically resistant to AmB and that tolerate an otherwise lethal transient exposure to AmB. Until cells that are not exposed to fluconazole are simultaneously challenged with AmB, they are not protected to a significant extent from killing by AmB. Cells that are challenged with continuous exposure to AmB also acquire phenotypic resistance to AmB at increased frequencies by azole preexposure, but this requires that the azole be continuously present during incubation with AmB. In addition, Candida cells taken from mature colonies that are not actively growing are not susceptible to the short-term killing effects of AmB without azole preexposure. The adaptive responses of C. albicans to AmB and potentially other antifungal agents that may result from prior exposure to azoles in vitro or potentially in microenvironments in vivo that induce physiological changes may have major clinical implications.


Engaging Teammates in the Promotion of Concussion Help Seeking.
Concussion underreporting contributes to the substantial public health burden of concussions from sport. Teammates may be able to play an important role in encouraging injury identification and help seeking. This study assessed whether there was an association between beliefs about the consequences of continued play with a concussion and intentions to engage as a proactive bystander in facilitating or encouraging teammate help seeking for a possible concussion. Participants were 328 (male and female) members of 19 U.S. collegiate contact or collision sports teams. Athletes who believed that there were negative health or performance consequences of continued play with a concussion were significantly more likely than their peers to intend to encourage teammate help seeking, but not more likely to alert a coach or medical personnel. Additionally, athletes who believed that their teammates were more supportive of concussion safety were more likely to intend to engage as proactive bystanders in encouraging teammate help seeking. Exploring how to encourage bystander promotion of concussion safety is an important direction for future programming and evaluation research and may provide an opportunity to improve the effectiveness of concussion education.


Scaphoid fracture and scaphoid pseudarthrosis.
Careful diagnostic and early therapy are especially important in cases of scaphoid fractures. This is due to the patients being mostly young and the high number of non-unions of these carpal bones. Conservative and various operative treatments are therapeutical options. Out of the patients who underwent surgery from January 1993 to February 1999 42 patients with a scaphoid fracture and 88 patients with a scaphoid non-union were, in addition to standard X-ray examination, examined clinically and by MRI pre- and post-operatively. Fractures of the scaphoid were treated by Herbert screw fixtion. The operative treatment of non-unions of the scaphoid included the transplantation of an iliac crest graft and Herbert screw fixation. Post-operatively a cast-immobilisation was done. Subjective statements of the patients and clinical results were assessed. The classification of Herbert and Fisher (1984)/Filan and Herbert (1996) for X-rays was used. The signal intensities of the MRI in the fragments of the scaphoid were determined qualitatively and quantitatively by computer calculation, comparing the pre- and post-operative results with one another. Post-operative results of the scaphoid fractures were in most cases good and excellent. 67 patients with a scaphoid non-union and 11 with a scaphoid fracture showed a pre-operative diminishing of the signal in the proximal fragment. For these patients, the fusion rate was lower than in patients without pre-operative signal reduction. The examination shows that in most cases bony fusions with good clinical results could be achieved by Herbert screw fixation. The MRI seems to be able to complete the radiological classification of the fractures regarding a prognosis.


Prevalence of hypertension among professional drivers: Evidence from 2000 to 2017-A systematic review and meta-analysis.
Hypertension is one of the leading causes of premature deaths worldwide. Drivers have an additional risk of hypertension when compared to the general population because of the nature of their profession. Hence, the current review was done to estimate the global burden of hypertension among professional drivers. We conducted a systematic search for articles on the prevalence of hypertension among drivers published from 2000 to 2017 in Medline and Embase. Meta-analysis was performed using the random-effects model and pooled prevalence of hypertension was reported. Heterogeneity was assessed using the likelihood ratio (LR) test and publication bias was assessed using Egger's test. In total, 26 studies with 15,702 drivers were included. The pooled prevalence of hypertension among the drivers worldwide was 34% (95% confidence interval [CI]: 27-40%). World Health Organization (WHO) region-wise estimates showed that prevalence was highest among the drivers in the Western Pacific region (56%) and lowest in the Eastern Mediterranean and African region (21%). Studies showed significant evidence of heterogeneity (χ2 = 1816.1,P < 0.001) but there was no significant publication bias (P = 0.967). More than one-third of drivers have hypertension globally which is in excess of the general population. Hence, more focus needs to be given for allocating resources and developing workplace interventions for prevention and control of hypertension.


Quantitative analysis in alkaline solutions by Raman spectroscopy.
A detailed investigation has been made of the analysis of concentrated alkaline aluminate solutions (synthetic Bayer liquors) by Fourier transform (FT) Raman spectroscopy. Satisfactory determinations of Al(OH)4-, SO42- and CO32- were achieved at industrially-relevant concentrations. Possible extensions to a number of other inorganic and organic anions of interest to the alumina refining industry were demonstrated. No significant interferences were observed except for a small but readily correctable contribution of a minor SO42- mode at ∼615 cm-1 to the Al(OH)4- envelope centred at ∼620 cm-1. Hydroxide (OH-) could not be determined with the present FT instrument, due to the low detector sensitivity at high wavenumbers, but might be possible with other spectrometers. Successful extension of the analyses to industrial Bayer process solutions is briefly discussed.


Mechanical Ventilation Training During Graduate Medical Education: Perspectives and Review of the Literature.
Management of mechanical ventilation (MV) is an important and complex aspect of caring for critically ill patients. Management strategies and technical operation of the ventilator are key skills for physicians in training, as lack of expertise can lead to substantial patient harm. We performed a narrative review of the literature describing MV education in graduate medical education (GME) and identified best practices for training and assessment methods. We searched MEDLINE, PubMed, and Google Scholar for English-language, peer-reviewed articles describing MV education and assessment. We included articles from 2000 through July 2018 pertaining to MV education or training in GME. Fifteen articles met inclusion criteria. Studies related to MV training in anesthesiology, emergency medicine, general surgery, and internal medicine residency programs, as well as subspecialty training in critical care medicine, pediatric critical care medicine, and pulmonary and critical care medicine. Nearly half of trainees assessed were dissatisfied with their MV education. Six studies evaluated educational interventions, all employing simulation as an educational strategy, although there was considerable heterogeneity in content. Most outcomes were assessed with multiple-choice knowledge testing; only 2 studies evaluated the care of actual patients after an educational intervention. There is a paucity of information describing MV education in GME. The available literature demonstrates that trainees are generally dissatisfied with MV training. Best practices include establishing MV-specific learning objectives and incorporating simulation. Next research steps include developing competency standards and validity evidence for assessment tools that can be utilized across MV educational curricula.


Parallel compensatory evolution stabilizes plasmids across the parasitism-mutualism continuum.
Plasmids drive genomic diversity in bacteria via horizontal gene transfer [1, 2]; nevertheless, explaining their survival in bacterial populations is challenging [3]. Theory predicts that irrespective of their net fitness effects, plasmids should be lost: when parasitic (costs outweigh benefits), plasmids should decline due to purifying selection [4-6], yet under mutualism (benefits outweigh costs), selection favors the capture of beneficial accessory genes by the chromosome and loss of the costly plasmid backbone [4]. While compensatory evolution can enhance plasmid stability within populations [7-15], the propensity for this to occur across the parasitism-mutualism continuum is unknown. We experimentally evolved Pseudomonas fluorescens and its mercury resistance mega-plasmid, pQBR103 [16], across an environment-mediated parasitism-mutualism continuum. Compensatory evolution stabilized plasmids by rapidly ameliorating the cost of plasmid carriage in all environments. Genomic analysis revealed that, in both parasitic and mutualistic treatments, evolution repeatedly targeted the gacA/gacS bacterial two-component global regulatory system while leaving the plasmid sequence intact. Deletion of either gacA or gacS was sufficient to completely ameliorate the cost of plasmid carriage. Mutation of gacA/gacS downregulated the expression of ∼17% of chromosomal and plasmid genes and appears to have relieved the translational demand imposed by the plasmid. Chromosomal capture of mercury resistance accompanied by plasmid loss occurred throughout the experiment but very rarely invaded to high frequency, suggesting that rapid compensatory evolution can limit this process. Compensatory evolution can explain the widespread occurrence of plasmids and allows bacteria to retain horizontally acquired plasmids even in environments where their accessory genes are not immediately useful.


Development of anti-human colonic mucin monoclonal antibodies. Characterization of multiple colonic mucin species.
Structural relationships between colonic mucin species were assessed using a library of monoclonal antibodies (MAbs) directed against purified human colonic mucin (HCM). After immunization of mice with purified mucin from normal human colonic mucosa, 14% of 1,920 fusion products screened were positive for anti-HCM activity in a solid-phase assay. Patterns of selective binding by hybridomas to six discrete HCM species (I-VI) separated by DEAE-cellulose chromatography suggested the presence of both shared and species-specific antigenic determinants among HCM species I-VI. 23 anti-HCMs MAbs (7 IgM, 7 IgG1, and 9 IgG2) demonstrating a range of anti-HCM species specificities, were produced and used to study structural relationships between mucin species. Binding of various mucin species by individual anti-HCM MAbs was shown by competitive solid-phase radioimmunoassay to reflect the presence of identical epitopes on the different species. Adsorption of HCM species on a variety of affinity resins prepared with anti-HCM MAbs demonstrated that binding to multiple mucin species by a single MAb was related to intrinsic structural determinants. Four anti-HCM MAbs recognized protease-sensitive antigenic structures, which suggests that they may be directed to core HCM proteins. 12 of the anti-HCM MAbs were shown by solid-phase assay to recognize either complete (n = 5) or partial (n = 7) isolated colonic mucin oligosaccharide side chains of defined structure. Collectively, these data show the presence of both shared and unique antigenic structural determinants among colonic mucin species. Chromatographic heterogeneity of mucin glycoproteins seems to be related to the existence of biologically significant subclasses in the normal human colon.


Structure-activity relationship of lidocaine homologs producing tonic and frequency-dependent impulse blockade in nerve.
Experiments were done to assess the relationship of the chemical properties of local anesthetics to their ability to block neuronal impulse conduction, using a series of hitherto unavailable homologs of lidocaine. These molecules varied in the number and arrangement of alkyl groups attached to the tertiary amine nitrogen. Each compound was applied to desheathed sciatic nerves of frogs (Rana pipiens) mounted in a sucrose gap recording chamber. Compound action potentials (AP) were recorded at room temperature (20-23 degrees C) and the potency of each anesthetic determined from the concentration required to produce a 40% reduction in the amplitude of the AP at low-frequency stimulation: 1 min-1. This reduction was called Bt. An additional Bt was measured from the further decrease in amplitude of the AP during high-frequency stimulation (10 and 40 Hz). Tonic and phasic blocking potencies were analyzed as functions of the calculated drug partition coefficients, and the known molecular weights, molecular configurations and pKa values. Potency for Bt increased with increasing length of n-alkyl groups attached to the terminal amine, whereas it decreased as the length of the alkyl group connecting the amide bond to the terminal amine was increased. However, when considered in terms of their physicochemical properties, the homologs showed a potency for Bt that increased uniformly with increasing partition coefficient. This analysis revealed a strong positive correlation between tonic potency and partitioning into octanol for both neutral and protonated anesthetic species but little correlation with molecular weight or pKa. However, Bt did not depend uniquely on hydrophobicity, as predicted if lipophilic partitioning alone determined potency.(ABSTRACT TRUNCATED AT 250 WORDS)


Force spectroscopy of collagen fibers to investigate their mechanical properties and structural organization.
Tendons are composed of collagen and other molecules in a highly organized hierarchical assembly, leading to extraordinary mechanical properties. To probe the cross-links on the lower level of organization, we used a cantilever to pull substructures out of the assembly. Advanced force probe technology, using small cantilevers (length <20 microm), improved the force resolution into the sub-10 pN range. In the force versus extension curves, we found an exponential increase in force and two different periodic rupture events, one with strong bonds (jumps in force of several hundred pN) with a periodicity of 78 nm and one with weak bonds (jumps in force of <7 pN) with a periodicity of 22 nm. We demonstrate a good correlation between the measured mechanical behavior of collagen fibers and their appearance in the micrographs taken with the atomic force microscope.


Molecular phylogeny of the Microsporidia: ecological, ultrastructural and taxonomic considerations.
The Microsporidia are a group of obligate intracellular parasites, now thought to be derived fungi. Presented here is a comparative small subunit rDNA (ssrDNA) analysis of 125 species of Microsporidia (sequences obtained from GenBank). This analysis shows that groups or clades are formed based largely on habitat and host. This result is supported by comparative molecular analyses of the past decade, and indicates that structural and ultrastructural characters are unreliable for distinguishing among higher-level microsporidian taxa. Our findings indicate the presence of five major clades of Microsporidia which group according to habitat. We present three new classes of Microsporidia based on natural phylogenetic groupings as illustrated by the ssrDNA analysis: Aquasporidia, Marinosporidia and Terresporidia. The names of the proposed classes reflect the habitat of each group. The class Aquasporidia, found primarily in freshwater habitats, is a paraphyletic group consisting of three clades. The Marinosporidia are found in hosts of marine origin and the Terresporidia are primarily from terrestrial environments.


Design and control of the MINDWALKER exoskeleton.
Powered exoskeletons can empower paraplegics to stand and walk. Actively controlled hip ab/adduction (HAA) is needed for weight shift and for lateral foot placement to support dynamic balance control and to counteract disturbances in the frontal plane. Here, we describe the design, control, and preliminary evaluation of a novel exoskeleton, MINDWALKER. Besides powered hip flexion/extension and knee flexion/extension, it also has powered HAA. Each of the powered joints has a series elastic actuator, which can deliver 100 Nm torque and 1 kW power. A finite-state machine based controller provides gait assistance in both the sagittal and frontal planes. State transitions, such as stepping, can be triggered by the displacement of the Center of Mass (CoM). A novel step-width adaptation algorithm was proposed to stabilize lateral balance. We tested this exoskeleton on both healthy subjects and paraplegics. Experimental results showed that all users could successfully trigger steps by CoM displacement. The step-width adaptation algorithm could actively counteract disturbances, such as pushes. With the current implementations, stable walking without crutches has been achieved for healthy subjects but not yet for SCI paraplegics. More research and development is needed to improve the gait stability.


Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus.
Antibody paratopes are formed by hypervariable complementarity-determining regions (CDRH3s) and variable gene-encoded CDRs. The latter show biased usage in human broadly neutralizing antibodies (bnAbs) against both HIV and influenza virus, suggesting the existence of gene-endowed targeting solutions that may be amenable to pathway amplification. To test this, we generated transgenic mice with human CDRH3 diversity but simultaneously constrained to individual user-defined human immunoglobulin variable heavy-chain (VH) genes, including IGHV1-69, which shows biased usage in human bnAbs targeting the hemagglutinin stalk of group 1 influenza A viruses. Sequential immunization with a stalk-only hemagglutinin nanoparticle elicited group 1 bnAbs, but only in IGHV1-69 mice. This VH-endowed response required minimal affinity maturation, was elicited alongside pre-existing influenza immunity, and when IGHV1-69 B cells were diluted to match the frequency measured in humans. These results indicate that the human repertoire could, in principle, support germline-encoded bnAb elicitation using a single recombinant hemagglutinin immunogen.


Using corticosteroids to reshape the gut microbiome: implications for inflammatory bowel diseases.
Commensal gut microbiota play an important role in regulating metabolic and inflammatory conditions. Reshaping intestinal microbiota through pharmacologic means may be a viable treatment option. We sought to delineate the functional characteristics of glucocorticoid-mediated alterations on gut microbiota and their subsequent repercussions on host mucin regulation and colonic inflammation. Adult male C57Bl/6 mice, germ-free, Muc2-heterozygote (±), or Muc2-knockout (-/-) were injected with dexamethasone, a synthetic glucocorticoid, for 4 weeks. Fecal samples were collected for gut microbiota analysis through 16S rRNA terminal restriction fragment length polymorphism and amplicon sequencing. Intestinal mucosa was collected for mucin gene expression studies. Germ-free mice were conventionalized with gut microbes from treated and nontreated groups to determine their functional capacities in recipient hosts. Exposure to dexamethasone in wild-type mice led to substantial shifts in gut microbiota over a 4-week period. Furthermore, a significant downregulation of colonic Muc2 gene expression was observed after treatment. Muc2-knockout mice harbored a proinflammatory environment of gut microbes, characterized by the increase or decrease in prevalence of specific microbiota populations such as Clostridiales and Lactobacillaceae, respectively. This colitogenic phenotype was transmissible to IL10-knockout mice, a genetically susceptible model of colonic inflammatory disorders. Microbiota from donors pretreated with dexamethasone, however, ameliorated symptoms of inflammation. Commensal gut bacteria may be a key mediator of the anti-inflammatory effects observed in the large intestine after glucocorticoid exposure. These findings underscore the notion that intestinal microbes comprise a "microbial organ" essential for host physiology that can be targeted by therapeutic approaches to restore intestinal homeostasis.


Management and outcome of fractures of the distal phalanx: a retrospective study of 285 horses with a long term outcome in 223 cases.
A multicentre study of 285 cases was performed to enhance the management of distal phalangeal fractures on the basis of clinical evidence. The outcome after treatment was available for 223 of the cases. Horses with a non-articular type I fracture had a better prognosis (91.7%) for return to original or expected level of use than horses with an articular type II or III fracture (69.6% and 74.1%, respectively). The prognosis for types IV and V fractures was fair (57.7% and 57.1%, respectively) and for type VI good (80%). Horses with a hindlimb fracture had a significantly greater chance of a successful outcome. No significant association between age or time to start treatment and success rate was noted. The best treatment option for types I-III fractures was a conservative approach (box rest). Type IV fractures were best treated by arthroscopic removal of the fragment. Immobilisation of the hoof did not seem to influence outcome. Radiological findings and clinical healing were not accurately correlated and the re-commencement of training should be based on clinical rather than radiological findings. Complete osseous union of the fracture was not essential for a successful return to athletic activity.


Pyruvate Oxidase as a Critical Link between Metabolism and Capsule Biosynthesis in Streptococcus pneumoniae.
The pneumococcus is one of the most prodigious producers of hydrogen peroxide amongst bacterial pathogens. Hydrogen peroxide production by the pneumococcus has been implicated in antibiotic synergism, competition between other bacterial colonizers of the nasopharynx, and damage to epithelial cells. However, the role during invasive disease has been less clear with mutants defective in hydrogen peroxide production demonstrating both attenuation and heightened invasive disease capacity depending upon strain and serotype background. This work resolves these conflicting observations by demonstrating that the main hydrogen peroxide producing enzyme of the pneumococcus, SpxB, is required for capsule formation in a strain dependent manner. Capsule production by strains harboring capsules with acetylated sugars was dependent upon the presence of spxB while capsule production in serotypes lacking such linkages were not. The spxB mutant had significantly lower steady-state cellular levels of acetyl-CoA, suggesting that loss of capsule arises from dysregulation of this intermediary metabolite. This conclusion is corroborated by deletion of pdhC, which also resulted in lower steady-state acetyl-CoA levels and phenocopied the capsule expression profile of the spxB mutant. Capsule and acetyl-CoA levels were restored in the spxB and lctO (lactate oxidase) double mutant, supporting the connection between central metabolism and capsule formation. Taken together, these data show that the defect in pathogenesis in the spxB mutant is due to a metabolic imbalance that attenuates capsule formation and not to reduced hydrogen peroxide formation.


Complicated congenital splenic cyst: saved by a splenunculus.
A 12-year-old girl presented with a large congenital splenic cyst complicated by Salmonella organisms. After failure of conservative management and percutaneous drainage, a splenectomy was performed. An incidental splenunculus was preserved. On follow up the splenunculus had increased to normal splenic size and there was no evidence of Howell-Jolly bodies, suggesting normal splenic function.


Advanced smile diagnostics using CAD/CAM mock-ups.
Diagnostics are essential for predictable restorative dentistry. Both patient and clinician must agree on a treatment goal before the final restorations are delivered to avoid future disappointments. However, fully understanding the patient's desires is difficult. A useful tool to overcome this problem is the diagnostic wax-up and mock-up. A potential treatment outcome is modeled in wax prior to treatment and transferred into the patient's mouth using silicon indexes and autopolymerizing resin to obtain the patient's approval. Yet, this time-consuming procedure only produces a single version of the possible treatment outcome, which can be unsatisfactory for both the patient and the restorative team. Contemporary digital technologies may provide advantageous features to aid in this diagnostic treatment step. This article reviews opportunities digital technologies offer in the diagnostic phase, and presents clinical cases to illustrate the procedures.