Arthroscopic anterior cruciate ligament reconstruction with bone-patellar tendon-bone allograft or autograft. A prospective study with an average follow up of 4 years.
A prospective study was performed with 36 patients who underwent an anterior cruciate ligament (ACL) reconstruction with the use of a fresh-frozen bone-patellar tendon-bone (BPTB) allograft. A group of 26 patients who underwent the same operation conducted by the same surgeon in the same period but with the use of an autograft BPTB served as controls. The average follow-up was 46 (range 30-64) months in the allograft group and 52 (range 42-74) months in the autograft group. The allograft group consisted of 17 men and 19 women with a mean age of 28 years (mean trauma to reconstruction interval was 55 months). The autograft group consisted of 9 men and 17 women with a mean age of 28 years (mean trauma to reconstruction interval was 30 months). Clinical and functional evaluation was performed according to the IKDC guidelines. Analysis of tibial tunnel placement with respect to the Blumenstaat line on a lateral radiograph with the knee in hyperextension was done in relation to an extension deficit and clinical score. In the autograft group 18 (70%) patients had a normal or nearly normal knee and 8, a fair result. In the allograft group 30 (85%) patients had a normal or nearly normal knee, 5 (13%) patients had a fair result, and one (2%) knee was poor. The difference between the two groups was not significant. The allograft BPTB is a good alternative graft in ACL reconstruction.


Prognostic Value of Peak Oxygen Uptake in Patients Supported With Left Ventricular Assist Devices (PRO-VAD).
The purpose of this study was to examine whether peak oxygen uptake (pVO2) and other cardiopulmonary exercise test (CPET)-derived variables could predict intermediate-term mortality in stable continuous flow LVAD recipients. pVO2 is a cornerstone in the selection of patients for heart transplantation, but the prognostic power of pVO2 obtained in patients treated with a left ventricular assist device (LVAD) is unknown. We collected data for pVO2 and outcomes in adult LVAD recipients in a retrospective, multicenter study and evaluated cutoff values for pVO2 including: 1) values above or below medians; 2) grouping patients in tertiles; and 3) pVO2 ≤14 ml/kg/min if the patient was not treated with beta-blockers (BB) or pVO2 ≤12 ml/kg/min if the patient was taking BB therapy. Nine centers contributed data from 450 patients. Patients were 53 ± 13 years of age; 78% were male; body mass index was 25 ± 5 kg/m2 with few comorbidities (stroke: 11%; diabetes: 18%; and peripheral artery disease: 4%). The cause of heart failure (HF) was most often nonischemic (66%). Devices included were the HeartMate II and 3 (Abbott); and Heartware ventricular assist devices Jarvik and Duraheart (Medtronic). The index CPET was performed at a median of 189 days (154-225 days) after LVAD implantation, and mean pVO2 was 14.1 ± 5 ml/kg/min (47% ± 14% of predicted value). Lower pVO2 values were strongly associated with poorer survival regardless of whether patients were analyzed for absolute pVO2 in ml/kg/min, pVO2 ≤12 BB/14 ml/kg/min, or as a percentage of predicted pVO2 values (P ≤ 0.001 for all). For patients with pVO2 >12 BB/14 and ventilation/carbon dioxide relationship (VE/VCO2) slope <35, the 1-year survival was 100%. Even after LVAD implantation, pVO2 has prognostic value, similar to HF patients not supported by mechanical circulatory support devices. (PROgnostic Value of Exercise Capacity Measured as Peak Oxygen Uptake [pVO2] in Recipients of Left Ventricular Assist Devices [PRO-VAD]; NCT04423562).


Tendovaginitis with arthritis, a new syndrome of chickens: isolation and characterization of an infectious agent.
The findings with an infectious agent isolated from cases of tendovaginitis or arthritis of chickens were as follows:- Cultures, stains, and darkfield studies of material containing this agent for spirochetes, bacteria, and pleuropneumonia-like organisms were negative. The yolk sac was the preferred route of inoculation, all of the embryos dying in 4 to 12 days. The agent passed through a bacteria-retaining filter, but with a drop in titer. Antibiotic sensitivity tests revealed that the agent was most sensitive to the tetracycline antibiotics, less sensitive to chloromycetin, dihydrostreptomycin, and resistant to penicillin. From electron micrographs it was concluded that the agent is a rigid, dense, coccobacillus from 0.2 micro to 0.5 micro, in size. The agent produced a cytopathogenic effect in tissue cultures of chick heart fibroblasts. The agent had no gross effect on suckling or newly weaned mice, pigs, or guinea pigs. Reasons for suggesting that the agent is most similar to a rickettsia or possibly a large virus are discussed.


Transcription by T7 RNA polymerase of DNA containing abasic sites.
The effects of abasic (AP) sites on RNA synthesis were studied in vitro, using T7 RNA polymerase and a plasmid template containing a T7 promoter. The presence of increasing numbers of AP sites caused a progressive decline in RNA synthesis. The average RNA chain length, calculated from the ratio of initiation to chain elongation, decreased with increasing numbers of AP sites, revealing that complete blocks must occur during synthesis. The probability that RNA polymerase would be blocked at an AP site in the DNA template strand was estimated to be 0.3 in our experimental conditions. These results demonstrate that RNA synthesis by T7 RNA polymerase is inhibited by AP sites and that readthrough of the lesion occurs more frequently than premature chain termination. Chemical reduction of AP sites in the template did not change the block/bypass pattern.


Accuracy Assessment of Two Electromagnetic Articulographs: Northern Digital Inc. WAVE and Northern Digital Inc. VOX.
Purpose This study compares two electromagnetic articulographs manufactured by Northern Digital, Inc.: the NDI Wave System (from 2008) and the NDI Vox-EMA System (from 2020). Method Four experiments were completed: (a) comparison of statically positioned sensors, (b) tracking dynamic movements of sensors manipulated using a motor-driven LEGO apparatus, (c) tracking small and large movements of sensors mounted in a rigid bar manipulated by hand, and (d) tracking movements of sensors rotated on a circular disc. We assessed spatial variability for statically positioned sensors, variability in the transduced Euclidean distances between sensor pairs, and missing data rates. For sensors tracking circular movements, we compared the fit between fitted ideal circles and actual trajectories. Results The average sensor pair tracking error (i.e., the standard deviation of the Euclidean distances) was 1.37 mm for the WAVE and 0.12 mm for the VOX during automated trials at the fastest speed, and 0.35 mm for the WAVE and 0.14 mm for the VOX during the tracking of large manual movements. The average standard deviation of the fitted circle radii charted by manual circular disc movements was 0.72 mm for the WAVE sensors and 0.14 mm for the VOX sensors. There was no significant difference between the WAVE and the VOX in the number of missing frames. Conclusions In general, the VOX system significantly outperformed the WAVE on measures of both static precision and dynamic accuracy (automated and manual). For both systems, positional precision and spatial variability were influenced by the sensors' position relative to the field generator unit (worse when further away). Supplemental Material https://doi.org/10.23641/asha.14787846.


Intra-individual consistency in the quality of neonatal general movements.
The qualitative assessment of general movements (GMs) proved to be a highly sensitive and specific diagnostic tool for the assessment of the integrity of the young nervous system. It is essential that the quality of GMs remains consistent in an individual during a given recording at a certain date. The aim of the study was to investigate the intra-individual consistency of the quality of GMs during one recording. 39 preterm infants were recorded at least twice; some were recorded three times. In all, 88 recordings were available but three recordings were excluded due to frequent crying, seizures or hypokinesia. Three scorers assessed 2-3 sequences of these 85 GM recordings. The inter-scorer agreement was high (kappa 0.85-0.94). Intra-individual consistency revealed a kappa of 0.90 with a 95% CI (0.51, 1.00) for preterm GMs, 0.96 with a 95% CI (0.57, 1.00) for writhing GMs, and 0.92 with a 95% CI (0.53, 1.00) for fidgety GMs. The individual quality of GMs remains consistent for a neonate or young infant at a certain date.


Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches.
Growing evidence suggests psilocybin, a naturally occurring psychedelic, is a safe and promising pharmacotherapy for treatment of mood and substance use disorders when administered as part of a structured intervention. In most trials to date, psilocybin dose has been administered on a weight-adjusted basis rather than the more convenient procedure of administering a fixed dose. The present post hoc analyses sought to determine whether the subjective effects of psilocybin are affected by body weight when psilocybin is administered on a weight-adjusted basis and when psilocybin is administered as a fixed dose. We analyzed acute subjective drug effects (mystical, challenging, and intensity) associated with therapeutic outcomes from ten previous studies (total N = 288) in which psilocybin was administered in the range 20 to 30 mg/70 kg (inclusive). Separate multivariate regression analyses examined the relationships between demographic variables including body weight and subjective effects in participants receiving 20 mg/70 kg (n = 120), participants receiving 30 mg/70 kg (n = 182), and participants whose weight-adjusted dose was about 25 mg (to approximate the fixed dose that is currently being evaluated in registration trials for major depressive disorder) (n = 103). In the 20 mg/70 kg and 30 mg/70 kg weight-adjusted groups, and in the fixed dose group, no significant associations were found between subjective effects and demographic variables including body weight or sex. Across a wide range of body weights (49 to 113 kg) the present results showed no evidence that body weight affected subjective effects of psilocybin. These results suggest that the convenience and lower cost of administering psilocybin as a fixed dose outweigh any potential advantage of weight-adjusted dosing.


School violence and teacher professional disengagement.
Most studies of school violence have focused on students. Consequently, precursors and consequences of violence experienced by teachers are less well documented. Previous research indicates that (a) verbal victimization, student misbehaviour and perceived violence at school impair teacher emotional well-being, (b) support from principal and colleagues reduces these difficulties and fosters well-being, (c) well-being impacts on professional involvement. However, it is still not clear how those variables relate to each other. To test and compare - through structural equation modelling - two models of the relationships between perceived school support, exposure to school violence, subjective well-being and professional disengagement. To test - through multigroup analysis - the buffering effect of school support between school violence and well-being. Participants in this study were 487 French-speaking teachers (57% female) randomly selected from 24 secondary schools in Belgium. Participants completed a questionnaire on school leadership, relationships with colleagues, verbal victimization, students' misbehaviour, perceived violence, depression, somatization, anxiety and professional disengagement. The results support a model in which perceived school support has a direct effect on exposure to school violence, subjective well-being and professional disengagement, while the effect of school violence on disengagement is totally mediated by well-being. No evidence of a moderating effect of school support was found. The results of this study suggest that the negative emotional impact of some forms of school violence could be an important factor in a teacher's intention to leave, and that school support could be even more important for both teacher emotional well-being and professional disengagement.


Antipyrine plasma half-life. In vivo indicator of oxidative metabolic capability in Rhesus monkeys (Macaca mulatta).
Antipyrine plasma half-life (APH) has been used as an indicator of hepatic oxidase activity in rhesus monkeys (Macaca mulatta). Plasma disappearance of 14CH3-N-antipyrine (AP) was measured radiometrically. AP and 3 metabolites were detected using high pressure liquid chromatography. APH was assessed during a 300-day control period and following phenobarbital (PB) pretreatments. Significant interindividual variability was observed requiring that animals be used as their own controls. PB (15 mg/kg i.m., 2/day X 4 days) reduced mean APH values from 81 +/- 12 to 41 +/- 2 min. PB treatment also increased monooxygenase catalyzed aldrin epoxidation, dihydroisodrin hydroxylation and benzo(a)pyrene oxidation measured using liver biopsy homogenates. These parameters permit 'continual' assessment of HMO activity in rhesus monkeys under a variety of experimental conditions.


Efficacy and Safety of Dapagliflozin According to Background Use of Cardiovascular Medications in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical Trial.
Dapagliflozin was shown to reduce the cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes. However, data are limited on the relationship of the effect and safety with the concurrent use of CV medications in patients with type 2 diabetes. To assess whether the cardiorenal efficacy and safety of dapagliflozin were consistent with and without background use of CV medications commonly used for heart failure (HF) and kidney disease in patients with type 2 diabetes. This study is a prespecified secondary analysis of DECLARE-TIMI 58, which was a randomized trial of dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and either atherosclerotic disease or multiple risk factors for CV disease. Patients were stratified by baseline use of the following CV medications: angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARBs), β-blockers, diuretics, and mineralocorticoid receptor antagonists (MRAs). The study was conducted from May 2013 to September 2018, and data were evaluated for this analysis from February 2021 to May 2022. Dapagliflozin or placebo. The outcomes of interest were the composite of CV death or hospitalization for HF (HHF), HHF alone, and a kidney-specific composite outcome (persistent ≥40% decrease in estimated glomerular filtration rate [eGFR], end-stage kidney disease, or kidney-related death). Among 17 160 patients, 13 950 (81%) used ACEI/ARBs, 9030 (53%) used β-blockers, 6205 (36%) used diuretics, and 762 (4%) used MRAs at baseline. Changes in blood pressure and eGFR at 48 months with dapagliflozin compared with placebo did not differ regardless of concurrent therapy (placebo-corrected change, -1.6 mm Hg [95% CI, -4.2 to 1.0] to -2.6 mm Hg [95% CI, -3.3 to -2.9]; P > .05 for each interaction). Dapagliflozin consistently reduced the risk of CV death/HHF, HHF alone, and the kidney-specific composite outcome regardless of background use of selected medications (hazard ratio [HR] range: HR, 0.50; 95% CI, 0.39-0.63; to HR, 0.82; 95% CI, 0.72-0.95; P > .05 for each interaction). In patients receiving ACEI/ARBs + β-blockers + diuretics (n = 4243), dapagliflozin reduced the risk of CV death/HHF and of the kidney-specific outcome by 24% (HR, 0.76; 95% CI, 0.62-0.93) and 38% (HR, 0.62; 95% CI, 0.44-0.87), respectively. There were no significant treatment interactions with the concomitant CV medications for adverse events of volume depletion, acute kidney injury, or hyperkalemia (range: HR, 0.12; 95% CI, 0.02-0.99; to HR, 1.04; 95% CI, 0.83-1.32; P > .05 for each interaction). Dapagliflozin consistently reduced the risk of CV and kidney outcomes irrespective of background use of various CV medications without any treatment interaction for key safety events. These data show the clinical benefit and safety of dapagliflozin in a broad range of patients with type 2 diabetes regardless of background therapy. ClinicalTrials.gov Identifier: NCT01730534.


Undue influence of weight and shape: is it distinct from body dissatisfaction and concern about weight and shape?
Three cognitive constructs are risk factors for eating disorders: undue influence of weight and shape, concern about weight and shape, and body dissatisfaction (BD). Undue influence, a diagnostic criterion for eating disorders, is postulated to be closely associated with self-esteem whereas BD is postulated to be closely associated with body mass index (BMI). We understand less about the relationships with concern about weight and shape. The aim of the current investigation was examine the degree of overlap across these five phenotypes in terms of latent genetic and environmental risk factors in order to draw some conclusions about the similarities and differences across the three cognitive variables. A sample of female Australian twins (n=1056, including 348 complete pairs), mean age 35 years (S.D.=2.11, range 28-40), completed a semi-structured interview about eating pathology and self-report questionnaires. An independent pathways model was used to investigate the overlap of genetic and environmental risk factors for the five phenotypes. In terms of variance that was not shared with other phenotypes, self-esteem emerged as being separate, with 100% of its variance unshared with the other phenotypes, followed by undue influence (51%) and then concern (34%), BD (28%) and BMI (32%). In terms of shared genetic risk, undue influence and concern were more closely related than BD, whereas BMI and BD were found to share common sources of risk. With respect to environmental risk factors, concern, BMI and BD were more closely related to each other than to undue influence.


Sports-Related Sudden Cardiac Injury or Death.
Symptoms such as syncope and chest pain, especially if they are accompanied by palpitations or occur with exercise in any combination, require cardiac evaluation before adolescent athletes are allowed to return to the sports field. Some life-threatening conditions will likely be associated with a family history of HCM or LQTS, but the family history may not be discovered at the first medical visit. A family history of CPVT, for example, is hard to elicit unless this diagnosis has already been established in an affected family member. The keys will be the timing of symptoms and the documentation of arrhythmia with exercise. The ECG at baseline in CPVT may be deceptively normal. Hypertrophic cardiomyopathy is progressive, so evaluation during early childhood may be negative. Long QT syndrome may not always result in an abnormal ECG, even in genetically positive individuals. A high index of suspicion is needed to make these diagnoses, especially if the family history is not available.


Differences between and within genders in caregiving strain: a comparison between caregivers of demented and non-caregivers of non-demented elderly people.
Fifty-two caregivers for demented and 66 non-caregivers for non-demented elderly were investigated both within a gender and between genders. All participants were relatives and a burden questionnaire was used. The results showed that there was not always a difference between the caregivers for demented and the non-caregivers for non-demented elderly which may indicate that being a relative, even to a non-demented elderly, has obviously its own problems and importance. However, results showed more significant differences between female caregivers and female non-caregivers than between male caregivers and male non-caregivers, with females caring for a demented elderly suffering most strain. Their strain was exhibited by health problems, conflicts in the family, strained relations with family and others, a less positive outlook and limits in social support because of the caregiving situation. When investigating the group of male caregivers and male non-caregivers, it was found that males caring for a demented elderly person experienced a lack of positive outlook and a need for social support. The elderly person's residence in the group of caregivers for demented elderly people and in the group of non-caregivers for non-demented elderly people did not, however, appear to indicate any significant differences.


Viable spores of Coccidioides posadasii Δcps1 are required for vaccination and provide long lasting immunity.
Coccidioidomycosis is a systemic fungal infection for which a vaccine has been sought for over fifty years. The avirulent Coccidioides posadasii strain, Δcps1, which is missing a 6 kb gene, showed significant protection in mice. These studies explore conditions of protection in mice and elucidate the immune response. Mice were vaccinated with different doses and viability states of Δcps1 spores, challenged with virulent C. posadasii, and sacrificed at various endpoints, dependent on experimental objectives. Tissues from vaccinated mice were harvested for in vitro elucidation of immune response. Vaccination with viable Δcps1 spores was required for protection from lethal challenge. Viable spore vaccination produced durable immunity, lasting at least 6 months, and prolonged survival (≥6 months). The C. posadasii vaccine strain also protected mice against C. immitis (survival ≥ 6 months). Cytokines from infected lungs of vaccinated mice in the first four days after Cp challenge showed significant increases of IFN-γ, as did stimulated CD4+ spleen cells from vaccinated mice. Transfer of CD4+ cells, but not CD8+ or B cells, reduced fungal burdens following challenge. IFN-γ from CD4+ cells in vaccinated mice indicates a Th1 response, which is critical for host control of coccidioidomycosis.


HEMOGLOBIN AND PLASMA PROTEIN PRODUCTION : VARIOUS PROTEINS, CONCENTRATES, AND DIGESTS INFLUENCE BLOOD PROTEIN PRODUCTION IN ANEMIA AND HYPOPROTEINEMIA.
Given healthy dogs, fed abundant iron and protein-free or low protein diets, with sustained anemia and hypoproteinemia due to bleeding, we can study the capacity of these animals to produce simultaneousiy new hemoglobin and plasma protein. The reserve stores of blood protein-producing materials in this way are largely depleted, and levels of 6 to 8 gm. per cent for hemoglobin and 4 to 5 gm. per cent for plasma protein can be maintained for considerable periods of time. These dogs are very susceptible to infection and to injury by many poisons. Dogs tire of these diets and loss of appetite terminates many experiments. These incomplete experiments are not recorded in the present paper but give supporting evidence in harmony with those tabulated. Under these conditions (double depletion) the dogs use effectively the proteins listed above-egg, lactalbumin, meat, beef plasma, and digests of various food proteins and hemoglobin. Egg protein at times seems to favor slightly the production of plasma protein when compared with the average response (Tables 1 and 2). Various digests and concentrates compare favorably with good food proteins in the production of new hemoglobin and plasma protein in these doubly depleted dogs. Whole beef plasma by mouth is well utilized and the production of new hemoglobin is, if anything, above the average-certainly plasma protein production is not especially favored. "Modified" beef plasma by vein causes fatal anaphylaxis (Table 4). Hemoglobin digests are well used by mouth to form both hemoglobin and plasma protein. Supplementation by amino acids is recorded. Methionine in one experiment may have been responsible for a better protein output and digest utilization (Table 7).


Citizenship, immigration, and the European social project: rights and obligations of individuality.
As envisioned by T.H. Marshall, social citizenship was a corrective to the injustices caused by the capitalist market. Entitlements and protections guaranteed by the welfare state would prevent social and economic exclusions that civil and political rights, on their own, simply could not. Such protections consequently would ensure social cohesion and solidarity, as well as a productive economy and market. European welfare states successfully followed this formula for the most part of the post-World War II period, however the last couple of decades witnessed significant changes. For one, the very meaning of 'work' and 'worker' on which the welfare state is based has changed - flexibility, risk, and precariousness have become defining elements of working life. The welfare state itself has gone through a transformation as well, increasingly moving away from a system of 'passive benefits' to 'social investment' in human capital. These developments are coupled with an emphasis on education in 'active citizenship', which envisions participatory individuals who are adaptable in an increasingly globalized society, and ready to contribute at local, national and transnational levels. The emergent European social project draws on a re-alignment between these strands: work, social investment, and active participation. In this article, I consider the implications of this project for immigrant populations in Europe in particular and for the conceptions of citizenship and human rights in general. In contrast to the recent commentary on the neoliberal turn and the return of nation-state centered citizenship projects in Europe, I emphasize the broader trends in the post-World War II period that indicate a significant shift in the very foundations of good citizenship and social justice. The new social project transpires a citizenship model that privileges individuality and its transformative capacity as a collective good. Thus, while expanding the boundaries and forms of participation in society, this project at the same time burdens the individual, rather than the state, with the obligation of ensuring social cohesion and solidarity, disadvantaging not only non-European migrants but also the 'lesser' Europeans. The new social project brings into focus the relationship between universalistic individual rights and their effective exercise. I conclude that rather than treating human rights and citizenship as a dichotomy we should pay attention to their entangled practice in order to understand the contingent accomplishments and possible expansions of citizenship in Europe.


Stabilization with the Dynamic Cervical Implant: a novel treatment approach following cervical discectomy and decompression.
Although cervical total disc replacement (TDR) has shown equivalence or superiority to anterior cervical discectomy and fusion (ACDF), potential problems include nonphysiological motion (hypermobility), accelerated degeneration of the facet joints, particulate wear, and compromise of the mechanical integrity of the endplate during device fixation. Dynamic cervical stabilization is a novel motion-preserving concept that facilitates controlled, limited flexion and extension, but prevents axial rotation and lateral bending, thereby reducing motion across the facet joints. Shock absorption of the Dynamic Cervical Implant (DCI) device is intended to protect adjacent levels from accelerated degeneration. The authors conducted a prospective evaluation of 53 consecutive patients who underwent DCI stabilization for the treatment of 1-level (n = 42), 2-level (n = 9), and 3-level (n = 2) cervical disc disease with radiculopathy or myelopathy. Forty-seven patients (89%) completed all clinical and radiographic outcomes at a minimum of 24 months. Clinical outcomes consisted of Neck Disability Index (NDI) and visual analog scale (VAS) scores, neurological function at baseline and at latest follow-up, as well as patient satisfaction. Flexion-extension radiography was evaluated for device motion, implant migration, subsidence, and heterotopic ossification. Cervical sagittal alignment (Cobb angle), functional spinal unit (FSU) angle, and range of motion (ROM) at index and adjacent levels were evaluated with WEB 1000 software. The NDI score, VAS neck and arm pain scores, and neurological deficits were significantly reduced at each postoperative time point compared with baseline (p < 0.0001). At 24 months postoperatively, 91% of patients were very satisfied and 9% somewhat satisfied, while 89% would definitely and 11% would probably elect to have the same surgery again. In 47 patients with 58 operated levels, the radiographic assessment showed good motion (5°-12°) of the device in 57%, reduced motion (2°-5°) in 34.5%, and little motion (0-2°) in 8.5%. The Cobb and FSU angles improved, showing a clear tendency for lordosis with the DCI. Motion greater than 2° of the treated segment could be preserved in 91.5%, while 8.5% had a near segmental fusion. Mean ROM at index levels demonstrated satisfying motion preservation with DCI. Mean ROM at upper and lower adjacent levels showed maintenance of adjacent-level kinematics. Heterotopic ossification, including 20% minor and 15% major, had no direct impact on clinical results. There were 2 endplate subsidences detected with an increased segmental lordosis. One asymptomatic anterior device migration required reoperation. Three patients underwent a secondary surgery in another segment during follow-up, twice for a new disc herniation and once for an adjacent degeneration. There was no posterior migration and no device breakage. Preliminary results indicate that the DCI implanted using a proper surgical technique is safe and facilitates excellent clinical outcomes, maintains index-and adjacent-level ROM in the majority of cases, improves sagittal alignment, and may be suitable for patients with facet arthrosis who would otherwise not be candidates for cervical TDR. Shock absorption together with maintained motion in the DCI may protect adjacent levels from early degeneration in longer follow-up.


Prevalence of glaucoma in rural Myanmar: the Meiktila Eye Study.
To determine the prevalence of glaucoma in the Meiktila district of central, rural Myanmar. A cross-sectional, population-based survey of inhabitants > or =40 years of age from villages in Meiktila district, Myanmar, was performed; 2481 eligible participants were identified and 2076 participated in the study. The ophthalmic examination included Snellen visual acuity, slit-lamp examination, tonometry, gonioscopy, dilated stereoscopic fundus examination and full-threshold perimetry. Glaucoma was classified into clinical subtypes and categorised into three levels according to diagnostic evidence. Glaucoma was diagnosed in 1997 (80.5%) participants. The prevalence of glaucoma of any category in at least one eye was 4.9% (95% CI 4.1 to 5.7; n = 101). The overall prevalence of primary angle-closure glaucoma (PACG) was 2.5% (95% CI 1.5 to 3.5) and of primary open-angle glaucoma (POAG) was 2.0% (95% CI 0.9 to 3.1). PACG accounted for 84% of all blindness due to glaucoma, with the majority due to acute angle-closure glaucoma (AACG). The prevalence of glaucoma in the population aged > or =40 years in rural, central Myanmar was 4.9%. The ratio of PACG to POAG was approximately 1.25:1. PACG has a high visual morbidity and AACG is visually devastating in this community. Screening programmes should be directed at PACG, and further study of the underlying mechanisms of PACG is needed in this population.


A web server for predicting inhibitors against bacterial target GlmU protein.
The emergence of drug resistant tuberculosis poses a serious concern globally and researchers are in rigorous search for new drugs to fight against these dreadful bacteria. Recently, the bacterial GlmU protein, involved in peptidoglycan, lipopolysaccharide and techoic acid synthesis, has been identified as an important drug target. A unique C-terminal disordered tail, essential for survival and the absence of gene in host makes GlmU a suitable target for inhibitor design. This study describes the models developed for predicting inhibitory activity (IC50) of chemical compounds against GlmU protein using QSAR and docking techniques. These models were trained on 84 diverse compounds (GlmU inhibitors) taken from PubChem BioAssay (AID 1376). These inhibitors were docked in the active site of the C-terminal domain of GlmU protein (2OI6) using the AutoDock. A QSAR model was developed using docking energies as descriptors and achieved maximum correlation of 0.35/0.12 (r/r2) between actual and predicted pIC50. Secondly, QSAR models were developed using molecular descriptors calculated using various software packages and achieved maximum correlation of 0.77/0.60 (r/r2). Finally, hybrid models were developed using various types of descriptors and achieved high correlation of 0.83/0.70 (r/r2) between predicted and actual pIC50. It was observed that some molecular descriptors used in this study had high correlation with pIC50. We screened chemical libraries using models developed in this study and predicted 40 potential GlmU inhibitors. These inhibitors could be used to develop drugs against Mycobacterium tuberculosis. These results demonstrate that docking energies can be used as descriptors for developing QSAR models. The current work suggests that docking energies based descriptors could be used along with commonly used molecular descriptors for predicting inhibitory activity (IC50) of molecules against GlmU. Based on this study an open source platform, http://crdd.osdd.net/raghava/gdoq, has been developed for predicting inhibitors GlmU.


Indications and yield of ambulatory EEG recordings.
To study the yield of prolonged ambulatory electroencephalogram (aEEG). A retrospective chart review of all patients who underwent aEEG studies between 2013 and 2017 was performed. Reasons for aEEG were classified into five categories: detection of interictal epileptiform discharges (IEDs), capturing clinical events, detection of unrecognized seizures, monitoring IEDs during treatment, and unclassifiable. Ambulatory EEG reports were reviewed to evaluate whether the study answered the clinical question. A total of 1,264 patients were included. Forty studies were excluded for incomplete data and 234 for being a repeat study. The average number of recording days was 1.57 ± 0.73. Based on initial clinical evaluation, patients carried the following presumptive diagnosis: 61% epilepsy, 11% single unprovoked or acute symptomatic seizure and 28% non-epileptic paroxysmal events (PEs). Overall, focal IEDs were seen in 16.1% of studies, generalized IEDs in 10.8%, focal seizures in 4.1%, and generalized seizures in 1.9%. The most frequent reason for ordering aEEG was to detect IEDs for diagnostic purposes (48.1%). For this indication, additional information was provided by the aEEG in 19.1% of cases (58.6% focal IEDs, 33.5% generalized IEDs, 7.9% seizures without IEDs). Ambulatory EEG was ordered with the intent to capture and characterize clinical events in 18.9%, mostly in patients who reported daily or weekly events. In these, aEEG captured either epileptic seizures or PEs in 102 (42.7%) of the studies (83.3% PEs, 16.7% epileptic seizures). Ambulatory EEG was ordered to evaluate unrecognized seizures in 17.8% of patients, and electrographic seizures were identified in 13.3% of these studies. The yield of aEEG varies based on the indication for the study. Ambulatory EEG can be a useful tool for recording IEDs in the outpatient setting and in a select group of patients to capture clinical events or unrecognized seizures.


Comparison of radiation dose estimates, image noise, and scan duration in pediatric body imaging for volumetric and helical modes on 320-detector CT and helical mode on 64-detector CT.
Advanced multidetector CT systems facilitate volumetric image acquisition, which offers theoretic dose savings over helical acquisition with shorter scan times. Compare effective dose (ED), scan duration and image noise using 320- and 64-detector CT scanners in various acquisition modes for clinical chest, abdomen and pelvis protocols. ED and scan durations were determined for 64-detector helical, 160-detector helical and volume modes under chest, abdomen and pelvis protocols on 320-detector CT with adaptive collimation and 64-detector helical mode on 64-detector CT without adaptive collimation in a phantom representing a 5-year-old child. Noise was measured as standard deviation of Hounsfield units. Compared to 64-detector helical CT, all acquisition modes on 320-detector CT resulted in lower ED and scan durations. Dose savings were greater for chest (27-46%) than abdomen/pelvis (18-28%) and chest/abdomen/pelvis imaging (8-14%). Noise was similar across scanning modes, although some protocols on 320-detector CT produced slightly higher noise. Dose savings can be achieved for chest, abdomen/pelvis and chest/abdomen/pelvis examinations on 320-detector CT compared to helical acquisition on 64-detector CT, with shorter scan durations. Although noise differences between some modes reached statistical significance, this is of doubtful diagnostic significance and will be studied further in a clinical setting.


Reduced degranulation of NK cells in patients with frequently recurring herpes.
NK cells lyse virus-infected cells by degranulation; however, alterations in NK cell degranulation in persistent viral infections have not been directly studied. Earlier reports have documented a decrease in NK activity in patients with frequently recurring herpes (FRH). We corroborate these findings by showing that the degranulation responses of blood NK cells from patients with FRH, both during relapse and during remission, are significantly lower than those in healthy donors. The impaired degranulation was probably not caused by defective target cell recognition, since it was observed upon stimulation both with K562 cells and with a receptor-independent stimulus (phorbol 12-myristate 13-acetate plus ionomycin). We also show that the intracellular expression of perforin and CD107a by NK cells from patients with FRH is not different from that in healthy donors, thus excluding that the low NK cell degranulation in FRH is caused by a smaller size of the lytic granule compartment. We confirm previous reports on lowered NK activity in FRH patients and show that NK activity is significantly impaired only during remission, but not relapse; the causes for the discrepancy between the low degranulation and "normal" NK cell activity during relapse are discussed. In all, these data point at the deficit of NK cell degranulation in FRH. Whether this is a predisposing factor or a consequence of herpes simplex virus infection requires further investigation.


Estimating Determinants of Multiple Treatment Episodes for Substance Abusers.
BACKGROUND: Health services researchers have increasingly used hazard functions to examine illness or treatment episode lengths and related treatment utilization and treatment costs. There has been little systematic hazard analysis, however, of mental health/substance abuse (MH/SA) treatment episodes. AIMS OF THE STUDY: This article uses proportional hazard functions to characterize multiple treatment episodes for a sample of insured clients with at least one alcohol or drug treatment diagnosis over a three-year period. It addresses the lengths and timing of treatment episodes, and the relationships of episode lengths to the types and locations of earlier episodes. It also identifies a problem that occurs when a portion of the sample observations is ǣpossibly censored. Failure to account for sample censoring will generate biased hazard function estimates, but treating all potentially censored observations as censored will overcompensate for the censoring bias. METHODS: Using insurance claims data, the analysis defines health care treatment episodes as all events that follow the initial event irrespective of diagnosis, so long as the events are not separated by more than 30 days. The distribution of observations ranges from 1 day to 3 years, and individuals have up to 10 episodes. Due to the data collection process, observations may be right censored if the episode is either ongoing at the time that data collection starts, or when the data collection effort ends. The Andersen-Gill (AG) and Wei-Lin-Weissfeld (WLW) estimation methods are used to address relationships among individuals multiple episodes. These methods are then augmented by a probit censoring model that estimates censoring probability and adjusts estimated behavioral coefficients and related treatment utilization and treatment costs. There has been little systematic hazard analysis, however, of mental health/substance abuse (MH/SA) treatment episodes. RESULTS: Five sets of variables explain episode duration: (i) individual; (ii) insurance; (iii) employer; (iv) binary, indicating episode diagnosis, location, and sequence; and (v) linkage, relating current diagnoses to previous diagnoses in a sequence. Sociodemographic variables such as age or gender have impacts at both the individual and at the firm level. Coinsurance rates and deductibles also have impacts at the individual and the firm levels. Binary variables indicate that surgical/outpatient episodes were the shortest, and psychiatric/outpatient episodes were the longest. Linkage variables reveal significant impacts of prior alcoholism, drug, and psychiatric episodes on the lengths of subsequent episodes. DISCUSSION: Health care treatment episodes are linked to each other both by diagnosis and by treatment location. Both the AG and the WLW models have merit for treating multiple episodes. The AG model permits more flexibility in estimating hazards, and allows researchers to model impacts of prior diagnoses on future episodes. The WLW model provides a convenient way to examine impacts of sociodemographic variables across episodes. It also provides efficient pooled estimates of coefficients and their standard errors. LIMITATIONS: The insurance claims data set covers 1989 through 1991, predating current managed care plans. It cannot identify untreated substance abusers, nor can it identify those with out-of-plan use. It provides treatment information only if services are covered by the insurance plan and are defined with a substance abuse diagnosis code. Like medical records, insurance claims will not specify substance abuse treatment received within the context of other health care (and thus identified by a non-substance abuse diagnosis code) or community services. IMPLICATIONS FOR POLICY AND RESEARCH: This article characterizes multiple health treatment episodes for a sample of insured clients with at least one alcohol or drug treatment diagnosis within a three-year period. We identify both individual and employer effects on episode length. We find that episode lengths vary by the diagnosis type, and that the lengths (and by inference cost and utilization) may depend on the treatments that occurred in previous episodes. We also recognize that health care or illness episodes may be ongoing at times of health care events prior to the ends of data collection periods, leading to uncertain episode lengths. Corresponding estimates of costs or utilization are also uncertain. We provide a method that adjusts the episode lengths according to the probability of censoring.


Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures.
Nonunion is a challenging problem that may occur following certain bone fractures. However, there has been little investigation of the molecular basis of nonunions. Bone morphogenetic proteins (BMPs) play a significant role in osteogenesis. However, little is known about the expression patterns of BMPs in abnormal bone healing that results in nonunion formation. These facts prompted us to investigate and compare the gene expression patterns of BMPs and their antagonists in standard healing fractures and nonunions using rat experimental models. Standard closed healing fractures and experimental atrophic nonunions produced by periosteal cauterization at the fracture site were created in rat femurs. At postfracture days 3, 7, 10, 14, 21, and 28, total RNA was extracted from the callus of standard healing fracture and fibrous tissue of nonunion (n=4 per each time point and each group). Gene expression of BMPs, BMP antagonists, and other regulatory molecules were studied by methods including Genechip microarray and real-time quantitative RT-PCR. Gene expression of BMP-2, 3, 3B, 4, 6, 7, GDF-5, 7, and BMP antagonists noggin, drm, screlostin, and BAMBI were significantly lower in nonunions compared to standard healing fractures at several time points. Downregulation in expression of osteogenic BMPs may account for the nonunions of fracture. The balance between BMPs and their endogenous antagonists is critical for optimal fracture healing.


SARS-CoV-2 breakthrough infections in vaccinated individuals: measurement, causes and impact.
Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in fully vaccinated individuals are receiving intense scrutiny because of their importance in determining how long restrictions to control virus transmission will need to remain in place in highly vaccinated populations as well as in determining the need for additional vaccine doses or changes to the vaccine formulations and/or dosing intervals. Measurement of breakthrough infections is challenging outside of randomized, placebo-controlled, double-blind field trials. However, laboratory and observational studies are necessary to understand the impact of waning immunity, viral variants and other determinants of changing vaccine effectiveness against various levels of coronavirus disease 2019 (COVID-19) severity. Here, we describe the approaches being used to measure vaccine effectiveness and provide a synthesis of the burgeoning literature on the determinants of vaccine effectiveness and breakthrough rates. We argue that, rather than trying to tease apart the contributions of factors such as age, viral variants and time since vaccination, the rates of breakthrough infection are best seen as a consequence of the level of immunity at any moment in an individual, the variant to which that individual is exposed and the severity of disease being considered. We also address key open questions concerning the transition to endemicity, the potential need for altered vaccine formulations to track viral variants, the need to identify immune correlates of protection, and the public health challenges of using various tools to counter breakthrough infections, including boosters in an era of global vaccine shortages.


Tunable conduction type of solution-processed germanium nanoparticle based field effect transistors and their inverter integration.
In this work we demonstrate the fabrication of germanium nanoparticle (NP) based electronics. The whole process chain from the nanoparticle production up to the point of inverter integration is covered. Ge NPs with a mean diameter of 33 nm and a geometric standard deviation of 1.19 are synthesized in the gas phase by thermal decomposition of GeH4 precursor in a seeded growth process. Dispersions of these particles in ethanol are employed to fabricate thin particulate films (60 to 120 nm in thickness) on substrates with a pre-patterned interdigitated aluminum electrode structure. The effect of temperature treatment, polymethyl methacrylate encapsulation and alumina coating by plasma-assisted atomic layer deposition (employing various temperatures) on the performance of these layers as thin film transistors (TFTs) is investigated. This coating combined with thermal annealing delivers ambipolar TFTs which show an Ion/Ioff ratio in the range of 10(2). We report fabrication of n-type, p-type or ambipolar Ge NP TFTs at maximum temperatures of 450 °C. For the first time, a circuit using two ambipolar TFTs is demonstrated to function as a NOT gate with an inverter gain of up to 4 which can be operated at room temperature in ambient air.


Early childhood experience in Nepal: a study of sickness, treatment and mortality.
This article reports on a longitudinal study of almost 7,000 children under six years in selected villages in Nepal, giving their morbidity and mortality history, treatments given and costs involved. The study suggests that about two children out of three are defined as sick by their mothers in any given year and that treatment is sought for about 40 percent of sickness in small children. Three of four children treated are treated by scientific medicine, that is by physicians, nurses or pharmacists. The principal causes of death are fevers and diarrhea. Education of mothers in spacing of births, hygiene, nutrition and rehydration therapy would appear to be the most important primary health care service, along with increased access to potable water and to medical clinics.


Characteristic metabolic profiles revealed by 1H NMR spectroscopy for three types of human brain and nervous system tumours.
Cell culture techniques, high-resolution in vitro 1H NMR spectroscopy, and chromatographic analyses were used to compare the properties of three types of human brain and nervous system tumours. Cell lines were immunocytochemically characterized at all stages in culture with specific antibodies. Intracellular metabolites present in cell extracts were analysed by 1H NMR spectroscopy and by high performance liquid chromatography (HPLC). The spectra from meningiomas, neuroblastomas, and glioblastomas displayed, in addition to similarities-including the presence of signals from leucine, isoleucine, valine, threonine, lactate, acetate, glutamate, choline-containing compounds and glycine-certain distinguishing metabolic features. Spectra from meningiomas featured relatively high signals from alanine. Intense signals from creatine were present in neuroblastoma spectra, while in spectra from glioblastoma they were not detectable. We found statistically significant differences by 1H NMR spectroscopy in the amounts of alanine, glutamate, creatine, phosphorylcholine and threonine among the types of tumours examined. HPLC determinations confirmed that there were also other metabolites specific to a type of tumour, such as taurine, gamma-aminobutyric acid, and serine. We suggest that these findings have potential relevance for the development of non-invasive diagnosis of tumour lineage by 1H NMR spectroscopy in vivo.


Hepatic nontuberculous mycobacterial granulomas in patients with cancer mimicking metastases: an analysis of three cases.
Hepatic granulomas caused by nontuberculous mycobacteria (NTM) are an uncommon, insidious, and indolent disease. Making an accurate diagnosis of a hepatic nontuberculous granuloma is challenging because of nonspecific clinical presentations and radiological appearances, especially in patients with a history of malignant tumors, as these lesions may mimic metastases and make a dilemma for decision-making in treatment. Herein, we report three cases of hepatic nontuberculous granulomas following operations for malignant tumors, including colon cancer, ovarian adenocarcinoma, and both rectal and renal carcinoma, respectively. Two patients presented with multiple hepatic lesions and the third had a solitary nodule in the liver. Computed tomography (CT) showed low attenuating nodules without early enhancement in the arterial phase but a slight peripheral enhancement in the portal venous phase after the intravenous administration of contrast agent. Magnetic resonance imaging (MRI) showed high signal intensity on T2-weighted image, rim enhancement in the venous phase and no contrast agent of Gd-EOB-DTPA uptake in the hepatobiliary phase. The biopsy was performed, and histopathological examinations revealed the chronic granulomas composed of epithelioid histiocytes, inflammatory cells, and Langhans giant cells. The results of nested polymerase chain reaction (PCR) were positive for NTM.


Nanoscale uniformity in the active tuning of a plasmonic array by polymer gel volume change.
Active plasmonic tuning is an attractive but challenging research subject, leading to various promising applications. As one of the approaches, nanostructures are placed in or on soft matter, such as elastomers and gels, and their gap distances are tuned by the mechanical extension or volume change of the supporting matrices. As hydrogels possess various types of stimuli-responsiveness with large volume change and biocompatibility, they are good candidates as supporting materials for active nanostructure tuning. However, it remains unclear how accurately we can control their nanogap distance changes using polymer gels with a low deviation due to major difficulties in the precise observation of nanostructures on the gels. Here, we prepared gold arrays with sub-100 nm dots on silicon substrates by electron beam lithography and transferred them onto the hydrogel surface. Then, their nanopattern was actively tuned by the changes in gel size in water and their structural changes were confirmed by optical microscopy, microspectroscopy, and atomic force microscopy (AFM). Further, we successfully prepared ionic liquid (IL) gels with various degrees of swelling via solvent exchange. Scanning electron microscopy (SEM) observation of the IL gels provided clear pictures at nanoscale resolution. Finally, we calculated the plasmonic spectra using a finite difference time domain (FDTD) simulation based on the SEM images and compared them with the measured spectra. The results in this study totally support the notion that active changes in plasmonic nanodot patterns via volume changes in the hydrogel are quite homogenous on a several nanometer scale, making them ideal for precise active surface plasmon tuning.


Comparison of Phenylacetates with Benzoates and Phenylpropanoates as Antifeedants for the Pine Weevil, Hylobius abietis.
This study concludes an extensive investigation of antifeedants for the pine weevil, Hylobius abietis (Coleoptera: Curculionidae), an economically important pest of planted conifer seedlings. Building on the previously reported antifeedant effects of benzoates and phenylpropanoids (aromatic compounds with one- or three-carbon-atom substituents on the benzene ring), we here report the antifeedant effects of compounds with two-carbon-atom side chains (i.e., phenylacetates). We also present new results; the best antifeedants from the benzoate class were tested at 10-fold lower concentrations in order to find the optimal antifeedants. Generally, for all three compound classes, efficient antifeedants were found to have one or two methyl, chloro, or methoxy substituents on the aromatic ring. For monosubstituted phenylpropanoids, the substituent preferably should be in the para-position. In the search for synergistic antifeedant effects among the three compound classes, combinations of compounds from the three classes were tested in binary and ternary mixtures.


OptoCRISPRi-HD: Engineering a Bacterial Green-Light-Activated CRISPRi System with a High Dynamic Range.
The ability to modulate gene expression is crucial for studying gene function and programming cell behaviors. Combining the reliability of CRISPRi and the precision of optogenetics, the optoCRISPRi technique is emerging as an advanced tool for live-cell gene regulation. Since previous versions of optoCRISPRi often exhibit no more than a 10-fold dynamic range due to the leakage activity, they are not suitable for targets that are sensitive to such leakage or critical for cell growth. Here, we describe a green-light-activated CRISPRi system with a high dynamic range (40 fold) and the flexibility of changing targets in Escherichia coli. Our optoCRISPRi-HD system can efficiently repress essential genes, nonessential genes, or inhibit the initiation of DNA replication. Providing a regulative system with high resolution over space-time and extensive targets, our study would facilitate further research involving complex gene networks, metabolic flux redirection, or bioprinting.


What is an unconscious emotion?(The case for unconscious "liking").
Ever since William James, psychologists of emotion have tended to view affective states as intrinsically conscious. We argue that nonconscious affect also exists, and focus specifically on the possibility of unconscious "liking". We present evidence that positive and negative affective reactions can be elicited subliminally, while a person is completely unaware of any affective reaction at all (in addition to being unaware of the causal stimulus). Despite the absence of any detectable subjective experience of emotion, subliminally induced unconscious "liking" can influence later consumption behaviour. We suggest that unconscious "liking" is mediated by specific subcortical brain systems, such as the nucleus accumbens and its connections. Ordinarily, conscious liking (feelings of pleasure) results from the interaction of separate brain systems of conscious awareness with those core processes of unconscious affect. But under some conditions, activity in brain systems mediating unconscious core "liking" may become decoupled from conscious awareness. The result is a genuinely unconscious emotion.


The Evolution of Earned, Transparent, and Quantifiable Faculty Salary Compensation: The Johns Hopkins Pathology Experience.
Faculty value equitable and transparent policies for determining salaries and expect their compensation to compare favorably to the marketplace. Academic institutions use compensation to recruit and retain talented faculty as well as to reward accomplishment. Institutions are therefore working to decrease salary disparities that appear arbitrary or reflect long-standing biases and to identify metrics for merit-based remuneration. Ours is a large academic pathology department with 97 tenure-track faculty. Faculty salaries are comprised of 3 parts (A + B + C). Part A is determined by the type of appointment and years at rank; part B recognizes defined administrative, educational, or clinical roles; and part C is a bonus to reward and incentivize activities that forward the missions of the department and medical school. A policy for part C allocations was first codified and approved by department faculty in 1993. It rewarded performance using a semiquantitative scale, based on subjective evaluations of the department director (chair) in consultation with deputy directors (vice chairs) and division directors. Faculty could not directly calculate their part C, and distributions data were not widely disclosed. Over the last 2 years (2015-2017), we have implemented a more objective formula for quantifying an earned part C, which is primarily designed to recognize scholarship in the form of research productivity, educational excellence, and clinical quality improvement. Here, we share our experience with this approach, reviewing part C calculations as made for individual faculty members, providing a global view of the resulting allocations, and considering how the process and outcomes reflect our values.


Video-EEG evidence of lateralized clinical features in primary generalized epilepsy with tonic-clonic seizures.
Whether cortical or subcortical structures, specifically the thalamus, play the dominant role in generating primary generalized seizures has been the subject of long debate. Most experimental data implicate a hyperexcitable cortical generator of spike-and-wave activity, with the thalamus quickly recruited to sustain the generalized oscillations through a reverberating thalamocortical network. However, there is little clinical evidence to support the cortical generator hypothesis. We present video-EEG recordings of generalized tonic-clonic seizures in three patients with proven primary generalized epilepsy (PGE), all of whom showed a consistent pattern of lateralized seizure onset compatible with a focal frontal lobe generator. Among 300 patients referred for video-EEG monitoring for intractable epilepsy, three were found to have PGE with tonic-clonic convulsions. All had a positive family history for epilepsy and no other epilepsy risk factors. Epilepsy onset was during adolescence (2/3) or childhood (1/3). Patients were taking 1-4 antiepileptic drugs (AEDs) at admission, none of which was valproic acid. Interictal EEG showed very active, bilaterally synchronous generalized spike-and-wave or polyspike-and-wave discharges between 2.5-4.5 Hz, maximal over the midfrontal structures symmetrically in all patients. Ictal EEG showed generalized rhythmic activity without lateralization at seizure onset. Surprisingly, in all 6 recorded tonic-clonic seizures there was a sustained (10-15 seconds), stereotyped, clinical lateralization at onset, which took the form of a tonic "fencing posture" in one patient (two seizures) and forced head/eye/torso version in two patients (four seizures). Two patients became seizure-free shortly after switching to valproate monotherapy. One patient refused valproate but has improved more than 90% with a change in AEDs to lamotrigine and phenobarbital (follow-up in all patients>18 months). Tonic-clonic seizures are presumed to be generalized from onset in patients with PGE. However, video-EEG monitoring in these patients is rarely performed and the actual clinical features of the seizures maybe underappreciated. The demonstration of sustained lateralization at onset in our patients, with features clinically indistinguishable from focal onset frontal lobe seizures, is compatible with the hypothesis of a focal region of cortical hyperexcitability situated in the frontal lobes of some patients with PGE. Whether this cortical generator is autonomous or "triggered" by ascending, possibly normal, thalamocortical volleys is unresolved.


Preinvasive and invasive breast and cervical cancer prior to or during pregnancy.
In conclusion, cervical and breast cancer are the two most frequently encountered malignancies during pregnancy. Although cervical cancer generally is diagnosed in its early stages, breast cancer tends to be discovered in more advanced stages. Therefore, the physician must have a high index of suspicion and must aggressively pursue the diagnosis of breast masses in pregnant women to try to detect the disease as early as possible. Premalignant lesions of the cervix also must be evaluated thoroughly. Therapy for these two cancers is similar to the treatment of nonpregnant women, with some modifications made due to fetal considerations and informed maternal desires. Pregnancy does not affect the progression or prognosis of either disease significantly. Pregnancy following the treatment for cervical cancer is unlikely, if not impossible, because current standard therapies will render these women infertile. There have, however, been some recent reports describing trachelectomy followed by laparoscopic lymph-node dissection for the treatment of early-stage cervical cancer in an attempt to preserve future fertility. Successful pregnancies are possible following the treatment of breast cancer and do not influence recurrence.


The Gulf War and its impact on burnout and well-being of working civilians.
Burnout signifies the chronic depletion of coping resources following prolonged exposure to emotionally charged demands. It is manifested by symptoms of emotional, physical and cognitive exhaustion, and is usually studied in relation to occupational stressors. We hypothesized that the major life crisis engendered by missile attacks would give rise to burnout or exacerbate preexisting burnout symptoms. We also hypothesized that individuals suffering from prewar burnout would appraise the war as being more threatening and would be more vulnerable to upper respiratory infections (URI). Wartime and pre-war (baseline) levels of burnout and related symptomatology (cognitive weariness, listlessness, tension and somatic complaints) were compared among 162 Israeli civilians who carried on with their employment duties throughout the Gulf War. We found that the war impacted primarily on younger individuals (age < 45). All the pre-war levels of the above measures increased significantly (except for a marginal increase in tension). The impact of the war was mediated by threat appraisal, as indicated by worry and apprehension. Worry was positively associated with pre-war burnout, and negatively with age and education. Pre-war burnout was associated positively with wartime URIs. It was concluded that the war accelerated the depletion of coping resources and that burnout may be affected by factors other than occupational stress.


Recent advances in 3D printing of biomaterials.
3D Printing promises to produce complex biomedical devices according to computer design using patient-specific anatomical data. Since its initial use as pre-surgical visualization models and tooling molds, 3D Printing has slowly evolved to create one-of-a-kind devices, implants, scaffolds for tissue engineering, diagnostic platforms, and drug delivery systems. Fueled by the recent explosion in public interest and access to affordable printers, there is renewed interest to combine stem cells with custom 3D scaffolds for personalized regenerative medicine. Before 3D Printing can be used routinely for the regeneration of complex tissues (e.g. bone, cartilage, muscles, vessels, nerves in the craniomaxillofacial complex), and complex organs with intricate 3D microarchitecture (e.g. liver, lymphoid organs), several technological limitations must be addressed. In this review, the major materials and technology advances within the last five years for each of the common 3D Printing technologies (Three Dimensional Printing, Fused Deposition Modeling, Selective Laser Sintering, Stereolithography, and 3D Plotting/Direct-Write/Bioprinting) are described. Examples are highlighted to illustrate progress of each technology in tissue engineering, and key limitations are identified to motivate future research and advance this fascinating field of advanced manufacturing.


FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas.
Idiopathic Pulmonary Fibrosis is a lethal fibrotic disease characterized by the unrelenting proliferation and persistence of fibroblasts in a type I collagen-rich matrix that result in an expanding reticular network of fibrotic tissue. However, the underlying mechanism responsible for the persistence of myofibroblasts in IPF remains unclear. During normal tissue repair, unwanted fibroblasts are eliminated during collagen-matrix contraction by a mechanism whereby high PTEN activity suppresses Akt. We have previously found that FoxO3a, a transcriptional activator of apoptosis-inducing proteins, is inactivated in IPF fibroblasts resulting from aberrantly high PI3K/Akt activity due to inappropriately low PTEN activity. Here we demonstrate that this low FoxO3a activity confers IPF fibroblasts with resistance to collagen-mediated apoptosis. We show that the mechanism by which low FoxO3a activity confers IPF fibroblasts with an apoptotic resistant phenotype involves suppression of Fas expression as a result of down regulation of cav-1 expression via a PTEN/Akt-dependent pathway. We demonstrate that PTEN over-expression or Akt inhibition increases FoxO3a expression in IPF fibroblasts, resulting in up-regulation of caveolin-1. We show that FoxO3a binds to the cav-1 promoter region and ectopic expression of FoxO3a transcriptionally increases cav-1 mRNA and protein expression. In turn, we show that overexpression of caveolin-1 increases Fas levels and caspase-3/7 activity and promotes IPF fibroblast apoptosis on polymerized type I collagen. We have found that the expression of caveolin-1, Fas and cleaved caspase-3 proteins in fibroblasts within the fibroblastic foci of IPF patient specimens is low. Our data indicate that the pathologically altered PTEN/Akt axis inactivates FoxO3a down-regulating cav-1 and Fas expression. This confers IPF fibroblasts with an apoptosis-resistant phenotype and may be responsible for IPF progression.


Mesencephalic type 1 astrocytes rescue dopaminergic neurons from death induced by serum deprivation.
We have established a primary neuronal culture of the embryonic day 14 rat, ventral mesencephalic region, centered on the A8, A9, and A10 dopaminergic nuclei (approximately 1.0 mm3 of tissue). At 16 hr after plating on a substrate of poly-D-lysine, in a serum-free or serum-supplemented growth medium, using a microisland culturing method, 95% of the cells stained positive for neuron-specific enolase, 20% for tyrosine hydroxylase, and < 5% for vimentin. When the growth medium was supplemented with 10% fetal calf serum, the percentage of tyrosine hydroxylase-positive neurons increased significantly (p < 0.05) at the 7th and 10th days in culture, compared with the percentage present at 16 hr after plating. When cultured in a serum-free growth medium, the percentage of tyrosine hydroxylase-positive neurons decreased to < 5% and to 0% by the 5th and 7th days, respectively, while the percentage of GABA-IR neurons increased. The addition of serum to the serum-free culture rescued dopaminergic neurons from death induced by serum deprivation. The effect of serum was dependent both on the time of addition after plating, and on the percentage added. When the cells were plated in a serum-free medium, on a confluent, type 1 astrocyte monolayer, prepared from the ventral mesencephalon of the embryonic day 16 rat, the survival of dopaminergic neurons increased significantly (p < 0.01) at DIV5, versus survival after plating on poly-D-lysine. Conditioned medium prepared from the same mesencephalic type 1 astrocyte monolayer also rescued dopaminergic neurons from death. The rescue mediated by the astrocyte monolayer or the conditioned medium was not inhibited by the mitotic inhibitor cytosine arabino furanoside (1.0 microM). Type 1 astrocyte monolayers and conditioned media prepared from the striatum and cerebral cortex of the embryonic day 16 rat had weaker trophic effects than those mediated by mesencephalic glia. We conclude that serum deprivation causes the selective death of dopaminergic neurons in a primary culture of the rat E14 ventral mesencephalon. Type 1 astrocytes or the conditioned medium from type 1 astrocytes can rescue dopaminergic neurons from death induced by serum deprivation.(ABSTRACT TRUNCATED AT 400 WORDS)


Improving Self-Efficacy and Self-Care in Adult Patients With a Urinary Diversion: A Pilot Study.
To evaluate the feasibility and acceptability of a multimodality educational intervention for improving self-efficacy (SE) and self-care in patients with a new urinary diversion (UD). . Two-arm randomized, controlled trial. . Academic medical center in New York. . 8 adults diagnosed with bladder cancer requiring UD. . A multimodality educational intervention consisting of video, Microsoft PowerPoint® slides, and medical illustrations was developed. SE was assessed pre- and postintervention related to care of the UD. Education scale scores provided evidence for intervention acceptability and assessment of UD self-care skills. . Feasibility, acceptability, results of SE, and self-care scales. . Enrollment and retention was 100%. All participants took part in every aspect of the study. No issues were apparent with administration of the study; however, a lack of self-care independence was noted between the study arms. The control group was younger in age than the intervention group. . A supplemental multimethod educational intervention is acceptable in this population and feasible to integrate into hospital care or into an appropriately powered study. . A need exists for ongoing postdischarge support and education in this population. Additional studies are needed to determine the best approach for this.


Hepatoid prostatic carcinoma with adrenal metastasis and novel genetic alterations.
Hepatoid carcinoma (HC) encompasses epithelial extrahepatic tumors exhibiting features of hepatocellular carcinoma (HCC) both by morphology and immunohistochemistry. Distinguishing metastatic HCC from HC may be challenging, particularly when limited material, such as a cytologic specimen, is available. HC from prostatic origin is unusual and has only rarely been characterized by cytology. Herein we present an 86-year-old male with history of castration-resistant prostate cancer developing a left adrenal gland nodule. Fine needle aspiration revealed a poorly differentiated malignant neoplasm diagnosed as metastatic hepatoid prostatic adenocarcinoma based on immunohistochemistry (positive for HepPar1, AFP, NKX3.1, PSMA, and Racemase; and negative for CK7, CK20, cytokeratin 34betaE12, p63, and Arg-1). Because prostatic carcinoma with hepatoid features is rare, and the patient had failed standard therapy, next generation sequencing was performed in an attempt to identify druggable molecular targets. Well-known prostate carcinoma-related alterations were found in three genes (CDK12, AR, and SPOP). In addition, three variants of uncertain significance (DDR2 R128C, SRC P428L, and HNRNPU K574Sfs*32) were identified, which to the best of our knowledge have not been previously reported. Our results support the power of an immunohistochemistry panel including Arg-1 and HepPar1 when HC is suspected, and highlight the value of cytology for comprehensive diagnostic evaluation.


Contemporary techniques and outcomes of robotic cystectomy and intracorporeal urinary diversions.
Robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) is being increasingly performed worldwide. This review summarizes recent technical developments and outcome data for RARC with ICUD. With the recent description of intracorporeal continent cutaneous diversion, all classes of urinary diversion can presently be performed totally intracorporeally. The summary of our seven cases of intracorporeal continent cutaneous diversion in this article brings the number of reported cases in the literature to 17. Additional recent advancements in ICUD focus on novel technical descriptions and outcome data. Several intracorporeal orthotopic ileal neobladder techniques have been described with intermediate perioperative outcomes. There is some rationale for reduced overall, wound, gastrointestinal and genitourinary complications with ICUD. RARC with intracorporeal diversion is a feasible option for patients with bladder cancer. Prospective and randomized outcome data are needed to better characterize the benefit of ICUD in patients following radical cystectomy.


Wearable-Measured Sleep and Resting Heart Rate Variability as an Outcome of and Predictor for Subjective Stress Measures: A Multiple N-of-1 Observational Study.
The effects of stress may be alleviated when its impact or a decreased stress-resilience are detected early. This study explores whether wearable-measured sleep and resting HRV in police officers can be predicted by stress-related Ecological Momentary Assessment (EMA) measures in preceding days and predict stress-related EMA outcomes in subsequent days. Eight police officers used an Oura ring to collect daily Total Sleep Time (TST) and resting Heart Rate Variability (HRV) and an EMA app for measuring demands, stress, mental exhaustion, and vigor during 15-55 weeks. Vector Autoregression (VAR) models were created and complemented by Granger causation tests and Impulse Response Function visualizations. Demands negatively predicted TST and HRV in one participant. TST negatively predicted demands, stress, and mental exhaustion in two, three, and five participants, respectively, and positively predicted vigor in five participants. HRV negatively predicted demands in two participants, and stress and mental exhaustion in one participant. Changes in HRV lasted longer than those in TST. Bidirectional associations of TST and resting HRV with stress-related outcomes were observed at a weak-to-moderate strength, but not consistently across participants. TST and resting HRV are more consistent predictors of stress-resilience in upcoming days than indicators of stress-related measures in prior days.


Optical grooming switch with regenerative functionality for transparent interconnection of networks.
We demonstrate a regenerative optical grooming switch for buffer-less interconnection of metro/access and metro/core ring networks with switching functionality in time, space and wavelength domain. Key functionalities of the router are the traffic aggregation with time-slot interchanging (TSI) functionality, the WDM-to-ODTM multiplexing and the OTDM-to-WDM demultiplexing of high-speed channel into lower bit-rate tributaries as well as multi-wavelength all-optical 2R regeneration of several higher-speed signals. BER and Q-factor measurements of different switching scenarios show excellent performance with no error floor and Q-factors above 21 dB.


Demystifying Dens Invaginatus: Suggested Modification of the Classification based on a Comprehensive Case Series.
Dens invaginatus (DI) is one of the most common developmental anomalies observed in maxillary lateral incisors. An early diagnosis requires thorough clinical knowledge, advanced radiographic evaluation as well as the use of cone beam computed tomography (CBCT) and dental operating microscope (DOM), dictates the successful endodontic management of such teeth. A total of 7 cases with (DI) in maxillary lateral incisors were collected from dental practitioners worldwide, analysed and reported in the present case series. Our aim was to analyse and understand the various morphological patterns of DI in maxillary lateral incisors with their varied treatment protocols employed worldwide. This article illustrates the aberrant morphological patterns and the diverse treatment protocols followed by the clinicians worldwide. The use of biomaterials enhances post-operative healing. Further, a modification in the existing classification has been proposed in this report which would enable the clinicians to easily diagnose, categorise and effectively manage DI. The different treatment protocols employed for the management of DI has been discussed and the use of CBCT and DOM in identifying and managing the anatomical variation of DI were emphasised.


Antagonistic regulation of the glucose/glucose 6-phosphate cycle by insulin and glucagon in cultured hepatocytes.
Flux through the glucose/glucose 6-phosphate cycle in cultured hepatocytes was measured with radiochemical techniques. Utilization of [2-3H]glucose was taken as a measure of glucokinase flux. Liberation of [14C]glucose from [U-14C]glycogen and from [U-14C]lactate, as well as the difference between the utilization of [2-3H]glucose and of [U-14C]glucose, were taken as measures of glucose-6-phosphatase flux. At constant 5 mM-glucose and 2 mM-lactate concentrations insulin increased glucokinase flux by 35%; it decreased glucose-6-phosphatase flux from glycogen by 50%, from lactate by 15% and reverse flux from external glucose by 65%, i.e. overall by 40%. Glucagon had essentially no effect on glucokinase flux; it enhanced glucose-6-phosphatase flux from glycogen by 700%, from lactate by 45% and reverse flux from external glucose by 20%, i.e. overall by 110%. At constant glucose concentrations cellular glucose 6-phosphate concentrations were essentially not altered by insulin, but were increased by glucagon by 230%. In conclusion, under basic conditions without added hormones the glucose/glucose 6-phosphate cycle showed only a minor net glucose uptake, of 0.03 mumol/min per g of hepatocytes; this flux was increased by insulin to a net glucose uptake of 0.21 mumol/min per g and reversed by glucagon to a net glucose release of 0.22 mumol/min per g. Since the glucose 6-phosphate concentrations after hormone treatment did not correlate with the glucose-6-phosphatase flux, it is suggested that the hormones influenced the enzyme activity directly.


Decolonising violence against women research: a study design for co-developing violence prevention interventions with communities in low and middle income countries (LMICs).
There has been substantial progress in research on preventing violence against women and girls (VAWG) in the last 20 years. While the evidence suggests the potential of well-designed curriculum-based interventions that target known risk factors of violence at the community level, this has certain limitations for working in partnership with communities in low- and middle-income (LMIC) countries, particularly when it comes to addressing the power dynamics embedded within north-south research relationships. As an alternative approach, we outline the study design for the EVE Project: a formative research project implemented in partnership with community-based researchers in Samoa and Amantaní (Peru) using a participatory co-design approach to VAWG prevention research. We detail the methods we will use to overcome the power dynamics that have been historically embedded in Western research practices, including: collaboratively defining and agreeing research guidelines before the start of the project, co-creating theories of change with community stakeholders, identifying local understandings of violence to inform the selection and measurement of potential outcomes, and co-designing VAWG prevention interventions with communities. Indigenous knowledge and ways of thinking have often been undermined historically by Western research practices, contributing to repeated calls for better recognition of Southern epistemologies. The EVE Project design outlines our collective thinking on how to address this gap and to further VAWG prevention through the meaningful participation of communities affected by violence in the research and design of their own interventions. We also discuss the significant impact of the COVID-19 pandemic on the project in ways that have both disrupted and expanded the potential for a better transfer of power to the communities involved. This article offers specific strategies for integrating Southern epistemologies into VAWG research practices in four domains: ethics, theories of change, measurement, and intervention design. Our aim is to create new spaces for engagement between indigenous ways of thinking and the evidence that has been established from the past two decades of VAWG prevention research and practice.


Acute tryptophan depletion. Part II: clinical effects and implications.
This is the second of two articles reviewing the modern dietary technique of acute tryptophan depletion (ATD), a method of transiently reducing central serotonin levels in both healthy volunteers and clinical populations. This article details the clinical studies to date and discusses the implications of this research methodology. The authors present a review of clinical ATD studies collated from a MEDLINE search, unpublished communications and the authors' considerable experience with this paradigm. Following from the initial use of ATD in subjects with depressive illness, studies of anxiety disorders and other psychiatric illnesses have been reported. Sleep, aggressive and cognitive effects are also active areas of research and are reviewed here. Acute tryptophan depletion remains a useful psychiatric research tool. The findings from the clinical studies reviewed here are summarized and implications for future research detailed.


Nutrition and exercise prevent excess weight gain in overweight pregnant women.
To determine the effect of a Nutrition and Exercise Lifestyle Intervention Program (NELIP) for overweight (OW) and obese (OB) pregnant women on pregnancy weight gain, birth weight, and maternal weight retention at 2 months postpartum. This is a single-arm intervention matched by prepregnant body mass index, age, and parity to a historical cohort (4:1). Women with a prepregnancy body mass index of > or = 25.0 kg x m(-2) (N = 65) participated in a NELIP starting at 16-20 wk of pregnancy, continuing until delivery. NELIP consisted of an individualized nutrition plan with total energy intake of approximately 2000 kcal x d(-1) (8360 kJ x d(-1)) and 40%-55% of total energy intake from carbohydrate. Exercise consisted of a walking program (30% HR reserve), three to four times per week, using a pedometer to count steps. Matched historical cohort (MC; N = 260) was from a large local perinatal database. Weight gained by women on the NELIP was 6.8 +/- 4.1 kg (0.38 +/- 0.2 kg x wk(-1)), with a total pregnancy weight gain of 12.0 +/- 5.7 kg. Excessive weight gain occurred before NELIP began at 16 wk of gestation. Eighty percent of the women did not exceed recommended pregnancy weight gain on NELIP. Weight retention at 2 months postpartum was 2.2 +/- 5.6 kg with no difference between the OW and the OB women on NELIP. Mean birth weight was not different between NELIP (3.59 +/- 0.5 kg) and MC (3.56 +/- 0.6 kg, P > 0.05). NELIP reduces the risk of excessive pregnancy weight gain with minimal weight retention at 2 months postpartum in OW and OB women. This intervention may assist OW and OB women in successful weight control after childbirth.


Estimated costs to the Pennsylvania criminal justice system resulting from the opioid crisis.
The opioid crisis has made financial impacts across all levels of the public sector. This report focuses on costs related to the criminal justice system (CJS) in Pennsylvania. Costs impacting 3 principal areas of the CJS are examined: opioid-related arrests, court costs, and incarceration. Analysis of the state-level CJS is our main focus; no local-level costs are included. Through this examination, costs of the opioid crisis for the period of 2007 to 2016 were estimated using opioid costs for 2006 as a baseline. Total costs to the Pennsylvania CJS during this period were over $526 million, with most of that accounted for by state corrections. Opioid-related trends in arrests, court proceedings, and incarceration were not sufficiently well documented to allow for rigorous analysis in earlier periods, and this was the primary limitation to our analysis.


The effects of long-distance migration on the evolution of moult strategies in Western-Palearctic passerines.
Although feathers are the unifying characteristic of all birds, our understanding of the causes, mechanisms, patterns and consequences of the feather moult process lags behind that of other major avian life-history phenomena such as reproduction and long-distance migration. Migration, which evolved in many species of the temperate and arctic zones, requires high energy expenditure to endure long-distance journeys. About a third of Western-Palearctic passerines perform long-distance migrations of thousands of kilometres each year using various morphological, physiological, biomechanical, behavioural and life-history adaptations. The need to include the largely non-overlapping breeding, long-distance migration and feather moult processes within the annual cycle imposes a substantial constraint on the time over which the moult process can take place. Here, we review four feather-moult-related adaptations which, likely due to time constraints, evolved among long-distance Western-Palearctic migrants: (i) increased moult speed; (ii) increased overlap between moult and breeding or migration; (iii) decreased extent of plumage moult; and (iv) moult of part or all of the plumage during the over-wintering period in the tropics rather than in the breeding areas. We suggest that long-distance migration shaped the evolution of moult strategies and increased the diversity of these strategies among migratory passerines. In contrast to this variation, all resident passerines in the Western Palearctic moult immediately after breeding by renewing the entire plumage of adults and in some species also juveniles, while in other species juvenile moult is partial. We identify important gaps in our current understanding of the moult process that should be addressed in the future. Notably, previous studies suggested that the ancestral moult strategy is a post-breeding summer moult in the Western Palearctic breeding areas and that moult during the winter evolved due to the scheduling of long-distance migration immediately after breeding. We offer an alternative hypothesis based on the notion of southern ancestry, proposing that the ancestral moult strategy was a complete moult during the 'northern winter' in the Afro-tropical region in these species, for both adults and juveniles. An important aspect of the observed variation in moult strategies relates to their control mechanisms and we suggest that there is insufficient knowledge regarding the physiological mechanisms that are involved, and whether they are genetically fixed or shaped by environmental factors. Finally, research effort is needed on how global climate changes may influence avian annual routines by altering the scheduling of major processes such as long-distance migration and feather moult.


Importance of the Unstirred Water Layer and Hepatocyte Membrane Integrity In Vitro for Quantification of Intrinsic Metabolic Clearance.
Prediction of clearance-a vital component of drug discovery-remains in need of improvement and, in particular, requires more incisive assessment of mechanistic methodology in vitro, according to a number of recent reports. Although isolated hepatocytes have become an irreplaceable standard system for the measurement of intrinsic hepatic clearance mediated by active uptake transport and metabolism, the lack of prediction reliability appears to reflect a lack of methodological validation, especially for highly cleared drugs, as we have previously shown. Here, novel approaches were employed to explore fundamental experimental processes and associated potential limitations of in vitro predictions of clearance. Rat hepatocytes deemed nonviable by trypan blue staining showed undiminished metabolic activity for probe cytochrome P450 (P450) substrates midazolam and propranolol; supplementation with NADPH enhanced these activities. Extensive permeabilization of the plasma membrane using saponin showed either full or minimal P450 activity, depending on the presence or absence of 1 mM NADPH, respectively. The shaking of incubations facilitated P450 metabolic rates up to 5-fold greater than static incubation, depending on intrinsic clearance, indicating the critical influence of the unstirred water layer (UWL). Permeabilization allowed static incubation metabolic rates to approach those of shaking for intact cells, indicating an artificially induced breakdown of the UWL. Permeabilization combined with shaking allowed an increased metabolic rate for saquinavir, resolving the membrane permeability limitation for this drug. These findings advance the interpretation of the rate-limiting processes involved in intrinsic clearance measurements and could be critical for successful in vitro prediction.


Association between inbreeding depression and floral traits in a generalist-pollinated plant.
Individual variation in the magnitude of inbreeding depression (ID) in plants and its association with phenotypic traits may have important consequences for mating system evolution. This association has been investigated only scarcely, and always considering traits functionally related to autogamy. Here, we explore the association between individual variation in ID and plant traits associated with pollinator attractiveness (related to plant size, corolla size and corolla shape) in two populations of Erysimum mediohispanicum (Brassicaceae). ID was calculated along the entire life cycle of the plants. In addition, we also explored the relationship between phenotypic traits and the individual levels of heterozygosity. We found significant associations between ID and corolla diameter and stalk height, being taller plants with larger corollas those undergoing a lower intensity of ID. Furthermore, we found a negative relationship between corolla diameter and heterozygosity, suggesting that plants with large flowers have purged their genetic load. Finally, we found a significant effect of corolla diameter on the intrapopulation genetic structure. All these findings suggest that plants with large flowers have secularly suffered frequent inbreeding in the study populations. Because corolla diameter is a trait frequently selected by pollinators in E. mediohispanicum, we believe that the observed relationship between this trait and ID could be mediated by pollinators, probably throughout an increasing in biparental inbreeding, geitonogamy or autogamy.


Vitamin D Status, Disease Activity, and Endothelial Dysfunction in Early Rheumatoid Arthritis Patients.
Cardiovascular diseases represent important complications in rheumatoid arthritis (RA) patients, generated by an accelerated atherosclerosis. The aim of this study is represented by the assessment of the correlations between serum levels of vitamin D, disease activity, and endothelial dysfunction in patients with early RA. Material and Methods. The study was performed on a group of 35 patients with early RA and 35 healthy subjects matched for age and gender, as controls. In all studied subjects, the following were determined: inflammatory markers, insulin resistance, vitamin D levels, and endothelial dysfunction. Statistical analysis were performed using the Student's t-test and the Pearson's test. p values of less than 0.05 were considered statistically significant. Results. The group of patients with RA patients presented inflammation, low levels of vitamin D, elevated insulin resistance, and reduced flow-mediated vasodilation, statistically significant compared to the control group (p < 0.00001). Significant inverse correlations between the levels of 25(OH) vitamin D and DAS28, respective insulin resistance, and significant positive correlation between 25(OH) vitamin D and endothelial function were demonstrated. Conclusion. In early RA patients with moderate and high disease activity, low serum levels of vitamin D were associated with disease activity, increased insulin resistance, and endothelial dysfunction.


Analytical solutions for nonlinear cable equations with calcium dynamics. I: Derivations.
The interaction between membrane potential and internal calcium concentration plays many important roles in regulating synaptic integration and neuronal firing. In order to gain a better theoretical understanding between the voltage-calcium interaction, a nonlinear cable equation with calcium dynamics is solved analytically. This general reaction-diffusion system represents a model of a cylindrical dendritic segment in which calcium diffuses internally in the presence of buffers, pumps and exchangers, and where ion channels are sparsely distributed over the membrane,in the form of hotspots, acting as point current sources along the dendritic membrane. In order to proceed, the reaction-diffusion system is recast into a system of coupled nonlinear integral equations, with which a perturbative expansion in dimensionless voltage and calcium concentration are used to find analytical solutions to this general system. The resulting solutions can be used to investigate, the interaction between the membrane potential and underlying calcium dynamics in a natural (non-discretized) setting.


MRC2014: Extensions to the MRC format header for electron cryo-microscopy and tomography.
The MRC binary file format is widely used in the three-dimensional electron microscopy field for storing image and volume data. Files contain a header which describes the kind of data held, together with other important metadata. In response to advances in electron microscopy techniques, a number of variants to the file format have emerged which contain useful additional data, but which limit interoperability between different software packages. Following extensive discussions, the authors, who represent leading software packages in the field, propose a set of extensions to the MRC format standard designed to accommodate these variants, while restoring interoperability. The MRC format is equivalent to the map format used in the CCP4 suite for macromolecular crystallography, and the proposal also maintains interoperability with crystallography software. This Technical Note describes the proposed extensions, and serves as a reference for the standard.