Geographical and socioeconomic disparities in opioid access in Mexico, 2015-19: a retrospective analysis of surveillance data.
In 2015, Mexico implemented regulatory changes and an electronic system to improve access to prescription opioids. We aimed to investigate trends in opioid dispensing after the implementation of these changes and assess how opioid dispensing varied geographically and by socioeconomic status. In this retrospective analysis of prescription medication surveillance data, we analysed dispensing data for group 1 medications (all opioids, including morphine, methadone, hydromorphone, oxycodone, tapentadol, fentanyl, sufentanil, and remifentanil) obtained from the Federal Commission for the Protection against Sanitary Risk database for 32 states and six large metropolitan areas in Mexico. We calculated crude annual opioid prescriptions per 10 000 people at the national, state, and municipal levels. Adapting methods from the report of the Lancet Commission on Palliative Care and Pain Relief, we calculated the need for palliative opioids by state, and then assessed the observed opioid dispensing rates as a percentage of expected need by geographical socioeconomic status. Within the six major metropolitan areas, we mapped the geocoded location of opioid prescriptions and assessed the association between opioid dispensing and socioeconomic status as well as the association between opioid dispensing and time to US border crossing for areas on the US-Mexico border. Between June 25, 2015, and Oct 7, 2019, opioid dispensing rates increased by an average of 13% (95% CI 6·8-19·6) per quarter (3 months). The overall national opioid dispensing rate during the study period was 26·3 prescriptions per 10 000 inhabitants. States with a higher socioeconomic status had higher opioid dispensing rates than states with lower socioeconomic status (rate ratio [RR] 1·88, 95% CI 1·33-2·58, p=0·00016) after controlling for the estimated opioid requirement per state, the presence of methadone clinics, and the presence of tertiary hospitals and cancer centres. The same association between opioid dispensing and socioeconomic status was observed in the metropolitan areas, and in those metropolitan areas on the US-Mexico border a 20% decrease (RR 0·80, 95% CI 0·75-0·86) in opioid dispensation was observed per each SD increase (SD 17·1 min) in travel time to the border. Measures introduced by the Mexican federal Government to increase opioid access for patients with palliative care needs were only marginally successful in raising opioid prescription rates. Opioid access should be improved for patients with palliative care needs who live in geographical areas of lower socioeconomic status. US National Institutes of Health.


Factors affecting first-month adherence to antiretroviral therapy among HIV-positive adults in South Africa.
This study explores the influence of baseline factors on first-month adherence to highly active antiretroviral therapy (HAART) among adults. The study design involved a review of routinely collected patient information in the CAPRISA AIDS Treatment (CAT) programme, at a rural and an urban clinic in KwaZulu-Natal Province, South Africa. The records of 688 patients enrolled in the CAT programme between June 2004 and September 2006 were analysed. Adherence was calculated from pharmacy records (pill counts) and patients were considered adherent if they had taken at least 95% of their prescribed drugs. Logistic regression was used to analyse the data and account for confounding factors. During the first month of therapy, 79% of the patients were adherent to HAART. HAART adherence was negatively associated with a higher baseline CD4 count. Women had better adherence if they attended voluntarily testing and counselling or if they had taken an HIV test because they were unwell, while men had higher adherence if they were tested due to perceived risk of HIV infection. HAART adherence was positively associated with higher age among patients who possessed cell phones and among patients who provided a source of income in the urban setting, but not in the rural setting. Though long-term data from this cohort is required to fully evaluate the impact of non-adherence in the first month of treatment, this study identifies specific groups of patients at higher risk for whom adherence counselling should be targeted and tailored. For example, first-month HAART adherence can be improved by targeting patients initiated on treatment with a high CD4 count.


phi2FLIM: a technique for alias-free frequency domain fluorescence lifetime imaging.
A new approach to alias-free wide-field fluorescence lifetime imaging in the frequency domain is demonstrated using a supercontinuum source for fluorescence excitation and a phase-modulated image intensifier for detection. This technique is referred to as phi-squared fluorescence lifetime imaging (phi(2)FLIM). The phase modulation and square-wave gating of the image intensifier eliminate aliasing by the effective suppression of higher harmonics. The ability to use picosecond excitation pulses without aliasing expands the range of excitation sources available for frequency-domain fluorescence lifetime imaging (fd-FLIM) and improves the modulation depth of conventional homodyne fd-FLIM measurements, which use sinusoidal intensity modulation of the excitation source. The phi(2)FLIM results are analyzed using AB-plots, which facilitate the identification of mono-exponential and multi-exponential fluorescence decays and provide measurements of the fluorophore fractions in two component mixtures. The rapid acquisition speed of the technique enables lifetime measurements in dynamic systems, such as temporally evolving samples and samples that are sensitive to photo-bleaching. Rapid phi(2)FLIM measurements are demonstrated by imaging the dynamic mixing of two different dye solutions at 5.5 Hz. The tunability of supercontinuum radiation enables excitation wavelength resolved FLIM measurements, which facilitates analysis of samples containing multiple fluorophores with different absorption spectra.


Detection of amyloid in abdominal fat pad aspirates in early amyloidosis: Role of electron microscopy and Congo red stained cell block sections.
Fine-needle aspiration biopsy (FNA) of the abdominal fat pad is a minimally invasive procedure to demonstrate tissue deposits of amyloid. However, protocols to evaluate amyloid in fat pad aspirates are not standardized, especially for detecting scant amyloid in early disease. We studied abdominal fat pad aspirates from 33 randomly selected patients in whom subsequent tissue biopsy, autopsy, and/or medical history for confirmation of amyloidosis (AL) were also available. All these cases were suspected to have early AL, but had negative results on abdominal fat pad aspirates evaluated by polarizing microscopy of Congo Red stained sections (CRPM). The results with CRPM between four reviewers were compared in 12 cases for studying inter observer reproducibility. 24 cases were also evaluated by ultrastructural study with electron microscopy (EM). Nine of thirty-three (27%) cases reported negative by polarizing microscopy had amyloidosis. Reanalysis of 12 mixed positive-negative cases, showed considerable inter-observer variability with frequent lack of agreement between four observers by CRPM alone (Cohen's Kappa index of 0.1, 95% CI -0.1 to 0.36). EM showed amyloid in the walls of small blood vessels in fibroadipose tissue in four out of nine cases (44%) with amyloidosis. In addition to poor inter-observer reproducibility, CRPM alone in cases with scant amyloid led to frequent false negative results (9 out of 9, 100%). For improved detection of AL, routine ultrastructural evaluation with EM of fat pad aspirates by evaluating at least 15 small blood vessels in the aspirated fibroadipose tissue is recommended. Given the high false negative rate for CRPM alone in early disease, routine reflex evaluation with EM is highly recommended to avert the invasive option of biopsying various organs in cases with high clinical suspicion for AL.


Shear-induced detachment of biofilms from hollow fiber silicone membranes.
A suite of techniques was utilized to evaluate the correlation between biofilm physiology, fluid-induced shear stress, and detachment in hollow fiber membrane aerated bioreactors. Two monoculture species biofilms were grown on silicone fibers in a hollow fiber membrane aerated bioreactors (HfMBR) to assess detachment under laminar fluid flow conditions. Both physiology (biofilm thickness and roughness) and nutrient mass transport data indicated the presence of a steady state mature biofilm after 3 weeks of development. Surface shear stress proved to be an important parameter for predicting passive detachment for the two biofilms. The average shear stress at the surface of Nitrosomonas europaea biofilms (54.5 ± 3.2 mPa) was approximately 20% higher than for Pseudomonas aeruginosa biofilms (45.8 ± 7.7 mPa), resulting in higher biomass detachment. No significant difference in shear stress was measured between immature and mature biofilms of the same species. There was a significant difference in detached biomass for immature vs. mature biofilms in both species. However, there was no difference in detachment rate between the two species.


Genetic Polymorphisms in Inflammasome-Dependent Innate Immunity among Pediatric Patients with Severe Renal Parenchymal Infections.
Inflammasome innate immune response activation has been demonstrated in various inflammatory diseases and microbial infections. However, to our knowledge, no study has examined the inflammasome-dependent pathways in patients with urinary tract infection. Defective or variant genes associated with innate immunity are believed to alter the host's susceptibility to microbial infection. This study investigated genetic polymorphisms in genes encoding inflammasomes and the subsequent released cytokines in pediatric patients with severe renal parenchymal infections. This study included patients diagnosed with acute pyelonephritis (APN) and acute lobar nephronia (ALN) who had no underlying disease or structural anomalies other than vesicoureteral reflux (VUR). Single nucleotide polymorphism (SNP) genotyping was performed in the genes associated with inflammasome formation and activation (NLRP3, CARD8) and subsequent IL-1β cytokine generation (IL-1β). A total of 40 SNPs were selected for initial genotyping. Analysis of samples from 48 patients each and 96 controls revealed that only nine SNPs (five SNPs in NLRP3; three SNPs in CARD8; one SNP in IL-1β) had heterozygosity rates >0.01. Hardy-Weinberg equilibrium was satisfied for the observed genotype frequencies of these SNPs. Analysis excluding patients with VUR, a well-known risk factor for severe UTIs, revealed a lower frequency of the CC genotype in NLRP3 (rs4612666) in patients with APN and ALN than in controls. Correction for multiple-SNP testing showed that the non-VUR subgroup of the APN+ALN combined patient groups remained significantly different from the control group (P < 0.0055). This study is the first to suggest that the inflammasome-dependent innate immunity pathway is associated with the pathogenesis of pediatric severe renal parenchymal infections. Further investigation is warranted to clarify its pathogenic mechanism.


All-optical 40 Gbits/s packet regeneration by means of cross-gain compression in a semiconductor optical amplifier.
We experimentally demonstrate all-optical reshaping of 40 Gbits/s packets by using cross-gain compression in a semiconductor optical amplifier (SOA). This scheme, which is based on cross-saturation effects between two conjugate signals copropagating in a single SOA, is wavelength preserving and polarization independent and does not suffer from any transient effect at packet edges. We report evidence of noise redistribution and packet reshaping by means of the bit-error rate versus threshold measurements for different input optical signal-to-noise ratios.


Transcriptional regulation of the stress response by mTOR.
The kinase mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation that integrates inputs from growth factor receptors, nutrient availability, intracellular ATP (adenosine 5'-triphosphate), and a variety of stressors. Since early works in the mid-1990s uncovered the role of mTOR in stimulating protein translation, this kinase has emerged as a rather multifaceted regulator of numerous processes. Whereas mTOR is generally activated by growth- and proliferation-stimulating signals, its activity can be reduced and even suppressed when cells are exposed to a variety of stress conditions. However, cells can also adapt to stress while maintaining their growth capacity and mTOR function. Despite knowledge accumulated on how stress represses mTOR, less is known about mTOR influencing stress responses. In this review, we discuss the capability of mTOR, in particular mTOR complex 1 (mTORC1), to activate stress-responsive transcription factors, and we outline open questions for future investigation.


Auditory neuroscience: sound segregation in the brainstem?
Separating a mixture of sounds into its constituent parts is a complex process likely to involve many processing stages. A new study suggests that the first steps in that process may occur already at the level of the first auditory processing centre in the brainstem.


Inhaled corticosteroids in children with persistent asthma: effects on growth.
Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth. To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment). We searched the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases to look for potential relevant unpublished studies. The literature search was conducted in January 2014. Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma. Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child. We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%. Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period. Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi(2) = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial. One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 μg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo. Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma. Do inhaled corticosteroids reduce growth in children with persistent asthma? Review question: We reviewed the evidence on whether inhaled corticosteroids (ICS) could affect growth in children with persistent asthma, that is, a more severe asthma that requires regular use of medications for control of symptoms. Treatment guidelines for asthma recommend ICS as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, parents and physicians always remain concerned about the potential negative effect of ICS on growth. Search date: We searched trials published until January 2014. Study characteristics: We included in this review trials comparing daily use of corticosteroids, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma. Twenty-five trials involving 8471 children with mild to moderate persistent asthma (5128 treated with ICS and 3343 treated with placebo or non-steroidal drugs) were included in this review. Eighty percent of these trials were conducted in more than two different centres and were called multi-centre studies; five were international multi-centre studies conducted in high-income and low-income countries across Africa, Asia-Pacifica, Europe and the Americas. Sixty-eight percent were financially supported by pharmaceutical companies. Meta-analysis (a statistical technique that combines the results of several studies and provides a high level of evidence) suggests that children treated daily with ICS may grow approximately half a centimeter per year less than those not treated with these medications during the first year of treatment. The magnitude of ICS-related growth reduction may depend on the type of drug. Growth reduction seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. Evidence provided by this review allows us to conclude that daily use of ICS can cause a small reduction in height in children up to 18 years of age with persistent asthma; this effect seems minor compared with the known benefit of these medications for asthma control. Eleven of 25 trials did not report how they guaranteed that participants had an equal chance of receiving ICS or placebo or non-steroidal drugs. All but six trials did not report how researchers were kept unaware of the treatment assignment list. However, this methodological limitation may not significantly affect the quality of evidence because the results remained almost unchanged when we excluded these trials from the analysis.


Pharmacokinetics of cis-dichloro-trans-dihydroxy-bis-isopropylamine platinum IV (iproplatinum, CHIP) in patients with normal and impaired renal function and following intraperitoneal administration.
CHIP is a quadrivalent platinum (Pt) complex, introduced clinically as a less toxic alternative to cis-platinum. The drug's major route of excretion is via the kidneys, and in this study the pharmacokinetics of unchanged CHIP, filterable Pt and total Pt have been determined following intravenous administration to patients with a range of renal function. Total Pt and filterable Pt in plasma decayed biexponentially and was fitted to a two-compartment model, whereas unchanged CHIP declined monoexponentially and was best fitted to a one-compartment model, according to Akaike's information criteria. There is a correlation between the unchanged CHIP clearance and 51Cr-EDTA clearance. The pharmacokinetics of CHIP was determined following intraperitoneal (i.p.) administration (dose, 150-300 mg m-2 4 h dwell time) and a regional advantage (peritoneal peak concentration/plasma peak concentration) of approximately 30 fold was seen. It is likely that the dose of CHIP will need to be reduced in patients with impaired renal function, and the use of i.p. CHIP in ovarian carcinoma warrants further study.


Comparison of diagnostic methods for diabetes mellitus based on prevalence of retinopathy in a Japanese population: the Hisayama Study.
The aims of this study were to compare the ability of tests measuring fasting plasma glucose, 2-h plasma glucose and HbA1c levels in predicting specific diabetic retinopathy, and to determine the cut-off level of each measurement for diagnosing diabetes in a Japanese population. In a total of 1637 subjects, fasting plasma glucose, 2-h plasma glucose and HbA1c levels were measured in a 75-g oral glucose tolerance test, and diabetic retinopathy was assessed by ophthalmic examination. We calculated receiver operating characteristic (ROC) curves as well as the prevalence of diabetic retinopathy by deciles of the distribution of these glycaemic measurements. Of the subjects, 37 (2.3%) had diabetic retinopathy. The prevalence of retinopathy dramatically increased in the tenth decile of each variable. Analysis with ROC curves showed that the optimal cut-off levels for diagnosis of diabetes were 6.4 mmol/l for fasting plasma glucose, 11.1 mmol/l for 2-h plasma glucose, and 5.7% for HbA1c. The sensitivities for the cut-off point of the three measurements were identical (86.5%), and the specificities were similar (fasting plasma glucose 87.3%; 2-h plasma glucose 89.6%; HbA1c 90.1%). The area under the ROC curve for 2-h plasma glucose (96.1%) was slightly but not significantly larger than that for fasting plasma glucose (90.0%) and that for HbA1c (94.5%). . Our findings suggest that measuring fasting plasma glucose or HbA1c is just as useful as measuring 2-h plasma glucose for the diagnosis of diabetes, and that the cut-off point for diagnostic fasting plasma glucose level is lower than that of the current diagnostic criteria.


Expanding Evolutionary Terminology Auditing with Historic Formal and Linguistic Intensions: A Case Study in SNOMED CT.
A method is described to use SNOMED CT's history mechanism as a means to compute how the formal and linguistic intensions of its concepts change over versions. As a result of this, it is demonstrated that the intended principle of concept permanence is not always adhered to. It is shown that the evolution of formal intensions can be monitored fully automatically and that the proposed procedure includes a method to suggest missing subsumers in a concept's transitive closure set by identifying mistakes that have been made in the past. Changes in linguistic intensions were found to be much more labor-intensive to identify. It is suggested that this could be improved if the history mechanism would come with more detailed motivations for change than the current and insufficiently used annotation to the effect that a fully specified name 'fails to comply with the current editorial guidance'.


Corticostriatal innervation of the patch and matrix in the rat neostriatum.
The distribution of rat corticostrial axons in the patch (striosome) and matrix compartments of the neostriatum was studied by using axonal labeling with biotinylated dextran amine (BDA) and identifying patch and matrix in the same section with calbindin immunocytochemistry. Small injections of BDA were made in the anterior cingulate, medial agranular, lateral agranular, or somatosensory cortex. Each area projected to both the patch and matrix compartments, except for the somatosensory cortex, which had only matrix projections. Within the remaining cortical areas, injections in layers Vb and VI preferentially labeled axons in patches whereas injections in layers III-Va preferentially labeled matrix axons. Axons from these injections formed varicosities preferentially, but not exclusively, in one compartment. There was a population of axons that crossed compartmental boundaries and arborized in both patch and matrix. Two distinct patterns of corticostriatal axonal arborizations were observed. Small, discrete foci of innervation were seen in the patch compartment and in some regions of the matrix. The focal arborizations in the matrix were observed through the rostrocaudal extent of the neostriatum but were most obvious in the caudal one-third. They resembled the matrisomes observed in cat and primate corticostriatal projections. The second pattern of innervation consisted of extended axonal arborizations that covered large regions of the rostral neostriatal matrix. These results support the concept of multiple classes of corticostriatal neurons having different targets within the neostriatum, following different topographical rules, and having different but overlapping distributions across cortical areas.


Asian and non-Asian origins of Mon-Khmer- and Mundari-speaking Austro-Asiatic populations of India.
In the present study, we analyzed 1,686 samples from 31 tribal populations of India for the mitochondrial DNA 9-base-pair deletion/insertion polymorphism, and characterized them based on the relevant mitochondrial DNA coding-region single nucleotide polymorphisms and hypervariable region I motifs, to test the genetic origins of the ethnically and linguistically heterogeneous Austro-Asiatic tribes of India. A comparative analysis of our results with the existing data suggests multiple origins of Austro-Asiatic tribes in India, and particularly the Asian and non-Asian origins of the Mon-Khmer and the Mundari populations. We also identified a novel subclade of haplogroup B in the Mon-Khmer Khasi tribes that distinguishes them from the Nicobarese, indicating two different waves of migration of the Mon-Khmer tribes in India.


Trophic effects of androgen: development and hormonal regulation of neuron number in a sexually dimorphic vocal motor nucleus.
In Xenopus laevis, the laryngeal motor nucleus (n. of cranial nerves IX-X) is part of a sexually differentiated, androgen sensitive neuromuscular system devoted to vocalization. Adult males have more n. IX-X neurons than females; however, during development of n. IX-X, the rate of neurogenesis does not appear to differ between the sexes. In this study, we explored the role of naturally occurring cell death in the development of this nucleus and asked whether cell death might be involved in establishing the sex difference in neuron number. Counts of n. IX-X neurons reveal that at tadpole stage 56, males and females have similar numbers of n. IX-X neurons, but by stage 64 male neuron numbers are greater. This sex difference arises owing to a greater net loss of neurons in females-males lose approximately 25% of their n. IX-X neurons between stages 56 and 64, while females lose approximately 47%. Sexual differentiation of n. IX-X neuron number coincides with a period of developmental cell death, as evidenced by terminal transferase-mediated dUTP nick-end labeling and the presence of pyknotic nuclei in n. IX-X. A role for gonadal hormones in controlling cell number was examined by treating tadpoles with exogenous androgen and determining the number of n. IX-X neurons at stage 64. Dihydrotestosterone (DHT) treatment from the beginning of the cell death period (stage 54) until stage 64 had no effect on the number of n. IX-X neurons in males but did significantly increase n. IX-X neuron number in females. This increase was sufficient to abolish the sex difference normally observed at stage 64. Although DHT induced increases in female neuron number, it did not induce increases in cell proliferation or addition of newly born neurons to n. IX-X. DHT may therefore have increased neuron number by protecting cells from death. We conclude that androgens can influence the survival of n. IX-X neurons during a period of naturally occurring cell death, and that this action of androgen is critical to the development of sex differences in n. IX-X neuron number.


The annexin A2/S100A10 system in health and disease: emerging paradigms.
Since its discovery as a src kinase substrate more than three decades ago, appreciation for the physiologic functions of annexin A2 and its associated proteins has increased dramatically. With its binding partner S100A10 (p11), A2 forms a cell surface complex that regulates generation of the primary fibrinolytic protease, plasmin, and is dynamically regulated in settings of hemostasis and thrombosis. In addition, the complex is transcriptionally upregulated in hypoxia and promotes pathologic neoangiogenesis in the tissues such as the retina. Dysregulation of both A2 and p11 has been reported in examples of rodent and human cancer. Intracellularly, A2 plays a critical role in endosomal repair in postarthroplastic osteolysis, and intracellular p11 regulates serotonin receptor activity in psychiatric mood disorders. In human studies, the A2 system contributes to the coagulopathy of acute promyelocytic leukemia, and is a target of high-titer autoantibodies in patients with antiphospholipid syndrome, cerebral thrombosis, and possibly preeclampsia. Polymorphisms in the human ANXA2 gene have been associated with stroke and avascular osteonecrosis of bone, two severe complications of sickle cell disease. Together, these new findings suggest that manipulation of the annexin A2/S100A10 system may offer promising new avenues for treatment of a spectrum of human disorders.


Association between Thyroid Function and Body Mass Index: A 10-Year Follow-Up.
We aimed to evaluate the association between change in thyroid function tests within the euthyroid range and body mass index (BMI) in persons with normal weight at baseline. This study investigated 1,100 normal-weight euthyroid persons in a population-based cohort study, Tehran Thyroid Study. BMI was calculated and serum concentrations of thyrotropin (TSH) and free T4 (FT4) were assayed at baseline and after 10 years of follow-up. We evaluated the relationship between thyroid and obesity based on 2 definitions for outcome: (1) a binary outcome as BMI <25 or ≥25 kg/m2, and (2) a multinomial outcome as normal BMI, overweight, and obese. A total of 569 women and 531 men, aged 36.3 ± 13.5 years, were included. Modified Poisson regression analysis for binary outcome, after adjustment for age, sex, smoking, and anti-thyroid peroxidase antibody status, revealed a negative association between delta serum FT4 and follow-up BMI (relative risk 0.55 [95% CI 0.37-0.80]) without any significant association between change in serum TSH and follow-up BMI. However, in multinomial logistic regression analysis, we found no relationship between delta serum FT4 or TSH and follow-up BMI categories, for either overweight or obese vs. normal-weight participants. In normal-weight euthyroid individuals, changes in serum concentrations of FT4, but not TSH, may contribute to change in body weight.


Getting personal: can systems medicine integrate scientific and humanistic conceptions of the patient?
The practicing doctor, and most obviously the primary care clinician who encounters the full complexity of patients, faces several fundamental but intrinsically related theoretical and practical challenges - strongly actualized by so-called medically unexplained symptoms (MUS) and multi-morbidity. Systems medicine, which is the emerging application of systems biology to medicine and a merger of molecular biomedicine, systems theory and mathematical modelling, has recently been proposed as a primary care-centered strategy for medicine that promises to meet these challenges. Significantly, it has been proposed to do so in a way that at first glance may seem compatible with humanistic medicine. More specifically, it is promoted as an integrative, holistic, personalized and patient-centered approach. In this article, we ask whether and to what extent systems medicine can provide a comprehensive conceptual account of and approach to the patient and the root causes of health problems that can be reconciled with the concept of the patient as a person, which is an essential theoretical element in humanistic medicine. We answer this question through a comparative analysis of the theories of primary care doctor Eric Cassell and systems biologist Denis Noble. We argue that, although systems biological concepts, notably Noble's theory of biological relativity and downward causation, are highly relevant for understanding human beings and health problems, they are nevertheless insufficient in fully bridging the gap to humanistic medicine. Systems biologists are currently unable to conceptualize living wholes, and seem unable to account for meaning, value and symbolic interaction, which are central concepts in humanistic medicine, as constraints on human health. Accordingly, systems medicine as currently envisioned cannot be said to be integrative, holistic, personalized or patient-centered in a humanistic medical sense.


Behavioral responses to orexin, orexin receptor gene expression, and spontaneous physical activity contribute to individual sensitivity to obesity.
There is significant variability in diet-induced obesity (DIO) among humans and rodents, which has been associated with differences in intrinsic spontaneous physical activity (SPA). The orexin neuropeptides positively modulate SPA through multiple brain sites, but the effects of DIO on orexin's activity are not well understood. In this study, we tested the hypothesis that DIO sensitivity is mediated by decreased SPA and changes in the function of the orexins. As a DIO model, we used male Sprague-Dawley rats fed a high-fat (HF; 45% kcal from fat) or a low-fat (LF; 10% kcal from fat) diet for 10 wk. We measured SPA before and after HF or LF feeding and expression of orexin receptors by real-time PCR after dietary treatments. We tested DIO effects on orexin signaling by measuring SPA after injection of orexin A in the rostral lateral hypothalamus (RLH) before and after 10 wk of HF feeding. Finally, we tested whether daily orexin A RLH injections prevent DIO caused by HF feeding. Our results show that resistance to DIO is associated with an increase in SPA, SPA after injection of orexin A in RLH, and orexin receptor expression in sites that mediate orexin's effect on SPA, including RLH. We show that daily injections of orexin peptide in RLH prevent DIO without altering food intake. We estimate that the energetic cost of SPA after orexin A RLH injection accounts for approximately 61% of the extra caloric intake associated with HF intake, suggesting additional effects of orexins. In summary, our results suggest that variability in DIO sensitivity is mediated through adaptations in the activity of the orexin peptides and their receptors.


Single-molecule transistors.
The use of a gate electrode allows us to gain deeper insight into the electronic structure of molecular junctions. It is widely used for spectroscopy of the molecular levels and its excited states, for changing the charge state of the molecule and investigating higher order processes such as co-tunneling and the Kondo effect. Gate electrodes have been implemented in several types of nanoscale devices such as electromigration junctions, mechanically controllable break junctions, and devices with carbon-based electrodes. Here we review the state-of-the-art in the field of single-molecule transitors. We discuss the experimental challenges and describe the advances made for the different approaches.


Efficacy of a long-acting formulation of ceftiofur crystalline-free acid for the treatment of naturally occurring infectious bovine keratoconjunctivitis.
To evaluate the efficacy of ceftiofur crystalline-free acid (CCFA) administered into the posterior aspect of an ear for treatment of corneal ulceration associated with naturally occurring infectious bovine keratoconjunctivitis (IBK). 78 beef calves located at Sierra Foothills Field Station (SFS) and 52 calves located at a commercial dairy (CD). All calves were from 3 to 9 months old. At each site, calves were randomly allocated to 1 of 2 treatment groups by use of a block design determined by corneal ulcer size. A single dose of CCFA (6.6 mg of ceftiofur equivalents/kg, s.c.) was administered into the posterior aspect of a pinna. A second group of calves received a single dose of vehicle (0.03 mL/kg, s.c.; controls). Corneal ulcers were photographed, and clinical signs were assessed in calves every 3 to 4 days for 21 days. A positive treatment effect was detected at SFS. Results at the CD were inconclusive because ulcer healing occurred rapidly in control and CCFA-treated calves. At SFS, treatment with CCFA resulted in shorter mean healing times, smaller corneal ulcer surface area measurements, amelioration of ocular discharge and photophobia, and a 50% increase in the percentage of calves healed by day 14. After adjustment for initial corneal ulcer size, treatment with CCFA resulted in a 4-fold increase in the odds of corneal ulcer healing by day 14, compared with controls. A single dose of CCFA administered into the posterior aspect of a pinna had a positive treatment effect against naturally occurring IBK in calves with corneal ulcerations.


Correlation analysis of alveolar bone loss in buccal/palatal and proximal surfaces in rats.
The aim was to correlate alveolar bone loss in the buccal/palatal and the mesial/distal surfaces of upper molars in rats. Thirty-three, 60-day-old, male Wistar rats were divided in two groups, one treated with alcohol and the other not treated with alcohol. All rats received silk ligatures on the right upper second molars for 4 weeks. The rats were then euthanized and their maxillae were split and defleshed with sodium hypochlorite (9%). The cemento-enamel junction (CEJ) was stained with 1% methylene blue and the alveolar bone loss in the buccal/palatal surfaces was measured linearly in 5 points on standardized digital photographs. Measurement of the proximal sites was performed by sectioning the hemimaxillae, restaining the CEJ and measuring the alveolar bone loss linearly in 3 points. A calibrated and blinded examiner performed all the measurements. Intraclass Correlation Coefficient revealed values of 0.96 and 0.89 for buccal/lingual and proximal surfaces, respectively. The Pearson Correlation Coefficient (r) between measurements in buccal/palatal and proximal surfaces was 0.35 and 0.05 for the group treated with alcohol, with and without ligatures, respectively. The best correlations between buccal/palatal and proximal surfaces were observed in animals not treated with alcohol, in sites both with and without ligatures (r = 0.59 and 0.65, respectively). A positive correlation was found between alveolar bone loss in buccal/palatal and proximal surfaces. The correlation is stronger in animals that were not treated with alcohol, in sites without ligatures. Areas with and without ligature-induced periodontal destruction allow detection of alveolar bone loss in buccal/palatal and proximal surfaces.


Structural and functional asymmetry of the neonatal cerebral cortex.
Features of brain asymmetry have been implicated in a broad range of cognitive processes; however, their origins are still poorly understood. Here we investigated cortical asymmetries in 442 healthy term-born neonates using structural and functional magnetic resonance images from the Developing Human Connectome Project. Our results demonstrate that the neonatal cortex is markedly asymmetric in both structure and function. Cortical asymmetries observed in the term cohort were contextualized in two ways: by comparing them against cortical asymmetries observed in 103 preterm neonates scanned at term-equivalent age, and by comparing structural asymmetries against those observed in 1,110 healthy young adults from the Human Connectome Project. While associations with preterm birth and biological sex were minimal, significant differences exist between birth and adulthood.


Manipulating propagating graphene plasmons at near field by shaped graphene nano-vacancies.
Surface plasmons in graphene have many promising properties, such as high confinement, low losses, and gate-tunability. However, it is also the high confinement that makes them difficult to excite due to their large momentum mismatch with free-space mid-infrared light. We propose to use shaped graphene nano-vacancies to compensate for the momentum mismatch, revealing its high flexibility in graphene plasmon (GP) excitation and manipulation. We first examine the electromagnetic standing waves generated with a pair of straight vacancies, in order to verify the excitation of GPs and to illustrate their tunability with gate voltage. Plasmonic lenses are then designed to achieve the super-focusing of mid-infrared light and to generate plasmonic vortices in graphene. A∼0.0125λ(0) hotspot is generated, far below the optical diffraction limit, hence revealing the capability of light control at deep-subwavelength scale.


Forecasting Influenza Outbreaks in Boroughs and Neighborhoods of New York City.
The ideal spatial scale, or granularity, at which infectious disease incidence should be monitored and forecast has been little explored. By identifying the optimal granularity for a given disease and host population, and matching surveillance and prediction efforts to this scale, response to emergent and recurrent outbreaks can be improved. Here we explore how granularity and representation of spatial structure affect influenza forecast accuracy within New York City. We develop network models at the borough and neighborhood levels, and use them in conjunction with surveillance data and a data assimilation method to forecast influenza activity. These forecasts are compared to an alternate system that predicts influenza for each borough or neighborhood in isolation. At the borough scale, influenza epidemics are highly synchronous despite substantial differences in intensity, and inclusion of network connectivity among boroughs generally improves forecast accuracy. At the neighborhood scale, we observe much greater spatial heterogeneity among influenza outbreaks including substantial differences in local outbreak timing and structure; however, inclusion of the network model structure generally degrades forecast accuracy. One notable exception is that local outbreak onset, particularly when signal is modest, is better predicted with the network model. These findings suggest that observation and forecast at sub-municipal scales within New York City provides richer, more discriminant information on influenza incidence, particularly at the neighborhood scale where greater heterogeneity exists, and that the spatial spread of influenza among localities can be forecast.


Parent and adolescent knowledge of HPV and subsequent vaccination.
Human papillomavirus (HPV) vaccination has been shown to have important health benefits, but vaccination rates are low. Parental and adolescent knowledge could possibly promote vaccination, but the relationship between knowledge and subsequent vaccination is unclear. This study examines how strongly HPV vaccination among high-risk adolescents is related to their or their parents' previous knowledge. A longitudinal cohort study enrolled participants from low-income, predominantly African American neighborhoods. Baseline questionnaires measuring knowledge of HPV and HPV vaccination, as well other variables, were completed by 211 adolescents and 149 parents of another adolescent sample. Adolescent vaccination was tracked prospectively for 12 months after baseline by using clinic reporting data. Analyses tested if parent or adolescent knowledge was associated with or predictive of adolescent HPV vaccination. On average, parents and adolescents answered slightly less than 50% of knowledge items correctly at baseline, with 5% of parents and 10% of adolescents not answering any knowledge items correctly. Within 12 months, 20 of 149 (13.4%) of the parents' daughters received an HPV vaccination and 32 of 211 (15.2%) of the other adolescent sample did so. Neither parental nor adolescent knowledge was associated with or predictive of adolescent vaccination. For example, when testing the relationship between adolescent vaccination and parental knowledge scores, all R(2) values were <0.005. Results were independent of available potential confounders. Those with higher levels of knowledge were not more likely to obtain vaccination for themselves or their daughters. Ideally, future interventions will target factors related to vaccination.


Targeting mitochondria to oppose the progression of nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by the excessive accumulation of triglycerides in hepatocytes. NAFLD is the most frequent chronic liver disease in developed countries, and is often associated with metabolic disorders such as obesity and type 2 diabetes. NAFLD definition encompasses a spectrum of chronic liver abnormalities, ranging from simple steatosis (NAFL), to steatohepatitis (NASH), significant liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD, therefore, represents a global public health issue. Mitochondrial dysfunction occurs in NAFLD, and contributes to the progression to the necro-inflammatory and fibrotic form (NASH). Disrupted mitochondrial function is associated with a decrease in the energy levels and impaired redox balance, and negatively affects cell survival by altering overall metabolism and subcellular trafficking. Such events reduce the tolerance of hepatocytes towards damaging hits, and favour the injurious effects of extra-cellular factors. Here, we discuss the role of mitochondria in NAFLD and focus on potential therapeutic approaches aimed at preserving mitochondrial function.


Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome. Insights from the LUNG SAFE Study.
Noninvasive ventilation (NIV) is increasingly used in patients with acute respiratory distress syndrome (ARDS). The evidence supporting NIV use in patients with ARDS remains relatively sparse. To determine whether, during NIV, the categorization of ARDS severity based on the PaO2/FiO2 Berlin criteria is useful. The LUNG SAFE (Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure) study described the management of patients with ARDS. This substudy examines the current practice of NIV use in ARDS, the utility of the PaO2/FiO2 ratio in classifying patients receiving NIV, and the impact of NIV on outcome. Of 2,813 patients with ARDS, 436 (15.5%) were managed with NIV on Days 1 and 2 following fulfillment of diagnostic criteria. Classification of ARDS severity based on PaO2/FiO2 ratio was associated with an increase in intensity of ventilatory support, NIV failure, and intensive care unit (ICU) mortality. NIV failure occurred in 22.2% of mild, 42.3% of moderate, and 47.1% of patients with severe ARDS. Hospital mortality in patients with NIV success and failure was 16.1% and 45.4%, respectively. NIV use was independently associated with increased ICU (hazard ratio, 1.446 [95% confidence interval, 1.159-1.805]), but not hospital, mortality. In a propensity matched analysis, ICU mortality was higher in NIV than invasively ventilated patients with a PaO2/FiO2 lower than 150 mm Hg. NIV was used in 15% of patients with ARDS, irrespective of severity category. NIV seems to be associated with higher ICU mortality in patients with a PaO2/FiO2 lower than 150 mm Hg. Clinical trial registered with www.clinicaltrials.gov (NCT 02010073).


Communication between pathogenic T cells and myeloid cells in neuroinflammatory disease.
Clinical and experimental data suggest that T helper (TH) cells are involved in the pathogenicity of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS), but it is unlikely that they are directly responsible for the observed demyelination and axonal loss. Instead, the cell population that targets the destruction of oligodendrocytes and axons, and the mechanism exploited by central nervous system (CNS)-invading encephalitogenic TH cells to instruct these cells to mediate tissue damage, are still under debate. Mature myeloid cells form a prominent component of the neuroinflammatory infiltrates and are the suspected culprits behind the CNS injury due to their arsenal of toxic factors. Here, we describe the process of encephalitogenic TH cell activation followed by their entry into the CNS and discuss how pathogenic TH cells influence the myeloid compartment.


Brain-Derived Neurotrophic Factor and Supraoptic Vasopressin Neurons in Hyponatremia.
Hyponatremia due to elevated arginine vasopressin (AVP) secretion increases mortality in liver failure patients. The mechanisms causing dysregulation of AVP secretion are unknown. Our hypothesis is that inappropriate AVP release associated with liver failure is due to increased brain-derived neurotrophic factor (BDNF) in the supraoptic nucleus (SON). BDNF diminishes GABAA inhibition in SON AVP neurons by increasing intracellular chloride through tyrosine receptor kinase B (TrkB) activation and downregulation of K+/Cl- cotransporter 2 (KCC2). This loss of inhibition could increase AVP secretion. This hypothesis was tested using shRNA against BDNF (shBDNF) in the SON in bile duct ligated (BDL) male rats. All BDL rats had significantly increased liver weight (p < 0.05; 6-9) compared to shams. BDL rats with control -shRNA injections (BDL scrambled [SCR]) developed hyponatremia with increased plasma AVP and copeptin (CPP; all p < 0.05; 6-9) compared to sham groups. This is the first study to show that phosphorylation of TrkB is significantly increased along with significant decrease in phosphorylation of KCC2 in BDL SCR rats compared to the sham rats (p < 0.05;6-8). Knockdown of BDNF in the SON of BDL rats (BDL shBDNF) significantly increased plasma osmolality and hematocrit compared to BDL SCR rats (p < 0.05; 6-9). The BDL shBDNF rats had significant (p < 0.05; 6-9) decreases in plasma AVP and CPP concentration compared to BDL SCR rats. The BDNF knockdown also significantly blocked the increase in TrkB phosphorylation and decrease in KCC2 phosphorylation (p < 0.05; 6-8). The results indicate that BDNF produced in the SON contributes to increased AVP secretion and hyponatremia during liver failure.


Increased plasma ghrelin suppresses insulin release in wethers fed with a high-protein diet.
Ghrelin is a multifunctional peptide that promotes an increase of food intake and stimulates GH secretion. Ghrelin secretion is regulated by nutritional status and nutrients. Although a high-protein (HP) diet increases plasma ghrelin secretion in mammals, the mechanisms and the roles of the elevated ghrelin concentrations due to a HP diet have not been fully established. To clarify the roles of elevated acylated ghrelin upon intake of a HP diet, we investigated the regulation of ghrelin concentrations in plasma and tissues in wethers fed with either the HP diet or the control (CNT) diet for 14 days, and examined the action of the elevated plasma ghrelin by using a ghrelin-receptor antagonist. The HP diet gradually increased the plasma acylated-ghrelin concentrations, but the CNT diet did not. Although the GH concentrations did not vary significantly across the groups, an injection of ghrelin-receptor antagonist enhanced insulin levels in circulation in the HP diet group. In the fundus region of the stomach, the ghrelin levels did not differ between the HP and CNT diet groups, whereas ghrelin O-acyltransferase mRNA levels were higher in the group fed with HP diet than those of the CNT diet group were. These results indicate that the HP diet elevated the plasma ghrelin levels by increasing its synthesis; this elevation strongly suppresses the appearance of insulin in the circulation of wethers, but it is not involved in GH secretion. Overall, our findings indicate a role of endogenous ghrelin action in secretion of insulin, which acts as a regulator after the consumption of a HP diet.


Colorectal endoscopic submucosal dissection is here to stay.
Endoscopic mucosal resection (EMR) or mucosectomy and endoscopic submucosal dissection (ESD) are both techniques that have modified the therapeutic outlook of superficial gastrointestinal tract lesions and neoplasms. EMR is used for the en-bloc excision of lesions smaller than 2-3 cm or the piecemeal resection of larger ones. In theory, ESD achieves higher rates of en-bloc resections as compared to EMR with a lower rate of recurrence; however, it shows a higher percentage of complications, particularly in inexperienced centers or in centers at the start of their learning curve.


Insights from a general practice service evaluation supporting a lower carbohydrate diet in patients with type 2 diabetes mellitus and prediabetes: a secondary analysis of routine clinic data including HbA1c, weight and prescribing over 6 years.
In a single general practice (GP) surgery in England, there was an eightfold increase in the prevalence of type 2 diabetes (T2D) in three decades with 57 cases and 472 cases recorded in 1987 and 2018, respectively. This mirrors the growing burden of T2D on the health of populations round the world along with healthcare funding and provision more broadly. Emerging evidence suggests beneficial effects of carbohydrate-restricted diets on glycaemic control in T2D, but its impact in a 'real-world' primary care setting has not been fully evaluated. Advice on a lower carbohydrate diet was offered routinely to patients with newly diagnosed and pre-existing T2D or prediabetes between 2013 and 2019, in the Norwood GP practice with 9800 patients. Conventional 'one-to-one' GP consultations were used, supplemented by group consultations, to help patients better understand the glycaemic consequences of their dietary choices with a particular focus on sugar, carbohydrates and foods with a higher Glycaemic Index. Those interested were computer coded for ongoing audit to compare 'baseline' with 'latest follow-up' for relevant parameters. By 2019, 128 (27%) of the practice population with T2D and 71 people with prediabetes had opted to follow a lower carbohydrate diet for a mean duration of 23 months. For patients with T2D, the median (IQR) weight dropped from of 99.7 (86.2, 109.3) kg to 91.4 (79, 101.1) kg, p<0.001, while the median (IQR) HbA1c dropped from 65.5 (55, 82) mmol/mol to 48 (43, 55) mmol/mol, p<0.001. For patients with prediabetes, the median (IQR) HbA1c dropped from 44 (43, 45) mmol/mol to 39 (38, 41) mmol/mol, p<0.001. Drug-free T2D remission occurred in 46% of participants. In patients with prediabetes, 93% attained a normal HbA1c. Since 2015, there has been a relative reduction in practice prescribing of drugs for diabetes leading to a T2D prescribing budget £50 885 per year less than average for the area. This approach to lower carbohydrate dietary advice for patients with T2D and prediabetes was incorporated successfully into routine primary care over 6 years. There were statistically significant improvements in both groups for weight, HbA1c, lipid profiles and blood pressure as well as significant drug budget savings. These results suggest a need for more empirical research on the effects of lower carbohydrate diet and long-term glycaemic control while recording collateral impacts to other metabolic health outcomes.


Strength of TCR signal determines the costimulatory requirements for Th1 and Th2 CD4+ T cell differentiation.
Differentiation of naive CD4 T cells into cytokine-secreting effector Th1 and Th2 cells is influenced by several factors. We have previously reported that the affinity of antigen for TCR and antigen dose can influence the differentiation of Th1 and Th2 cells. Several in vitro and in vivo models have demonstrated a role for the costimulatory molecules, B7-1 (CD80) and B7-2 (CD86), in the generation of distinct effector T cell responses. To determine whether the strength of TCR signaling controls the involvement of CD28 costimulation in selective CD4 T cell differentiation, naive CD4 T cells bearing a transgenic TCR are primed by a weak or strong TCR signal (signal 1) in the presence or absence of B7 costimulatory molecules (signal 2). In this system, IL-4-producing Th2 cells are generated by priming with a weak but not a strong TCR signal. Th2 cell differentiation is dependent on CD28/B7 interactions in that disruption of CD28/B7 interactions inhibits the priming of Th2 cells and cross-linking CD28 with anti-CD28 antibody augments the priming of Th2 cells. In contrast, however, IL-4-producing Th2 cells cannot be generated by priming with a strong TCR signal even in the presence of strong costimulation or high doses of IL-2. Thus, our results suggest that naive CD4 T cells are receptive to CD28-dependent IL-4 production only if they receive a weak TCR signal.


Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept.
Structure-activity relationship and crystallographic data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor-like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chemical modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors.


Social, familial and psychological risk factors for mood and anxiety disorders in childhood and early adulthood: a birth cohort study using the Danish Registry System.
A number of social, familial, and psychological factors have been identified to explain the onset of mood and anxiety disorders among adolescent and young adult populations. The purpose of this study is to identify the shared and unique predictors of anxiety and mood disorders by simultaneously testing a range of established psychosocial risk factors. A national birth cohort of the Danish population born in 1984 and tracked over the course of the first 21 years of their life was used in the current study (n = 54,458). Psychosocial risk factors including paternal and maternal history of any anxiety and mood disorder, parental history of self-harming behaviour, advanced paternal age, gender, urban dwelling, economic deprivation, family dissolution, and childhood adversity were used to predict diagnosis of both anxiety and mood disorders from ages 10 to 21 years. Binary logistic regression analysis showed that being female and a parental history of a mood or anxiety disorder are the strongest predictors of both disorders. Economic deprivation, and family dissolution also increase likelihood of both disorders. Urban dwelling and childhood adversity are predictors of anxiety disorders but not mood disorders. Between the ages of 10 and 21 years, anxiety and mood disorders share many common risk factors. However, urban dwelling and childhood adversity appear to be unique predictors of anxiety disorders. Results suggest there is no dominant factor in the prediction of either disorder, rather the accumulation of different risk factors is most deleterious.


Prevalence of tuberculosis, hepatitis C virus, and HIV in homeless people: a systematic review and meta-analysis.
100 million people worldwide are homeless; rates of mortality and morbidity are high in this population. The contribution of infectious diseases to these adverse outcomes is uncertain. Accurate estimates of prevalence data are important for public policy and planning and development of clinical services tailored to homeless people. We aimed to establish the prevalence of tuberculosis, hepatitis C virus, and HIV in homeless people. We searched PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature for studies of the prevalence of tuberculosis, hepatitis C virus, and HIV in homeless populations. We also searched bibliographic indices, scanned reference lists, and corresponded with authors. We explored potential sources of heterogeneity in the estimates by metaregression analysis and calculated prevalence ratios to compare prevalence estimates for homeless people with those for the general population. We identified 43 eligible surveys with a total population of 63,812 (59 736 homeless individuals when duplication due to overlapping samples was accounted for). Prevalences ranged from 0·2% to 7·7% for tuberculosis, 3·9% to 36·2% for hepatitis C virus infection, and 0·3% to 21·1% for HIV infection. We noted substantial heterogeneity in prevalence estimates for tuberculosis, hepatitis C virus infection, and HIV infection (all Cochran's χ(2) significant at p<0·0001; I(2)=83%, 95% CI 76-89; 95%, 94-96; and 94%, 93-95; respectively). Prevalence ratios ranged from 34 to 452 for tuberculosis, 4 to 70 for hepatitis C virus infection, and 1 to 77 for HIV infection. Tuberculosis prevalence was higher in studies in which diagnosis was by chest radiography than in those which used other diagnostic methods and in countries with a higher general population prevalence than in those with a lower general prevalence. Prevalence of HIV infection was lower in newer studies than in older ones and was higher in the USA than in the rest of the world. Heterogeneity in prevalence estimates for tuberculosis, hepatitis C virus, and HIV suggests the need for local surveys to inform development of health services for homeless people. The role of targeted and population-based measures in the reduction of risks of infectious diseases, premature mortality, and other adverse outcomes needs further examination. Guidelines for screening and treatment of infectious diseases in homeless people might need to be reviewed. The Wellcome Trust.


Optimisation of ex vivo memory B cell expansion/differentiation for interrogation of rare peripheral memory B cell subset responses.
Background: Human memory B cells play a vital role in the long-term protection of the host from pathogenic re-challenge. In recent years the importance of a number of different memory B cell subsets that can be formed in response to vaccination or infection has started to become clear. To study memory B cell responses, cells can be cultured ex vivo, allowing for an increase in cell number and activation of these quiescent cells, providing sufficient quantities of each memory subset to enable full investigation of functionality. However, despite numerous papers being published demonstrating bulk memory B cell culture, we could find no literature on optimised conditions for the study of memory B cell subsets, such as IgM + memory B cells. Methods: Following a literature review, we carried out a large screen of memory B cell expansion conditions to identify the combination that induced the highest levels of memory B cell expansion. We subsequently used a novel Design of Experiments approach to finely tune the optimal memory B cell expansion and differentiation conditions for human memory B cell subsets. Finally, we characterised the resultant memory B cell subpopulations by IgH sequencing and flow cytometry. Results: The application of specific optimised conditions induce multiple rounds of memory B cell proliferation equally across Ig isotypes, differentiation of memory B cells to antibody secreting cells, and importantly do not alter the Ig genotype of the stimulated cells. Conclusions: Overall, our data identify a memory B cell culture system that offers a robust platform for investigating the functionality of rare memory B cell subsets to infection and/or vaccination.


Characterization of a polyclonal cytolytic T lymphocyte response to human immunodeficiency virus in persons without clinical progression.
A total of 82 human immunodeficiency virus (HIV)-1-specific cytolytic T lymphocyte (CTL) clones were isolated and characterized from 5 HIV-infected subjects, utilizing multiple HLA class I alleles. B62-restricted, HIV-1 gag-specific CTL clones isolated from a single blood sample from 1 subject used four different Vbeta gene rearrangements. Multiple CTL clones could be isolated from the same time point directed against HIV-1 gag, nef, and env from 1 subject. A prospective analysis resulted in the isolation of CTL clones from 1 subject directed against multiple HIV-1 antigens, including the same highly conserved nef peptide, over a 1-year period, in the absence of detectable circulating viral plasma RNA. These data suggest that in some persons without clinical progression and low levels of circulating HIV-1, the CTL response is polyclonal, is directed against multiple HIV-1 proteins, including highly conserved peptides within these proteins, and is maintained over time.


Quantifying canopy complexity and effects on productivity and resilience in late-successional hemlock-hardwood forests.
The regrowing forests of eastern North America have been an important global C sink over the past 100+ years, but many are now transitioning into late succession. The consequences of this transition are unclear due to uncertainty around the C dynamics of old- growth forests. Canopy structural complexity (CSC) has been shown to be an important source of variability in C dynamics in younger forests (e.g., in productivity and resilience to disturbance), but its role in late-successional forests has not been widely addressed. We investigated patterns of CSC in two old-growth forest landscapes in the Upper Peninsula of Michigan, USA, to assess factors associated with CSC and its influence on productivity and disturbance resilience (to moderate-severity windstorm). CSC was quantified using a portable below-canopy LiDAR (PCL) system in 65 plots that also had long-term (50-70+ years). inventory data, which were used to quantify aboveground net primary productivity (ANPP), disturbance history, and stand characteristics. We found high and variable CSC relative to younger forests across a suite of PCL-derived metrics. Variation in CSC was driven by species composition and size structure, rather than disturbance history or site characteristics. Recent moderate severity wind disturbance decreased plot-scale CSC, but increased stand-scale variation in CSC. The strong positive correlation between CSC and productivity illustrated in younger forests was not present in undisturbed portions of these late-successional ecosystems. Moderate severity disturbance appeared to reestablish the positive link between CSC and productivity, but this relationship was scale and severity dependent. A positive CSC-productivity relationship was evident at the plot scale with low-severity, dispersed disturbance, but only at a patch scale in more severely disturbed areas. CSC does not appear to strongly correlate With variation in productivity in undisturbed old-growth forests, but may play a very important (and scale/severity-dependent) role in their response to disturbance. Understanding potential, drivers and consequences of CSC in late-successional forests will inform management focused on promoting complexity and old-growth conditions, and illustrate potential inipacts of such treatments on regional C dynamics.


Impact of Adding Oseltamivir to Usual Care on Quality-Adjusted Life-Years During Influenza-Like Illness.
The ALIC4E trial has shown that oseltamivir reduces recovery time while increasing the risk of nausea. This secondary analysis of the ALIC4E trial aimed to determine the gain in quality-adjusted life-years (QALYs) associated with adding oseltamivir to usual primary care in patients presenting with influenza-like illness (ILI). Patients with ILI were recruited during the influenza season (2015-2018) in 15 European countries. Patients were assigned to usual care with or without oseltamivir through stratified randomization (age, severity, comorbidities, and symptom onset). Patients' health status was valued with the EQ-5D and visual analog scale (VAS) for up to 28 days. Average EQ-5D and VAS scores over time were estimated for both treatment groups using one-inflated beta regression in children (<13 years old) and adults (≥13 years old). QALY gain was calculated as the difference between the groups. Sensitivity analysis considered the value set to convert EQ-5D answers to summary scores and the follow-up period. In adults, oseltamivir gained 0.0006 (95% confidence interval 0.0002-0.0010) QALYs, whereas no statistically significant gain was found in children (14-day follow-up, EQ-5D). QALY gains were statistically significant in patients aged ≥65 years, patients without relevant comorbidities, or patients experiencing symptoms for ≤48 hours. Using VAS and accounting for 28-day follow-up resulted in higher QALY gain. QALY gain owing to oseltamivir is limited compared with other diseases, and its clinical meaningfulness remains to be determined. Further analysis is needed to evaluate whether QALY gain and its impact on ILI treatment cost render oseltamivir cost-effective.


Novel method for evaluation of anaerobic germination in rice and its application to diverse genetic collections.
Direct seeding saves time and labour in the cultivation of rice. However, seedling establishment is often unstable, and yields are lower than in transplanting. Anaerobic germination (AG) is a key trait for improvement of direct seeding of rice. We established a simple and reliable method of evaluating AG in rice breeding. We germinated seeds in distilled water or deoxygenated water and measured coleoptile length several days later; compared the results of each method with survival rate in flooded soil; and used the anoxic water method for QTL analysis and for testing cultivars. Coleoptile elongation in anoxic water and survival rate in flooded soil were significantly correlated (r = 0.879, P < 0.01). A significant QTL, likely to be a major gene (AG1), was found in chromosome segment substitution lines and in a backcrossed F2 population derived from tolerant and sensitive lines. Diverse rice genetic resources were classified into tolerant or sensitive accession groups reflecting their ecotypes. Our study revealed that anoxic water evaluation method saves space and time in a stable environment compared with flooded soil evaluation. It is applicable to QTL analysis and isolation of genes underlying anaerobic germination.


A molecular electron density theory study of the insertion of CO into frustrated Lewis pair boron-amidines: a [4 + 1] cycloaddition reaction.
The insertion of CO into hydrogenated boron-amidine 1 yielding five-membered diazaborolone (5DAB) 3 has been studied within the molecular electron density theory (MEDT) at the DFT ωB97X-D/6-311G(d,p) level. This is a domino process comprised of two consecutive reactions: (i) the dehydrogenation of 1 yielding the frustrated Lewis pair (FLP) boron-amidine 4, which quickly equilibrates with four-membered diazaborolone (4DAB) 2; and (ii) the addition of CO into FLP 4, yielding the final 5DAB 3. Analysis of the Gibbs free energies indicates that the extrusion of H2 demands a high ΔG≠ of 28.6 kcal·mol-1, being endergonic by 6.7 kcal·mol-1. The subsequent addition of CO into FLP 4 presents a low ΔG≠ of 15.0 kcal·mol-1; formation of 5DAB 3 being exergonic by -5.7 kcal·mol-1 from hydrogenated boron-amidine 1. An analysis of the bonding changes along the insertion of CO in a smaller FLP model indicates that this reaction can be considered a [4 + 1] cycloaddition reaction taking place via a five-membered pseudocyclic transition state associated with a two-stage one-step mechanism. Analysis of the conceptual DFT reactivity indices suggests that the initial attack of CO on FLP 4 is an acid/base process in which the carbenoid carbonyl character allows CO to participate as a Lewis base, rather than a nucleophilic/electrophilic interaction. The results arising from the analysis of the Parr functions, however, coincide with this behaviour.


Effects of 4-aminopyridine on nystagmus and vestibulo-ocular reflex in ataxia-telangiectasia.
Ataxia-telangiectasia (A-T) is a progressive neurodegenerative disorder with prominent eye movement deficits localizing to the cerebellum. We sought to determine if 4-aminopyridine (4-AP), which putatively enhances the precision of Purkinje neurons, could improve the disorders of eye movements and vestibular function in A-T. The influence of 4-AP on disorders of eye movements and vestibular function was studied in four A-T patients. The effects on the cerebellar control of vestibulo-ocular reflex (VOR) was quantitatively assessed by the decay time constant of per- and post-rotational nystagmus during constant velocity en bloc rotations. The length of the VOR time constant determines the fidelity of the vestibular velocity storage, a neural mechanism that increases the bandwidth of VOR under cerebellar control. The VOR time constant was not increased in A-T patients. The latter is explained by the extent of cerebellar lesion as previously described in A-T and other cerebellar disorders. Nevertheless, 4-AP shortened the VOR time constant during horizontal rotations. Severe disinhibition of velocity storage in subjects with putatively profound cerebellar degeneration manifest periodic alternating nystagmus (PAN). Among two A-T subjects who manifested PAN, 4-AP reduced the peak slow phase velocity of the more severely affected individual and abrogated the PAN in the other. Two A-T subjects manifested horizontal and vertical spontaneous nystagmus (SN) in primary gaze, 4-AP reduced its slow phase velocity. We conclude that in subjects with A-T 4-AP has a prominent effect on the ocular motor and vestibular deficits that are ascribed to the loss of cerebellar Purkinje neurons.


The effectiveness of selective thoracic fusion for treating adolescent idiopathic scoliosis: a systematic review protocol.
The objective of this review is to assess the effectiveness of selective thoracic fusion as a form of treatment in adolescent idiopathic scoliosis (AIS). This will be compared with all other forms of operative management for major structural thoracic curves. Scoliosis is defined as a lateral curvature of the spine of at least 10 degrees, as measured by the Cobb angle. It can be categorized into three broad categories - neuromuscular, congenital and idiopathic. Of these categories, idiopathic is by far the most common, and is a diagnosis of exclusion. Idiopathic scoliosis can then be further broken down into categories based on age of onset. Of these, AIS (children presenting at 10 years of age or older) accounts for 80-85% of cases.Scoliosis curves have a proven complex deformity, consisting of a three-dimensional deformity involving the coronal, sagittal and rotational planes. Each curve (of which there may be many in one patient) can be described with an apex (the vertebra with the greatest lateral distance from the centre of the spine) and the two vertebrae at the end of the curve (named the end vertebrae). The Cobb angle, measured by the intersection of parallel lines from the endplates of the superior and inferior end vertebrae, is the standard way of quantifying the magnitude of scoliosis curves.Major or primary curves are the largest abnormal curves as classified by the Cobb angle. These curves are almost always structural. In addition, secondary or tertiary curves are described as structural if the Cobb angle cannot be reduced to under 25 degrees, on side bending radiographs. Due to the permanent nature of physiological and morphological change of the vertebral bodies and ligaments, structural curves will usually progress as the patient matures, usually at 1 degree per year after maturity. Non-structural curves usually do not progress as the patient matures; instead they are hypothesized to be a product of the body's instinctive nature to provide truncal balance.For many years spinal surgeons have been debating whether a more rigid and straighter spine or a mobile and less straight spine provides better outcomes. The treatment for AIS can include both an operative and non-operative approach. However when the Cobb angle is above 40, the likelihood of curve progression is high and surgical treatment is warranted.Although technology has advanced, the primary goals for operative management have remained constant. The primary goals of surgical treatment in AIS should be to optimize coronal and sagittal correction and avoid further curve progression. This involves not only correction of the major primary curve but also any minor (secondary) curves, while maintaining adequate thoracic kyphosis and lumbar lordosis. Ideally, a balance should be struck between fusing the lowest number of mobile segments and properly correcting the existing deformity. This is where selective spinal fusion has a role to play.The premise of selective thoracic fusion is that after fixation of the primary thoracic curve, there is spontaneous coronal correction of the unfused lumbar curve. Thus the thoracic curve can be exclusively fused to allow for a more mobile lumbar spine. This has been described in studies since the 1950s. However since then, results have varied greatly in the extent of spontaneous lumbar correction. Studies have shown that the degree of spontaneous correction of the lumbar spine is somewhat close to the correction of the thoracic curve; however the extent of optimal correction that can be achieved is uncertain.The alternative to selective thoracic infusion involves complete fusion of both the primary thoracic and secondary lumbar curve in a consecutive series. This can be done via either an anterior or a posterior approach. Complete fusion gives better correction of both curves. It also diminishes the risk of coronal decompensation, adding on phenomenon, junctional kyphosis and eventual revision surgery. However this needs to be calculated against the risk of sagittal decompensation, increased risk of lumbar degeneration and chronic back pain, all of which seem to be more prevalent in patients with fusion of both curves.Another goal of surgical intervention is the need to avoid complications. Examples of complications of selective spinal fusion include: junctional kyphosis, coronal imbalance, adding-on and revision surgery. Junctional kyphosis is described as kyphosis of over 10 degrees more than pre-operative measurements. This is measured by the angle between the inferior end plate of the highest instrumented vertebrae and the superior end plate of the vertebra two levels higher. Coronal imbalance is when the distance between the C7 plumb line and the central sacral vertical line is greater than 2 centimeters. The adding-on phenomenon is described as progression or extension of the primary curve after fusion.In 2001, Lenke et al reported a classification for AIS that has been able to identify those patients who may benefit from a selective spinal fusion (1C, 2C, 5C). A three-tiered approach is used with the Lenke classification system involving curve type, lumbar modifier and sagittal modifier. Firstly the curves of the spinal column (proximal thoracic, main thoracic and thoracolumbar/lumbar) are classified as structural or non-structural before a lumbar modifier (A, B, C) based on the distance from the central sacral vertical line and the lumbar apical vertebra is applied. Further classification is then undertaken measuring the kyphosis of the thoracic curve T5-T12 (-, N, +).Lenke proposed that a selective thoracic fusion could be undertaken when the primary curve is structural and the compensatory lumbar curve is non-structural and that additionally certain radiological criteria were met such as the Cobb angle magnitude, apical vertebral translation and rotation. These are all objective markers that can be accurately measured on plain radiographs, with good inter-and intra-observer reliability.However all surgeons do not routinely accept these treatment guidelines. It has been reported that only approximately 49-67% of experienced surgeons are performing a selective thoracic fusion in Lenke 1C curves. This may be due to the fear of complications (of which the rates are relatively unknown) and well as misunderstanding of how much correction can be achieved by the un-fused compensatory lumbar curve. A search of PubMed, the Cochrane Library, PROSPERO and the JBI Databases of Systematic Reviews and Implementation Reports found no current systematic review assessing the effectiveness of selective thoracic fusion compared to other approaches. As such, the aim of this review is to evaluate and critically appraise available evidence on selective thoracic fusion in order to provide a suitable estimate of the radiological and functional outcomes of this type of surgical intervention as well as the approximate complication rate in order to give patients correct information prior to their providing their informed consent.


Thin, stubby or mushroom: spine pathology in Alzheimer's disease.
Since their first description by Ramon y Cajal at the end of the 19th century, dendritic spines have been proposed as important sites of neuronal contacts and it has been suggested that changes in the activity of neurons directly affect spine morphology. In fact, since then it has been shown that about 90% of excitatory synapses end on spines. Recent data indicate that spines are highly dynamic structures and that spine shape correlates with the strength of synaptic transmission. Furthermore, several mental disorders including Alzheimer's disease (AD) are associated with spine pathology suggesting that spine alterations play a central role in mental deficits. The aim of this review is to provide an overview about the current knowledge on spine morphology and function as well as about different experimental models to analyze spine changes and dynamics. The second part concentrates on disease-relevant factors that are associated with AD and which lead to spine alterations. In particular, data that provide evidence that Abeta oligomers or fibrillar Abeta deposits influence spine morphology and function will be presented and the contribution of tau pathology will be discussed. The review ends with the discussion of potential mechanisms how disease-relevant factors influence dendritic spines and whether and how spine changes could be therapeutically suppressed or reversed.


COVID-19: emerging challenges for oncological surgery.
After the initial description of COVID-19 in Wuhan, China, Italy was hit first in Europe and the impact has been rapidly enlarging. In early April 2020, at the epidemic peak, there were more than 33,000 patients hospitalized including more than 4,000 in Intensive Care Units (ICU). On May 15, the confirmed cases in Italy approached 224,000 patients (5th highest number worldwide), with more than 31,000 deaths (3rd highest number worldwide). Non-urgent, non-cancer procedures were stopped to reallocate nurses and anesthetists to face the COVID-19 emergency. The timeline of the progressive involvement by COVID-19 patients of 36 hospitals referrals for surgical oncology in Italy was shown in this article. Only emergency, and elective oncological procedures were allowed with obvious limitations in terms of numbers of operable cases. Criteria for prioritizing oncologic patients waiting for surgery were released by each region, mainly issuing main factors for decision making, biological aggressiveness or symptomatic disease, the interval from the latest treatment, and the risk of un-resectability if delayed. However, the lack of facilities mostly influenced the decision or not to proceed. The risk of operating on oncological patients with ongoing SARS-CoV-2 syndrome is real, and a preoperative flowchart for ruling out this occurrence has been promoted. In our center, the day before surgery, chest CT and swab testing have been introduced, and a similar behavior has been recommended prior to patients' discharge. The care of patients addressed for surgical oncology should be featured by dedicated paths to secure proper and prompt disease management.


Siglecs facilitate HIV-1 infection of macrophages through adhesion with viral sialic acids.
Human immunodeficiency virus type 1 (HIV-1) infects macrophages effectively, despite relatively low levels of cell surface-expressed CD4. Although HIV-1 infections are defined by viral tropisms according to chemokine receptor usage (R5 and X4), variations in infection are common within both R5- and X4-tropic viruses, indicating additional factors may contribute to viral tropism. Using both solution and cell surface binding experiments, we showed that R5- and X4-tropic HIV-1 gp120 proteins recognized a family of I-type lectin receptors, the Sialic acid-binding immunoglobulin-like lectins (Siglec). The recognition was through envelope-associated sialic acids that promoted viral adhesion to macrophages. The sialic acid-mediated viral-host interaction facilitated both R5-tropic pseudovirus and HIV-1(BaL) infection of macrophages. The high affinity Siglec-1 contributed the most to HIV-1 infection and the variation in Siglec-1 expression on primary macrophages from different donors was associated statistically with sialic acid-facilitated viral infection. Furthermore, envelope-associated sialoglycan variations on various strains of R5-tropic viruses also affected infection. Our study showed that sialic acids on the viral envelope facilitated HIV-1 infection of macrophages through interacting with Siglec receptors, and the expression of Siglec-1 correlated with viral sialic acid-mediated host attachment. This glycan-mediated viral adhesion underscores the importance of viral sialic acids in HIV infection and pathogenesis, and suggests a novel class of antiviral compounds targeting Siglec receptors.


New paradigms in the treatment of restless legs syndrome.
Restless legs syndrome (RLS) is a common neurologic disorder occurring in 3% to 15% of the general population, which contributes to poor quality of life. Many patients go undiagnosed for years after onset of symptoms, which delays or prevents effective treatment. Extensive research over the past decade has led to a better understanding of RLS and effective treatment options. This review encompasses the most recently published pathophysiology, epidemiology, criteria for diagnosis, and clinical drug efficacy trials to provide clinicians with the information to effectively manage RLS. A comprehensive review of the medical literature was conducted and original research articles pertaining to RLS were evaluated. The pathophysiology of primary RLS is associated with dopaminergic dysfunction and abnormal brain iron metabolism. Secondary RLS is most often a consequence of iron deficiency. The prevalence of primary RLS is twofold greater in women and increases with age in men and women, although onset of symptoms may occur in up to 45% of patients before age 20 years. Patients may present with a variety of complaints including sleep disruption. Several studies have demonstrated the efficacy of low-dose levodopa and dopamine agonists. Ropinirole is the most widely studied. Other drugs that may help control symptoms include gabapentin, opioids, and clonazepam. Clinicians must be aware of the high prevalence of RLS, the potential for onset before age 20, and the various clinical presentations. Dopamine agonists are first-line therapy and provide symptom relief in 70% to 100% of patients.


Hormonal and other factors in relation to survival among breast cancer patients.
We have examined the relationship between all-cause mortality and various hormonal and other factors in over 1,200 women with breast cancer recruited into 2 consecutive case-control studies between 1969 and 1984. The age at diagnosis ranged from 24 to 59 years, and the majority (74%) were pre-menopausal at diagnosis. Analyses were based on follow-up to 1 January 1994, by which time 608 (50%) of the women had died. Of the factors examined, weight was most strongly associated with survival, with a significant increase in the risk of death with increasing weight. Two hormonal factors, time since last birth and time since last oral contraceptive use, were also independently associated with survival. All of these associations remained after adjustment for stage and histological nodal status. Our findings provide new evidence to suggest that reproductive factors and exogenous hormones in the form of oral contraceptives may influence survival in women with breast cancer, even after differences in stage and nodal status have been taken into account.


Levetiracetam compared to valproic acid: plasma concentration levels, adverse effects and interactions in aneurysmal subarachnoid hemorrhage.
Both valproic acid and levetiracetam are anti-epileptic drugs, often used either alone or in combination. The present study compares valproate (VPA) with levetiracetam (LEV) as an intravenous (i.v.) anticonvulsant treatment in intensive care patients suffering from aneurysmal subarachnoid hemorrhage (aSAH) with a high risk of seizures. A prospective, single-center patient registry of 35 intensive care unit (ICU) patients with onset seizure and/or high risk of seizures underwent an anticonvulsive, first-line single treatment regimen either with VPA or LEV. Plasma concentrations (pc), interactions between drugs in the ICU context, adverse effects and seizure occurrences were observed and recorded. A significant decrease in the pc in patients treated with LEV was observed after changing from intravenous (160±51μmol/l) to enteral liquid application (113±58μmol/l), corresponding to a 70.3% bioavailability for enteral liquid applications. The pc in VPA patients decreased significantly, from (491±138μmol/l) to (141±50μmol/l), after adding meropenem to the therapy (p<0.05). Three epileptic seizures occurred during anticonvulsive therapy in the LEV group, and two in the VPA group, including one non-convulsive status epilepticus (NCSE). Though this finding needs further verification, the enteral liquid application of levetiracetam seems to be associated with lower bioavailability than the common oral application of levetiracetam. The use of the antibiotic drug meropenem together with valproic acid leads to lower pc levels in patients treated with of valproic acid. For clinical practice, this indicates the need to monitor the levels of valproic acid in combination with meropenem.


Association of midlife stroke risk with structural brain integrity and memory performance at older ages: a longitudinal cohort study.
Cardiovascular health in midlife is an established risk factor for cognitive function later in life. Knowing mechanisms of this association may allow preventative steps to be taken to preserve brain health and cognitive performance in older age. In this study, we investigated the association of the Framingham stroke-risk score, a validated multifactorial predictor of 10-year risk of stroke, with brain measures and cognitive performance in stroke-free individuals. We used a large (N = 800) longitudinal cohort of community-dwelling adults of the Whitehall II imaging sub-study with no obvious structural brain abnormalities, who had Framingham stroke risk measured five times between 1991 and 2013 and MRI measures of structural integrity, and cognitive function performed between 2012 and 2016 [baseline mean age 47.9 (5.2) years, range 39.7-62.7 years; MRI mean age 69.81 (5.2) years, range 60.3-84.6 years; 80.6% men]. Unadjusted linear associations were assessed between the Framingham stroke-risk score in each wave and voxelwise grey matter density, fractional anisotropy and mean diffusivity at follow-up. These analyses were repeated including socio-demographic confounders as well as stroke risk in previous waves to examine the effect of residual risk acquired between waves. Finally, we used structural equation modelling to assess whether stroke risk negatively affects cognitive performance via specific brain measures. Higher unadjusted stroke risk measured at each of the five waves over 20 years prior to the MRI scan was associated with lower voxelwise grey and white matter measures. After adjusting for socio-demographic variables, higher stroke risk from 1991 to 2009 was associated with lower grey matter volume in the medial temporal lobe. Higher stroke risk from 1997 to 2013 was associated with lower fractional anisotropy along the corpus callosum. In addition, higher stroke risk from 2012 to 2013, sequentially adjusted for risk measured in 1991-94, 1997-98 and 2002-04 (i.e. 'residual risks' acquired from the time of these examinations onwards), was associated with widespread lower fractional anisotropy, and lower grey matter volume in sub-neocortical structures. Structural equation modelling suggested that such reductions in brain integrity were associated with cognitive impairment. These findings highlight the importance of considering cerebrovascular health in midlife as important for brain integrity and cognitive function later in life (ClinicalTrials.gov Identifier: NCT03335696).


Effect of intermolecular orientation upon proton transfer within a polarizable medium.
Ab initio calculations are used to investigate the proton transfer process in bacteriorhodopsin. HN = CH2 serves as a small prototype of the Schiff base while HCOO- models its carboxylate-containing counterion and HO- the hydroxyl group of water of tyrosine, leading to the HCOO-..H+..NHCH2 and HO-..H+..NHCH2 complexes. In isolation, both complexes prefer a neutral pair configuration wherein the central proton is associated with the anion. However, the Schiff base may be protonated in the former complex, producing the HCOO-..+HNHCH2 ion pair, when there is a high degree of dielectric coupling with an external polarizable medium. Within a range of intermediate level coupling, the equilibrium position of the proton (on either the carboxylate or Schiff base) can be switched by suitable changes in the intermolecular angle. pK shift resulting from a 60 degrees reorientation are calculated to be some 5-12 pK U within the coupling range where proton transfers are possible. The energy barrier to proton transfer reinforces the ability of changes in angle and dielectric coupling to induce a proton transfer.


Communication: On the consistency of approximate quantum dynamics simulation methods for vibrational spectra in the condensed phase.
Including quantum mechanical effects on the dynamics of nuclei in the condensed phase is challenging, because the complexity of exact methods grows exponentially with the number of quantum degrees of freedom. Efforts to circumvent these limitations can be traced down to two approaches: methods that treat a small subset of the degrees of freedom with rigorous quantum mechanics, considering the rest of the system as a static or classical environment, and methods that treat the whole system quantum mechanically, but using approximate dynamics. Here, we perform a systematic comparison between these two philosophies for the description of quantum effects in vibrational spectroscopy, taking the Embedded Local Monomer model and a mixed quantum-classical model as representatives of the first family of methods, and centroid molecular dynamics and thermostatted ring polymer molecular dynamics as examples of the latter. We use as benchmarks D2O doped with HOD and pure H2O at three distinct thermodynamic state points (ice Ih at 150 K, and the liquid at 300 K and 600 K), modeled with the simple q-TIP4P/F potential energy and dipole moment surfaces. With few exceptions the different techniques yield IR absorption frequencies that are consistent with one another within a few tens of cm(-1). Comparison with classical molecular dynamics demonstrates the importance of nuclear quantum effects up to the highest temperature, and a detailed discussion of the discrepancies between the various methods let us draw some (circumstantial) conclusions about the impact of the very different approximations that underlie them. Such cross validation between radically different approaches could indicate a way forward to further improve the state of the art in simulations of condensed-phase quantum dynamics.