A metric model of amino acid substitution.
We address the question of whether there exists an effective evolutionary model of amino-acid substitution that forms a metric-distance function. There is always a trade-off between speed and sensitivity among competing computational methods of determining sequence homology. A metric model of evolution is a prerequisite for the development of an entire class of fast sequence analysis algorithms that are both scalable, O(log n) and sensitive. We have reworked the mathematics of the point accepted mutation model (PAM) by calculating the expected time between accepted mutations in lieu of calculating log-odds probabilities. The resulting substitution matrix (mPAM) forms a metric. We validate the application of the mPAM evolutionary model for sequence homology by executing sequence queries from a controlled yeast protein homology search benchmark. We compare the accuracy of the results of mPAM and PAM similarity matrices as well as three prior metric models. The experiment shows that mPAM significantly outperforms the other three metrics and sufficiently approaches the sensitivity of PAM250 to make it applicable to the management of protein sequence databases.


Evaluation of an Employment Intervention for Veterans Transitioning From the Military: A Randomized Controlled Trial.
Military personnel face numerous challenges transitioning from military jobs to meaningful civilian employment. The Independence Project compared an innovative employment program (National Career Coach Program) with standard employment services (Local Community Resources) in a randomized controlled trial. Study participants were transitioning veterans with self-reported service-connected disabilities seeking permanent employment. The primary outcomes were paid employment and disability ratings over 1 year. Secondary outcomes included health and well-being. At 1-year follow-up, National Career Coach Program participants were significantly more likely to work, had significantly greater earnings, and reported significantly greater improvements in physical and mental health compared with participants assigned to Local Community Resources. Both groups increased in disability ratings over 12 months, with no difference between groups. Multifaceted supports delivered by the National Career Coach Program increased employment, earnings, mental health, and physical health over 1 year. These significant differences appeared even though control group participants achieved considerable employment success.


Improving inhaler adherence in patients with chronic obstructive pulmonary disease: a cost-effectiveness analysis.
The PHARMACOP-intervention significantly improved medication adherence and inhalation technique for patients with COPD compared with usual care. This study aimed to evaluate its cost-effectiveness. An economic analysis was performed from the Belgian healthcare payer's perspective. A Markov model was constructed in which a representative group of patients with COPD (mean age of 70 years, 66% male, 43% current smokers and mean Forced Expiratory Volume in 1 second of % predicted of 50), was followed for either receiving the 3-month PHARMACOP-intervention or usual care. Three types of costs were calculated: intervention costs, medication costs and exacerbation costs. Outcome measures included the number of hospital-treated exacerbations, cost per prevented hospital-treated exacerbation and cost per Quality Adjusted Life-Year. Follow-up was 1 year in the basecase analysis. Sensitivity and scenario analyses (including long-term follow-up) were performed to assess uncertainty. In the basecase analysis, the average overall costs per patient for the PHARMACOP-intervention and usual care were €2,221 and €2,448, respectively within the 1-year time horizon. This reflects cost savings of €227 for the PHARMACOP-intervention. The PHARMACOP-intervention resulted in the prevention of 0.07 hospital-treated exacerbations per patient (0.177 for PHARMACOP versus 0.244 for usual care). Results showed robust cost-savings in various sensitivity analyses. Optimization of current pharmacotherapy (e.g. close monitoring of inhalation technique and medication adherence) has been shown to be cost-saving and should be considered before adding new therapies.


The role of the VEGF-C/VEGFRs axis in tumor progression and therapy.
Vascular endothelial growth factor C (VEGF-C) has been identified as a multifaceted factor participating in the regulation of tumor angiogenesis and lymphangiogenesis. VEGF-C is not only expressed in endothelial cells, but also in tumor cells. VEGF-C signaling is important for progression of various cancer types through both VEGF receptor-2 (VEGFR-2) and VEGF receptor-3 (VEGFR-3). Likewise, both receptors are expressed mainly on endothelial cells, but also expressed in tumor cells. The dimeric VEGF-C undergoes a series of proteolytic cleavage steps that increase the protein binding affinity to VEGFR-3; however, only complete processing, removing both the N- and C-terminal propeptides, yields mature VEGF-C that can bind to VEGFR-2. The processed VEGF-C can bind and activate VEGFR-3 homodimers and VEGFR-2/VEGFR-3 heterodimers to elicit biological responses. High levels of VEGF-C expression and VEGF-C/VEGFRs signaling correlate significantly with poorer prognosis in a variety of malignancies. Therefore, the development of new drugs that selectively target the VEGF-C/VEGFRs axis seems to be an effective means to potentiate anti-tumor therapies in the future.


Menstrually related migraine: breaking the cycle in your clinical practice.
The purpose of this review is to provide a simple, evidence-based approach to the diagnosis and treatment of migraine. The review is based on clinical experience data, results from placebo-controlled trials and pharmacokinetic information of clinical importance and is a distillation of material from a comprehensive literature review of the epidemiology, pathophysiology, diagnostic features and treatment of menstrual migraine. Migraine, particularly menstrual migraine, is most prevalent in women of childbearing age. Menstrual migraine is generally severe, lasts longer, recurs more frequently, results in greater disability and is more resistant to therapy than nonmenstrual migraine. Despite the associated disability for otherwise-healthy women, migraine is frequently not diagnosed. The initial visit to an obstetrician/gynecologist is an ideal time to screen women for menstrual migraine. Triptans are effective in the acute treatment of menstrual migraine. Naratriptan and frovatriptan also have been evaluated for prophylactic efficacy. Both agents were effective in reducing the incidence of menstrual migraine. Frovatriptan also reduced the severity and duration of breakthrough headaches. Acute treatment is typically the same for menstrual and nonmenstrual migraine, involving the use of nonsteroidal antiinflammatory agents (NSAIDs), triptans or, rarely, ergot derivatives. In addition, NSAIDs, magnesium supplementation, estrogen therapy and triptans have been proven effective for short-term prevention of menstrual migraine. In some patients, continuous estrogen therapy may be necessary to control these headaches. Improved diagnosis and treatment of menstrual migraine is critical to decrease the associated disability. Acute and shortterm preventive therapy with triptans is effective; oral contraceptives may be used for long-term preventive therapy.


Mild Coronavirus Disease 2019 (COVID-19) Is Marked by Systemic Oxidative Stress: A Pilot Study.
Oxidative stress has been implicated to play a critical role in the pathophysiology of coronavirus disease 2019 (COVID-19) and may therefore be considered as a relevant therapeutic target. Serum free thiols (R-SH, sulfhydryl groups) comprise a robust marker of systemic oxidative stress, since they are readily oxidized by reactive oxygen species (ROS). In this study, serum free thiol concentrations were measured in hospitalized and non-hospitalized patients with COVID-19 and healthy controls and their associations with relevant clinical parameters were examined. Serum free thiol concentrations were measured colorimetrically (Ellman's method) in 29 non-hospitalized COVID-19 subjects and 30 age-, sex-, and body-mass index (BMI)-matched healthy controls and analyzed for associations with clinical and biochemical disease parameters. Additional free thiol measurements were performed on seven serum samples from COVID-19 subjects who required hospitalization to examine their correlation with disease severity. Non-hospitalized subjects with COVID-19 had significantly lower concentrations of serum free thiols compared to healthy controls (p = 0.014), indicating oxidative stress. Serum free thiols were positively associated with albumin (St. β = 0.710, p < 0.001) and inversely associated with CRP (St. β = -0.434, p = 0.027), and showed significant discriminative ability to differentiate subjects with COVID-19 from healthy controls (AUC = 0.69, p = 0.011), which was slightly higher than the discriminative performance of CRP concentrations regarding COVID-19 diagnosis (AUC = 0.66, p = 0.042). This study concludes that systemic oxidative stress is increased in patients with COVID-19 compared with healthy controls. This opens an avenue of treatment options since free thiols are amenable to therapeutic modulation.


Time-Resolved Stark Spectroscopy in CdSe Nanoplatelets: Exciton Binding Energy, Polarizability, and Field-Dependent Radiative Rates.
We present a study of the application potential of CdSe nanoplatelets (NPLs), a model system for colloidal 2D materials, as field-controlled emitters. We demonstrate that their emission can be changed by 28% upon application of electrical fields up to 175 kV/cm, a very high modulation depth for field-controlled nanoemitters. From our experimental results we estimate the exciton binding energy in 5.5 monolayer CdSe nanoplatelets to be EB = 170 meV; hence CdSe NPLs exhibit highly robust excitons which are stable even at room temperature. This opens up the possibility to tune the emission and recombination dynamics efficiently by external fields. Our analysis further allows a quantitative discrimination of spectral changes of the emission energy and changes in PL intensity related to broadening of the emission line width as well as changes in the intrinsic radiative rates which are directly connected to the measured changes in the PL decay dynamics. With the developed field-dependent population model treating all occurring field-dependent effects in a global analysis, we are able to quantify, e.g., the ground state exciton transition dipole moment (3.0 × 10-29 Cm) and its polarizability, which determine the radiative rate, as well as the (static) exciton polarizability (8.6 × 10-8 eV cm2/kV2), all in good agreement with theory. Our results show that an efficient field control over the exciton recombination dynamics, emission line width, and emission energy in these nanoparticles is feasible and opens up application potential as field-controlled emitters.


Exposure of farm laborers and dairy cattle to formaldehyde from footbath use at a dairy farm in New York State.
Formalin footbaths are commonly used in the dairy industry to prevent cattle hoof diseases. Although formalin is a well-documented disinfectant, it is also a carcinogen and irritant. The aim of this study was to estimate the exposure of farm workers and dairy cattle to formaldehyde from footbaths located in a milking facility and a heifer facility at a dairy farm in western New York, USA. The dairy farm included approximately 3900 dairy cattle including young stock; of these, 1670 cows were milked three times per day in a 60-stall carousel milking parlor, and approximately 800 heifers were located at the heifer facility where footbaths with formalin were in use. The formaldehyde concentration of the air was measured using a Formaldemeter™ htV approximately 50cm above the 3% formalin footbaths in the milking (one footbath location) and heifer (three footbath locations) facilities on three consecutive days. The measured formaldehyde concentrations varied between 0.00 and 2.28ppm, falling within the safety guidelines established by the Occupation Safety and Health Administration (OSHA) of the United States. Significant differences were found in the formaldehyde concentrations at the different footbath locations in the heifer facility, potentially due to the varying levels of ventilation at each location. Changes in the ambient temperature during the 3-day sampling period did not significantly affect the concentrations. We believe that the substantial ventilation at both the heifer and milking facilities ensured that the formaldehyde concentrations did not exceed OSHA guidelines, thus permitting the safe use of formalin footbaths in this farm.


beta2-Subunit-containing nicotinic acetylcholine receptors are involved in nicotine-induced increases in conditioned reinforcement but not progressive ratio responding for food in C57BL/6 mice.
Nicotine administration potentiates conditioned reinforcement in rats, an effect that persists for weeks after chronic exposure. Little is known regarding the nicotinic receptor subtypes that may mediate this effect. The purpose of this study was to determine whether beta2-subunit-containing nicotinic acetylcholine receptors (beta2*nAChRs) are necessary for lasting effects of nicotine on conditioned and primary reinforcement in mice. Beta2 knockout (beta2KO) and wild-type (WT) mice received 14 days of nicotine exposure (NIC, 200 microg/ml in 2% saccharin) or saccharin alone (SAC) in their drinking water. Five days later, mice received paired presentations of a conditioned stimulus (CS) with water unconditioned stimulus (US) or explicitly unpaired presentations of the CS and US during Pavlovian discriminative approach training. Training was followed by two conditioned reinforcement tests. Mice were subsequently tested for food-reinforced responding in the absence of explicit cues followed by a progressive ratio test. During conditioned reinforcement testing, only mice in the paired condition showed increased responding in the CS-reinforced aperture over inactive apertures. WT-NIC mice showed enhanced conditioned reinforcement compared to WT-SAC animals. beta2KO-SAC mice showed elevated conditioned reinforcement compared to WT-SAC subjects, but beta2KO-NIC and beta2KO-SAC mice did not differ in responding with conditioned reinforcement. Prior nicotine exposure did not alter food-reinforced responding but resulted in elevated break points for food in both genotypes. These data show that nicotine exposure enhances conditioned reinforcement in mice and indicate that beta2*nAChRs are necessary for nicotine-dependent enhancement of incentive aspects of motivation but not motivation for primary reinforcement measured by progressive ratio responding.


Reclassification of Parapterulicium Corner (Pterulaceae, Agaricales), contributions to Lachnocladiaceae and Peniophoraceae (Russulales) and introduction of Baltazaria gen. nov.
The genus Parapterulicium was first introduced to accommodate two Brazilian species of coralloid fungi with affinities to Pterulaceae (Agaricales). Despite the coralloid habit and the presence of skeletal hyphae, other features, notably the presence of gloeocystidia, dichophyses and papillate hyphal ends, differentiate this genus from Pterulaceaesensu stricto. Fieldwork in Brazil resulted in the rediscovery of two coralloid fungi identifiable as Parapterulicium, the first verified collections of this genus since Corner's original work in the 1950s. Molecular phylogenetic analyses of nrITS and nrLSU sequences from these modern specimens revealed affinities with the /peniophorales clade in the Russulales, rather than Pterulaceae. The presence of distinctive hyphal elements, homologous to the defining features of /peniophorales, is consistent with the phylogenetic evidence and thus clearly distinguished Parapterulicium and its type species P.subarbusculum from Pterulaceae, placing this genus within /peniophorales. Parapterulicium was also found to be polyphyletic so Baltazaria gen. nov. is proposed to accommodate P.octopodites, Scytinostromagalactinum, S.neogalactinum and S.eurasiaticogalactinum also within /peniophorales.


Advanced Neurotechnologies for the Restoration of Motor Function.
Stroke is one of the leading causes of long-term disability. Advanced technological solutions ("neurotechnologies") exploiting robotic systems and electrodes that stimulate the nervous system can increase the efficacy of stroke rehabilitation. Recent studies on these approaches have shown promising results. However, a paradigm shift in the development of new approaches must be made to significantly improve the clinical outcomes of neurotechnologies compared with those of traditional therapies. An "evolutionary" change can occur only by understanding in great detail the basic mechanisms of natural stroke recovery and technology-assisted neurorehabilitation. In this review, we first describe the results achieved by existing neurotechnologies and highlight their current limitations. In parallel, we summarize the data available on the mechanisms of recovery from electrophysiological, behavioral, and anatomical studies in humans and rodent models. Finally, we propose new approaches for the effective use of neurotechnologies in stroke survivors, as well as in people with other neurological disorders.


A Scoping Review on Long COVID-19: Physiological and Psychological Symptoms Post-Acute, Long-Post and Persistent Post COVID-19.
Background: The identification of persistent symptoms of chronic/long COVID-19 is crucial in understanding the management of long haulers of post COVID-19. Methods: Pub Med (Medline) database was scoped for original articles based on a search strategy related to the objectives. The selected articles post-screening were analyzed for variables relating to chronic/long COVID-19. Results were analyzed using descriptive statistics. Results: A total of 33 studies were reviewed. A total of 60% of the studies were observational studies and most of them were from high income countries. Almost half of the studies were in phase 3 of post-COVID-19, i.e., symptoms lasting >24 weeks. Among the physiological and psychological symptoms studied, fatigue, dyspnea, cough, headache, memory loss, depression, brain fog and lack of concentration were found to be the most frequently reported symptoms. Excessive sleep, constipation and neuropathic pain were among the least reported symptoms. Prior hospitalization, the female gender was found to be a risk factor. Limitations were reported by all studies. Conclusions: The major physiological and psychological symptoms of long COVID-19 have been explained with risk factors and its impact on patients' lifestyles. The findings of this review hope to facilitate clinicians to draw conclusions to manage the long-term effects of post/chronic COVID-19.


Dantrolene sodium: long-term effects in patients with muscle spasticity.
Seventy-seven patients with muscle spasticity secondary to central nervous system pathology were treated with dantrolene sodium for periods of up to two years. The drug was effective in reducing muscle spasms, clonus, muscle tone, and the force of muscle contraction elicited by Achilles tendon tap and tibial nerve stimulation, but improvement of function was seen less often. The incidence of side-effects was considerable, and poses a problem regarding patient acceptance of drug treatment.


Differential pharmacokinetics of lithium in elderly patients.
The pharmacotherapeutic use of lithium in the elderly as acute and maintenance therapy in bipolar disorder and augmentation therapy for major depression is well documented. Differences in the response to lithium are explained, in part, by the effect of age-related physiological changes, comorbid conditions, and concurrent medications on the pharmacokinetics of lithium in the elderly. The pharmacokinetic profile of lithium has been studied for many years, primarily in younger adult populations. Lithium pharmacokinetics may be influenced by a number of factors including age. It was first noted several years ago that elderly individuals required lower doses of lithium to achieve serum concentrations similar to those observed in younger adults. This is due to the combination of a reduced volume of distribution and reduced renal clearance. The composition of the human body changes with aging producing an increase in body fat, a decrease in fat-free mass and a decrease in total body water. Lithium clearance decreases as the glomerular filtration rate decreases with increasing age. The effects of other medical conditions in the elderly on the pharmacokinetics of lithium are less well delineated. Reduced lithium clearance is expected in patients with hypertension, congestive heart failure or renal dysfunction. Larger lithium maintenance doses are required in obese compared with non-obese patients. The most clinically significant pharmacokinetic drug interactions associated with lithium involve drugs which are commonly used in the elderly. Thiazide diuretics, ACE inhibitors, and nonsteroidal anti-inflammatory drugs can increase serum lithium concentrations. The tolerability of lithium is lower in the elderly. Neurotoxicity clearly occurs in the elderly at concentrations considered 'therapeutic' in general adult populations. There are no placebo-controlled randomised trials of lithium in old age and recommendations for clinical use are based on extrapolations from pharmacokinetic studies, anecdotal reports from mixed age populations and clinical experience in old age psychiatry. Serum concentrations of lithium need to be markedly reduced in the elderly population and particularly so in the very old and frail elderly.


Clinical Aspects of Miscarriage.
It is estimated that 750,000 to 1,000,000 miscarriages occur every year in the United States. Women experiencing a miscarriage enter the healthcare system in a variety of ways. A family may be seen for a miscarriage in the prenatal clinic, the emergency department, same-day surgical department, or perhaps the labor and birth unit. Nurses must be prepared to guide and support these families. Understanding the clinical aspects of miscarriage as well as the emotional care of families experiencing early pregnancy loss is important to nurses in all areas of the medical center. Clinical aspects of miscarriage are reviewed along with the needed emotional care for families experiencing the most common cause of early pregnancy loss.


Targeted isolation of cloned genomic regions by recombineering for haplotype phasing and isogenic targeting.
Studying genetic variations in the human genome is important for understanding phenotypes and complex traits, including rare personal variations and their associations with disease. The interpretation of polymorphisms requires reliable methods to isolate natural genetic variations, including combinations of variations, in a format suitable for downstream analysis. Here, we describe a strategy for targeted isolation of large regions (∼35 kb) from human genomes that is also applicable to any genome of interest. The method relies on recombineering to fish out target fosmid clones from pools and thereby circumvents the laborious need to plate and screen thousands of individual clones. To optimize the method, a new highly recombineering-efficient bacterial host, including inducible TrfA for fosmid copy number amplification, was developed. Various regions were isolated from human embryonic stem cell lines and a personal genome, including highly repetitive and duplicated ones. The maternal and paternal alleles at the MECP2/IRAK 1 loci were distinguished based on identification of novel allele-specific single-nucleotide polymorphisms in regulatory regions. Additionally, we applied further recombineering to construct isogenic targeting vectors for patient-specific applications. These methods will facilitate work to understand the linkage between personal variations and disease propensity, as well as possibilities for personal genome surgery.


Do Pentavalent (DTwP-Hib-HBV) vaccines have sex-differential nonspecific effects? An observational study.
Vaccines may alter the ability to combat infections unrelated to the target disease, i.e. have "nonspecific effects." The non-live Diphtheria-Tetanus-Pertussis vaccine (DTP) has been associated with increased child mortality, especially for females. In 2008, the DTP-containing Pentavalent vaccine replaced DTP vaccine in Guinea-Bissau. We investigate female relative to male mortality after Penta vaccination. In Guinea-Bissau, Bandim Health Project (BHP) registered children's vaccination and vital status at biannual village visits and provided vaccines. Among children Penta-vaccinated by BHP, we compared mortality of males and females in Cox proportional hazards models. Children aged 6 weeks to 8 months entered the analysis at the date of vaccination and were followed for up to 6 months. Between September 2008 and December 2017, 33,989 children aged 6 weeks to 8 months were under surveillance. Of these 12,753 (females: 6,363; males: 6,390) received Penta by the BHP and entered the study contributing with 19,667 observations. The mortality rate following Penta vaccination was 25.2 per 1,000 person years for females and 26.6 for males, resulting in an adjusted Female/Male mortality rate ratio of (F/M aMRR) 1.01 (0.82-1.25). The association between sex and mortality differed by timeliness of vaccination, F/M aMRR: 0.62 (0.41-0.93) for children vaccinated below median age, and F/M aMRR: 1.38 (0.90-2.13) for children vaccinated above median age. We did not find higher overall mortality in females than males after Penta vaccination. Our findings suggest that mortality differences between males and females following Penta vaccination may depend on timeliness of Penta vaccination.


Neonatal anthropometrics and body composition in obese children investigated by dual energy X-ray absorptiometry.
Epidemiological and animal studies have suggested an effect of the intrauterine milieu upon the development of childhood obesity. This study investigates the relationship between body composition measured by dual energy X-ray absorptiometry expressed as body fat percent, body fat mass index (BFMI), and fat free mass index (FFMI) in obese children and the preceding in utero conditions expressed by birth weight, birth length, and birth weight for gestational age. The study cohort consisted of 776 obese Danish children (median age 11.6 years, range 3.6-17.9) with a mean Body Mass Index Standard Deviation Score (BMI SDS) of 2.86 (range 1.64-5.48) treated in our national referral centre. In a linear general regression model adjusted for age, gender, socioeconomic status, and duration of breastfeeding, we found the body fat percent, FFMI, and BFMI at the time of enrolment in childhood obesity treatment to be significantly correlated with both birth weight and birth weight for gestational age. These results indicate a prenatal influence upon childhood obesity. Although there are currently no sufficient data to suggest any recommendations to pregnant women, it is possible that the prenatal period may be considered as a potential window of opportunity for prevention of childhood overweight and obesity.


Prognostic value of routine preoperative electrocardiography in patients undergoing noncardiac surgery.
Electrocardiography is commonly performed as part of preoperative cardiovascular risk assessment in patients undergoing noncardiac surgery. However, the prognostic value of such electrocardiography is still not clear. This study retrospectively studied 23,036 patients who underwent 28,457 surgical procedures at Erasmus Medical Center from 1991 to 2000. Patients were screened before surgery by type of surgery, cardiovascular risk factors (history of coronary heart disease, heart failure, diabetes mellitus, renal dysfunction, and stroke), and preoperative electrocardiography. Electrocardiographic (ECG) results showing atrial fibrillation, left or right bundle branch block, left ventricular hypertrophy, premature ventricular complexes, pacemaker rhythm, or Q-wave or ST-segment changes were classified as abnormal. Multivariate logistic regression was applied to evaluate the relation between ECG abnormalities and cardiovascular death. In-hospital cardiovascular death was observed in 199 of 28,457 patients (0.7%). Patients with abnormal ECG findings had a greater incidence of cardiovascular death than those with normal ECG results (1.8% vs 0.3%; adjusted odds ratio 4.5, 95% confidence interval 3.3 to 6.0). Adding ECG data to clinical risk factors and the type of surgery resulted in an improved C index for the prediction of cardiovascular death (0.79 vs 0.72). However, in patients who underwent low-risk or low- to intermediate-risk surgery, the absolute difference in the incidence of cardiovascular death between those with and without ECG abnormalities was only 0.5%. In conclusion, preoperative electrocardiography provides prognostic information in addition to clinical characteristics and the type of surgery. However, the usefulness of its routine use in lower risk surgery is questionable.


Comparison of right and left grafts in renal transplantation.
This study compares outcomes and graft function of right and left grafts of deceased donor. We studied 120 kidney recipients from 60 deceased donors in Shiraz organ transplantation center from 1988 to 2004. We analyzed data regarding age, gender, side of grafts, duration of pre-transplant dialysis, hospital stay, serial creatinine levels, cold ischemic time, complications, graft function, patient survival rates, and post-operative complications. Recipients were divided into two groups: group 1 consisted of 60 recipients who received right renal graft (43 males, 17 females; mean age: 33.6 +/- 7.3 years), and group 2 consisted of 60 recipients who received left renal graft (45 males, 15 females; mean age: 29.2 +/- 6.4 years). No statistically significant differences were found in duration of pre-transplant dialysis, cold ischemic time, acute rejection rates, post-operative surgical and vascular complications' rates, hospital stay, renal function, and one year graft survival rates. We conclude that although it is advised to use left kidney from live donors because of longer vessel length, easier surgical technique and organ handling, and shorter ischemic time, we got the same outcome in left and right deceased renal grafts.


RASSF1A promotes ATM signaling and RASSF1A methylation is a synthetic lethal marker for ATR inhibitors.
Aim: The mechanism of RASSF1A in DNA damage repair remains to be further clarified for applying to synthetic lethal strategy. Materials & methods: Eight esophageal cancer cell lines, 181 cases of esophageal dysplasia and 1066 cases of primary esophageal squamous cell carcinoma (ESCC) were employed. Methylation-specific PCR, the CRISPR/Cas9 technique, immunoprecipitation assay and a xenograft mouse model were used. Results: RASSF1A was methylated in 2.21% of esophageal dysplasia and 11.73% of ESCC. RASSF1A was also involved in DNA damage repair through activating Hippo signaling. Loss of RASSF1A expression sensitized esophageal cancer cell lines to ataxia telangiectasia mutated and rad3-related (ATR) inhibitor (VE-822) both in vitro and in vivo. Conclusion: RASSF1A methylation is a synthetic lethal marker for ATR inhibitors.


Silencing spinal interneurons inhibits immune suppressive autonomic reflexes caused by spinal cord injury.
Spinal cord injury (SCI) at high spinal levels (e.g., above thoracic level 5) causes systemic immune suppression; however, the underlying mechanisms are unknown. Here we show that profound plasticity develops within spinal autonomic circuitry below the injury, creating a sympathetic anti-inflammatory reflex, and that chemogenetic silencing of this reflex circuitry blocks post-SCI immune suppression. These data provide new insights and potential therapeutic options for limiting the devastating consequences of post-traumatic autonomic hyperreflexia and post-injury immune suppression.


The acetochlor registration partnership surface water monitoring program for four corn herbicides.
A surface drinking water monitoring program for four corn (Zea mays L.) herbicides was conducted during 1995-2001. Stratified random sampling was used to select 175 community water systems (CWSs) within a 12-state area, with an emphasis on the most vulnerable sites, based on corn intensity and watershed size. Finished drinking water was monitored at all sites, and raw water was monitored at many sites using activated carbon, which was shown capable of removing herbicides and their degradates from drinking water. Samples were collected biweekly from mid-March through the end of August, and twice during the off-season. The analytical method had a detection limit of 0.05 microg L(-1) for alachlor [2-chloro-N-(2,6-diethylphenyl)-N-(methoxymethyl)-acetamide] and 0.03 microg L(-1) for acetochlor [2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl)-acetamide], atrazine [6-chloro-N-ethyl-N'-(1-methylethyl)-1,3,5-triazine-2,4-diamine], and metolachlor [2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)-acetamide]. Of the 16528 drinking water samples analyzed, acetochlor, alachlor, atrazine, and metolachlor were detected in 19, 7, 87, and 53% of the samples, respectively. During 1999-2001, samples were also analyzed for the presence of six major degradates of the chloroacetanilide herbicides, which were detected more frequently than their parent compounds, despite having higher detection limits of 0.1 to 0.2 microg L(-1). Overall detection frequencies were correlated with product use and environmental fate characteristics. Reservoirs were particularly vulnerable to atrazine, which exceeded its 3 microg L(-1) maximum contaminant level at 25 such sites during 1995-1999. Acetochlor annualized mean concentrations (AMCs) did not exceed its mitigation trigger (2 microg L(-1)) at any site, and comparisons of observed levels with standard measures of human and ecological hazards indicate that it poses no significant risk to human health or the environment.


Inductive processes leading to inner ear formation during Xenopus development.
This study examines the spatial and temporal attributes of inner ear induction in Xenopus embryos. These results are compared to recent experiments concerning lens induction to assess whether head sensory structures share common ontogenetic features. Ectoderm from different regions and stages was transplanted to the presumptive ear region of hosts of either early (neural plate) or late (neural tube) stages. Explants of the presumptive ear ectoderm were also taken from embryos at these stages to establish the time of otic ectoderm specification. We find that ectodermal competence for otic vesicle formation extends through neural plate stages, far longer than for lens formation. Otic vesicle specification occurs substantially earlier, at neural plate stages, than lens specification. Competent ectoderm forms otic vesicles in a high fraction of cases when exposed to the ear-inducing environment of either neural plate stages or neural tube stages, a result which contrasts with lens induction where the neural tube stage embryo provides a much weaker inducing environment than earlier stages. Otic vesicles induced in neural tube stage hosts are primarily in contact with presumptive hindbrain, suggesting that this neural tissue may be sufficient for otic vesicle induction. These studies reveal overall similarities between lens and inner ear induction, but sufficient differences to propose that some facets of determination of these sensory tissues may occur by independent mechanisms and not via a common developmental state.


Vacuolar Sequestration of Azoles, a Novel Strategy of Azole Antifungal Resistance Conserved across Pathogenic and Nonpathogenic Yeast.
Target alteration and overproduction and drug efflux through overexpression of multidrug transporters localized in the plasma membrane represent the conventional mechanisms of azole antifungal resistance. Here, we identify a novel conserved mechanism of azole resistance not only in the budding yeast Saccharomyces cerevisiae but also in the pathogenic yeast Candida albicans We observed that the vacuolar-membrane-localized, multidrug resistance protein (MRP) subfamily, ATP-binding cassette (ABC) transporter of S. cerevisiae, Ybt1, could import azoles into vacuoles. Interestingly, the Ybt1 homologue in C. albicans, Mlt1p, could also fulfill this function. Evidence that the process is energy dependent comes from the finding that a Mlt1p mutant version made by converting a critical lysine residue in the Walker A motif of nucleotide-binding domain 1 (required for ATP hydrolysis) to alanine (K710A) was not able to transport azoles. Additionally, we have shown that, as for other eukaryotic MRP subfamily members, deletion of the conserved phenylalanine amino acid at position 765 (F765Δ) results in mislocalization of the Mlt1 protein; this mislocalized protein was devoid of the azole-resistant attribute. This finding suggests that the presence of this protein on vacuolar membranes is an important factor in azole resistance. Further, we report the importance of conserved residues, because conversion of two serines (positions 973 and 976, in the regulatory domain and in the casein kinase I [CKI] consensus sequence, respectively) to alanine severely affected the drug resistance. Hence, the present study reveals vacuolar sequestration of azoles by the ABC transporter Ybt1 and its homologue Mlt1 as an alternative strategy to circumvent drug toxicity among pathogenic and nonpathogenic yeasts.


Dural MALT lymphoma with disseminated disease.
Central nervous system (CNS) lymphoma involving the dura mater is very rare and histologically is usually a subtype of non-Hodgkin's lymphoma (NHL) termed mucosa-associated lymphoid tissue (MALT) lymphoma. We present a case of a 46-year old woman with dural MALT lymphoma that was found to also involve a lacrimal gland, inguinal lymph nodes, and bone marrow. Magnetic resonance imaging of the brain showed an extra-axial enhancing mass approximately 6 cm in maximum diameter along the right frontotemporal convexity. Histopathology of the resected dural mass showed MALT lymphoma expressing CD20, CD52, CD19, and CD38. Molecular studies of the B-cell receptor heavy chain demonstrated monoclonality at the involved sites. The patient was treated with four cycles of fludarabine, mitoxantrone, and rituximab with complete remission. She had recurrence in the subcutaneous tissue of the back at 12 months but has remained free of intracranial disease for 31 months. A review of the literature reveals 57 cases of dural MALT lymphoma. Only 4 had extra-CNS involvement at presentation, and only 3 had local recurrence of the dural tumor. Because of the indolent behavior of this tumor, the intracranial portion can be treated conservatively after resection with or without chemotherapy. Deferral of brain radiation can be considered with close clinical and neuroimaging follow up.


Comparative Effects of Mindfulness and Support and Information Group Interventions for Parents of Adults with Autism Spectrum Disorder and Other Developmental Disabilities.
This study evaluated two community based interventions for parents of adults with autism spectrum disorder and other developmental disabilities. Parents in the mindfulness group reported significant reductions in psychological distress, while parents in the support and information group did not. Reduced levels of distress in the mindfulness group were maintained at 20 weeks follow-up. Mindfulness scores and mindful parenting scores and related constructs (e.g., self-compassion) did not differ between the two groups. Results suggest the psychological components of the mindfulness based group intervention were effective over and above the non-specific effects of group processes and informal support.


Effects of Zingiber officinale on the plasma pharmacokinetics and lung penetrations of ciprofloxacin and isoniazid.
The study was carried out to determine the effect of ginger on the plasma pharmacokinetics of ciprofloxacin and Isoniazid in a rat model in phase 1. The effects of the herb on the penetration of ciproflacin and Isoniazid into the lung tissues were also determined in phase 2. In phase 1, Albino rats of both sexes (n = 20) were divided into 4 groups of 5 rats per group. Two groups received oral ciprofloxacin (20 mg/kg) and isoniazid (15 mg/kg). Other groups were fed with ginger (5 mg/kg) for 10 days followed by the drug administration on the 11th day. Blood samples were collected from each group at 0-, 0.5-, 1-, 2-, 5-, 8-, 12-, and 24-hour intervals. Plasma concentrations of the drugs were determined by a spectrophotometric method and the pharmacokinetic parameters determined using noncompartmental method as implemented in the winNonlin program. In phase 2, where the effects of the herb on the penetration of the drugs were determined, the concentrations of ciprofloxacin and isoniazid attained in the lung fluid of rats in the presence and absence of the herb were compared after a single oral dose of the drugs used in the same dose range as in phase 1. In the first phase, treatment with ginger significantly increased the area under the concentration-time curve of ciprofloxacin, whereas Vz and Cl were decreased. Ginger significantly decreased the area under the concentration-time curve of isoniazid, whereas Vz and Cl were increased. Ginger enhanced the penetration of ciprofloxacin and Isoniazid into the lung tissues; however, their rates of penetration were delayed.


High-resolution microPET imaging of carcinoembryonic antigen-positive xenografts by using a copper-64-labeled engineered antibody fragment.
Rapid imaging by antitumor antibodies has been limited by the prolonged targeting kinetics and clearance of labeled whole antibodies. Genetically engineered fragments with rapid access and high retention in tumor tissue combined with rapid blood clearance are suitable for labeling with short-lived radionuclides, including positron-emitting isotopes for positron-emission tomography (PET). An engineered fragment was developed from the high-affinity anticarcinoembryonic antigen (CEA) monoclonal antibody T84.66. This single-chain variable fragment (Fv)-C(H)3, or minibody, was produced as a bivalent 80 kDa dimer. The macrocyclic chelating agent 1,4,7, 10-tetraazacyclododecane-N,N',N", N"'-tetraacetic acid (DOTA) was conjugated to the anti-CEA minibody for labeling with copper-64, a positron-emitting radionuclide (t(1/2) = 12.7 h). In vivo distribution was evaluated in athymic mice bearing paired LS174T human colon carcinoma (CEA positive) and C6 rat glioma (CEA negative) xenografts. Five hours after injection with (64)Cu-DOTA-minibody, microPET imaging showed high uptake in CEA-positive tumor (17.9% injected dose per gram +/- 3.79) compared with control tumor (6.0% injected dose per gram +/- 1.0). In addition, significant uptake was seen in liver, with low uptake in other tissues. Average target/background ratios relative to neighboring tissue were 3-4:1. Engineered antibody fragments labeled with positron-emitting isotopes such as copper-64 provide a new class of agents for PET imaging of tumors.


VAP-A and its binding partner CERT drive biogenesis of RNA-containing extracellular vesicles at ER membrane contact sites.
RNA transfer via extracellular vesicles (EVs) influences cell phenotypes; however, lack of information regarding biogenesis of RNA-containing EVs has limited progress in the field. Here, we identify endoplasmic reticulum membrane contact sites (ER MCSs) as platforms for the generation of RNA-containing EVs. We identify a subpopulation of small EVs that is highly enriched in RNA and regulated by the ER MCS linker protein VAP-A. Functionally, VAP-A-regulated EVs are critical for miR-100 transfer between cells and in vivo tumor formation. Lipid analysis of VAP-A-knockdown EVs revealed reductions in the EV biogenesis lipid ceramide. Knockdown of the VAP-A-binding ceramide transfer protein CERT led to similar defects in EV RNA content. Imaging experiments revealed that VAP-A promotes luminal filling of multivesicular bodies (MVBs), CERT localizes to MVBs, and the ceramide-generating enzyme neutral sphingomyelinase 2 colocalizes with VAP-A-positive ER. We propose that ceramide transfer via VAP-A-CERT linkages drives the biogenesis of a select RNA-containing EV population.


Maize responsiveness to Azospirillum brasilense: Insights into genetic control, heterosis and genomic prediction.
Several studies have shown differences in the abilities of maize genotypes to facilitate or impede Azospirillum brasilense colonization and to receive benefits from this association. Hence, our aim was to study the genetic control, heterosis effect and the prediction accuracy of the shoot and root traits of maize in response to A. brasilense. For that, we evaluated 118 hybrids under two contrasting scenarios: i) N stress (control) and ii) N stress plus A. brasilense inoculation. The diallel analyses were performed using mixed model equations, and the genomic prediction models accounted for the general and specific combining ability (GCA and SCA, respectively) and the presence or not of G×E effects. In addition, the genomic models were fitted considering parametric (G-BLUP) and semi-parametric (RKHS) kernels. The genotypes showed significant inoculation effect for five root traits, and the GCA and SCA were significant for both. The GCA in the inoculated treatment presented a greater magnitude than the control, whereas the opposite was observed for SCA. Heterosis was weakly influenced by the inoculation, and the heterozygosity and N status in the plant can have a role in the benefits that can be obtained from this Plant Growth-Promoting Bacteria (PGPB). Prediction accuracies for N stress plus A. brasilense ranged from 0.42 to 0.78, depending on the scenario and trait, and were higher, in most cases, than the non-inoculated treatment. Finally, our findings provide an understanding of the quantitative variation of maize responsiveness to A. brasilense and important insights to be applied in maize breeding aiming the development of superior hybrids for this association.


[Caring for children and adolescents with cancer: the intrathecal chemotherapy phase].
This study aims to explore the experiences of children and adolescents with cancer during the intrathecal chemotherapy phase, by means of a qualitative approach. Empirical data were collected on the basis of semi-structured interviews. Study participants were eleven children/adolescents who received intrathecal chemotherapy, between 07 and 16 years old, from both genders, attended at a hospital school in the interior of São Paulo State, Brazil. Results converged towards the following issues: intrathecal routine; fear, pain and relief fantasies and strategies. This study gave access to important information with a view to caring for children/adolescents during the intrathecal chemotherapy phase, which is considered as one of the most stressing situations. With respect to nursing implications, we identified the vital nature of information for children/adolescents with cancer since this makes it possible to minimize uncertainties and negative feelings and makes them collaborate and participate in treatment.


[The general principles of synaptic plasticity in the neocortex, hippocampus and cerebellum].
The unitary model of synaptic plasticity for the neocortical, hippocampal and cerebellar Purkinje cells is proposed. The model is based on the new modification rules. It was assumed that the necessary conditions for synaptic modifications are: the coincidence of pre- and postsynaptic cells activity (Hebbian rule) and the change of pre- and/or postsynaptic cell activity during the time that is sufficient for the shift of the ratio between protein kinases and protein phosphatases in postsynaptic cell. According to the suggested model similar mechanisms underlie homo-, hetero- and associative LTP and LTD of excitatory and inhibitory synaptic transmission. The involvement of cAMP and cGMP in synaptic plasticity of neocortical/hippocampal and Purkinje cells, correspondingly, may underlie the different Ca(2+)-dependent modification rules in these structures. The model is used for the analysis of stimulation parameters influence on the direction of synaptic modification. It is shown that stimulation frequency (Ca2+ rise) necessary for LTP or LTD induction is relative but not absolute.


Transcriptional states of CAR-T infusion relate to neurotoxicity - lessons from high-resolution single-cell SOM expression portraying.
Anti-CD19 CAR-T cell immunotherapy is a hopeful treatment option for patients with B cell lymphomas, however it copes with partly severe adverse effects like neurotoxicity. Single-cell resolved molecular data sets in combination with clinical parametrization allow for comprehensive characterization of cellular subpopulations, their transcriptomic states, and their relation to the adverse effects. We here present a re-analysis of single-cell RNA sequencing data of 24 patients comprising more than 130,000 cells with focus on cellular states and their association to immune cell related neurotoxicity. For this, we developed a single-cell data portraying workflow to disentangle the transcriptional state space with single-cell resolution and its analysis in terms of modularly-composed cellular programs. We demonstrated capabilities of single-cell data portraying to disentangle transcriptional states using intuitive visualization, functional mining, molecular cell stratification, and variability analyses. Our analysis revealed that the T cell composition of the patient's infusion product as well as the spectrum of their transcriptional states of cells derived from patients with low ICANS grade do not markedly differ from those of cells from high ICANS patients, while the relative abundancies, particularly that of cycling cells, of LAG3-mediated exhaustion and of CAR positive cells, vary. Our study provides molecular details of the transcriptomic landscape with possible impact to overcome neurotoxicity.


Dengue vaccines: problems and prospects.
The extent of cumulative disease burden caused by dengue virus has attained an unprecedented level in recent times with sharp increase in the size of human population at risk. Dengue disease presents highly complex medical, economic and ecologic problems. The surge in publications on the development of dengue vaccines, taking advantage of new generation of biotechnology techniques indicates the profound interest and urgency in the scientific and medical communities in combating this disease. This review summarizes the importance of critical subjects like pathogenesis of dengue haemorrhagic fever and inadequacy of animal model that have adversely affected dengue vaccine development. Further, the remarkable progresses so far made in dengue vaccine research not only employing a diverse range of new strategies but also re-using old techniques to improve the existing vaccines, have been presented. The efficacy and safety of some of the new vaccine candidates have been evaluated and proven in human preclinical/clinical trials. Besides the technical advancement in vaccine development, vaccine safety and vaccine formulation have been examined.


Psoas Muscle Index as a Predictor of Perioperative Outcomes in Geriatric Patients Undergoing Spine Surgery.
Single-center retrospective study. The objective of this study was to evaluate the association of psoas muscle mass defined sarcopenia with perioperative outcomes in geriatric patients undergoing elective spine surgery. We included geriatric patients undergoing thoracolumbar spinal surgery. Total psoas surface area (TPA) was measured on preoperative axial computerized tomography or magnetic resonance imaging at the L3 vertebra and normalized to the L3 vertebral body area. Patients were divided into quartiles by normalized TPA, and the fourth quartile (Q4) was compared to quartiles 1-3 (Q1-3). Outcomes included perioperative transfusions, length of stay (LOS), delirium, pseudoarthrosis, readmission, discharge disposition, revision surgery, and mortality. Of the patients who met inclusion criteria (n = 196), the average age was 73.4 y, with 48 patients in Q4 and 148 patients in Q1-3. Q4 normalized TPA cut-off was <1.05. Differences in Q4 preoperative characteristics included significantly lower body mass index, baseline creatinine, and a greater proportion of females (Table 1). Q4 patients received significantly more postoperative red blood cell and platelet transfusions and had longer ICU LOS (P < .05; Table 2). There was no difference in intraoperative transfusion volumes, delirium, initiation of walking, discharge disposition, readmission, pseudoarthrosis, or revision surgery (Tables 2 and 3). Mortality during follow-up was higher in Q4 but was not statistically significant (P = .075). Preoperative TPA in geriatric patients undergoing elective spine surgery is associated with increased need for intensive care and postoperative blood transfusion. Preoperative normalized TPA is a convenient measurement and could be included in geriatric preoperative risk assessment algorithms.


Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor.
The novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The escalating number of SARS-CoV-2-infected individuals has conferred the viral spread with the status of global pandemic. However, there are no prophylactic or therapeutic drugs available on the market to treat COVID-19, although several drugs have been approved. Recently, two articles using the comparative viral-human protein-protein interaction map revealed that the sigma-1 receptor in the endoplasmic reticulum plays an important role in SARS-CoV-2 replication in cells. Knockout and knockdown of SIGMAR1 (sigma-1 receptor, encoded by SIGMAR1) caused robust reductions in SARS-CoV-2 replication, which indicates that the sigma-1 receptor is a key therapeutic target for SARS-CoV-2 replication. Interestingly, a recent clinical trial demonstrated that treatment with the antidepressant fluvoxamine, which has a high affinity at the sigma-1 receptor, could prevent clinical deterioration in adult outpatients infected with SARS-CoV-2. In this review, we discuss the brief history of the sigma-1 receptor and its role in SARS-CoV-2 replication in cells. Here, we propose repurposing of traditional central nervous system (CNS) drugs that have a high affinity at the sigma-1 receptor (i.e., fluvoxamine, donepezil, ifenprodil) for the treatment of SARS-CoV-2-infected patients. Finally, we discussed the potential of other CNS candidates such as cutamesine and arketamine.


Negative cross-resistance of a pyrethroid-resistant Drosophila mutant to Phryma leptostachya-derived haedoxan A.
Voltage-gated sodium channels are the primary target of pyrethroid insecticides. Mutations in sodium channel confer knockdown resistance (kdr) to pyrethroids in various arthropod pests. Haedoxan A (HA) is the major insecticidal component from Phryma leptostachya. It has been shown that HA alters electrical responses at the Drosophila neuromuscular junction and modifies the gating properties of cockroach sodium channels expressed in Xenopus oocytes. However, whether sodium channel mutations that confer pyrethroid resistance also affect the action of HA is unknown. In this study, we conducted bioassays using HA and permethrin in two Drosophila melanogaster strains: w1118 , an insecticide-susceptible strain, and parats1 , a pyrethroid-resistant strain due to a I265N mutation in the sodium channel, and identified a new case of negative cross-resistance (NCR) between permethrin and HA. Both parats1 larvae and adults were more resistant to permethrin, as expected. However, both parats1 larvae and adults were more sensitive to HA compared to w1118 . We confirmed that the I265N mutation reduced the sensitivity to permethrin of a Drosophila sodium channel variant, DmNav 22, expressed in Xenopus oocytes. Interestingly, the I265N mutation also abolished the effect of HA on sodium channels. Further characterization showed that I265 on the sodium channels is critical for the action of both pyrethroids and HA on sodium channels, pointing to an overlapping mode of action between pyrethroids and HA on the sodium channel. Overall, our results suggest an I265N-independnt mechanism(s) in parats1 flies that is responsible for the NCR between permethrin and HA at the whole insect level.


Cities, traffic, and CO2: A multidecadal assessment of trends, drivers, and scaling relationships.
Emissions of CO2 from road vehicles were 1.57 billion metric tons in 2012, accounting for 28% of US fossil fuel CO2 emissions, but the spatial distributions of these emissions are highly uncertain. We develop a new emissions inventory, the Database of Road Transportation Emissions (DARTE), which estimates CO2 emitted by US road transport at a resolution of 1 km annually for 1980-2012. DARTE reveals that urban areas are responsible for 80% of on-road emissions growth since 1980 and for 63% of total 2012 emissions. We observe nonlinearities between CO2 emissions and population density at broad spatial/temporal scales, with total on-road CO2 increasing nonlinearly with population density, rapidly up to 1,650 persons per square kilometer and slowly thereafter. Per capita emissions decline as density rises, but at markedly varying rates depending on existing densities. We make use of DARTE's bottom-up construction to highlight the biases associated with the common practice of using population as a linear proxy for disaggregating national- or state-scale emissions. Comparing DARTE with existing downscaled inventories, we find biases of 100% or more in the spatial distribution of urban and rural emissions, largely driven by mismatches between inventory downscaling proxies and the actual spatial patterns of vehicle activity at urban scales. Given cities' dual importance as sources of CO2 and an emerging nexus of climate mitigation initiatives, high-resolution estimates such as DARTE are critical both for accurately quantifying surface carbon fluxes and for verifying the effectiveness of emissions mitigation efforts at urban scales.


Specific interaction between beta-lactams and soluble penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus: development of a chromogenic assay.
We investigated the enzymatic acylation of penicillin-binding protein 2a (PBP 2a) from methicillin-resistant Staphylococcus aureus by beta-lactams. Using a purified, soluble form of the protein (PBP 2a'), we observed beta-lactam-induced in vitro precipitation following first-order kinetics with respect to protein concentration. We used electrospray mass ionization spectrometry to show that the protein precipitate predominantly contained PBP 2a', with the beta-lactam bound to it in a 1:1 molar ratio. Using nitrocefin, a chromogenic beta-lactam, we confirmed the correlation between PBP 2a' precipitation and its beta-lactam-dependent enzymatic acylation by monitoring the absorbance associated with the precipitate. Finally, dissolving the precipitate in urea, we developed a simple in vitro chromogenic assay to monitor beta-lactam-dependent enzymatic acylation of PBP 2a'. This assay represents a significant improvement over the traditional radioactive penicillin-binding assay.


Thermal Model of an Omnimagnet for Performance Assessment and Temperature Control.
An Omnimagnet is an electromagnetic device that enables remote magnetic manipulation of devices such as medical implants and microrobots. It is composed of three orthogonal nested solenoids with a ferromagnetic core at the center. Electrical current within the solenoids leads to undesired temperature increase within the Omnimagnet. If the temperature exceeds the melting point of the wire insulation, device failure may occur. Thus, a study of heat transfer within an Omnimagnet is a necessity, particularly to maximize the performance of the device. A transient heat transfer model that incorporates all three heat transfer modes is proposed and experimentally validated with an average normalized root-mean-square error of less than 4% (data normalized by temperature in degree celsius). The transient model is not computationally expensive and is applicable to Omnimagnets with different structures. The code is applied to calculate the maximum safe operational time at a fixed input current or the maximum safe input current for a fixed time interval. The maximum safe operational time and maximum safe input current depend on size and structure of the Omnimagnet and the lowest critical temperature of all the Omnimagnet materials. A parametric study shows that increasing convective heat transfer during cooling, and during heating with low input currents, is an effective method to increase the maximum operational time of the Omnimagnet. The thermal model is also presented in a state-space equation format that can be used in a real-time Kalman filter current controller to avoid device failure due to excessive heating.


Preparation of 2H-furo[2,3-c]pyran-2-one derivatives and evaluation of their germination-promoting activity.
The butenolide, 3-methyl-2H-furo[2,3-c]pyran-2-one (1), has recently been identified as the germination stimulant present in smoke that promotes the germination of seeds from a wide range of plant species. In this paper, we describe the preparation of a number of analogues of 1 and compare their efficacy in promoting seed germination of three highly smoke-responsive plant species, Lactuca sativa L. cv. Grand Rapids (Asteraceae), Emmenanthe penduliflora Benth. (Hydrophyllaceae), and Solanum orbiculatum Poir. (Solanaceae). The results show that the methyl substituent at C-3 in 1 is important for germination-promoting activity while substitution at C-7 reduces activity. In contrast, bioactivity is mostly retained with analogues substituted at C-4 or C-5.


Immediate periodontal bone plate changes induced by rapid maxillary expansion in the early mixed dentition: CT findings.
This study aimed at evaluating buccal and lingual bone plate changes caused by rapid maxillary expansion (RME) in the mixed dentition by means of computed tomography (CT). The sample comprised spiral CT exams taken from 22 mixed dentition patients from 6 to 9 years of age (mean age of 8.1 years) presenting constricted maxillary arch treated with Haas-type expanders. Patients were submitted to spiral CT scan before expansion and after the screw activation period with a 30-day interval between T1 and T2. Multiplanar reconstruction was used to measure buccal and lingual bone plate thickness and buccal bone crest level of maxillary posterior deciduous and permanent teeth. Changes induced by expansion were evaluated using paired t test (p < 0.05). Thickness of buccal and lingual bone plates of posterior teeth remained unchanged during the expansion period, except for deciduous second molars, which showed a slight reduction in bone thickness at the distal region of its buccal aspect. Buccal bone dehiscences were not observed in the supporting teeth after expansion. RME performed in mixed dentition did not produce immediate undesirable effects on periodontal bone tissues.


Impact of sodium-glucose co-transporter inhibitors on cardiac autonomic function and mortality: no time to die.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to improve cardiovascular outcomes not only in patients with diabetes but also in those with heart failure, irrespective of diabetic status. However, the mechanisms underlying the cardioprotective effects of these newer anti-diabetic drugs remain to be fully elucidated. One exciting avenue that has been recently explored in both preclinical and clinical studies is the modulation of the cardiovascular autonomic nervous system. A reduction in sympathetic nervous system activity by SGLT2 inhibitors may potentially translate into a reduction in arrhythmic risk and sudden arrhythmic death, which may explain, at least partly, the cardioprotection shown in the cardiovascular outcome trials with different SGLT2 inhibitors. Although some of the data from the preclinical and clinical studies are promising, overall the findings can be contradictory. This highlights the need for more studies to address gaps in our knowledge of these novel drugs. The present review offers an in depth overview of the existing literature regarding the role of SGLT2 inhibitors in modulating cardiovascular autonomic function as one of the possible pathways of their cardioprotective effects.


Drug-Resistant Staphylococcus aureus Strains Reveal Distinct Biochemical Features with Raman Microspectroscopy.
Staphylococcus aureus ( S. aureus) is a leading cause of hospital-acquired infections, such as bacteremia, pneumonia, and endocarditis. Treatment of these infections can be challenging since strains of S. aureus, such as methicillin-resistant S. aureus (MRSA), have evolved resistance to antimicrobials. Current methods to identify infectious agents in hospital environments often rely on time-consuming, multistep culturing techniques to distinguish problematic strains (i.e., antimicrobial resistant variants) of a particular bacterial species. Therefore, a need exists for a rapid, label-free technique to identify drug-resistant bacterial strains to guide proper antibiotic treatment. Here, our findings demonstrate the ability to characterize and identify microbes at the subspecies level using Raman microspectroscopy, which probes the vibrational modes of molecules to provide a biochemical "fingerprint". This technique can distinguish between different isolates of species such as Streptococcus agalactiae and S. aureus. To determine the ability of this analytical approach to detect drug-resistant bacteria, isogenic variants of S. aureus including the comparison of strains lacking or expressing antibiotic resistance determinants were evaluated. Spectral variations observed may be associated with biochemical components such as amino acids, carotenoids, and lipids. Mutants lacking carotenoid production were distinguished from wild-type S. aureus and other strain variants. Furthermore, spectral biomarkers of S. aureus isogenic bacterial strains were identified. These results demonstrate the feasibility of Raman microspectroscopy for distinguishing between various genetically distinct forms of a single bacterial species in situ. This is important for detecting antibiotic-resistant strains of bacteria and indicates the potential for future identification of other multidrug resistant pathogens with this technique.


Cellular mechanisms associated with sub-optimal immune responses to SARS-CoV-2 bivalent booster vaccination in patients with Multiple Myeloma.
The real-world impact of bivalent vaccines for wild type (WA.1) and Omicron variant (BA.5) is largely unknown in immunocompromised patients with Multiple Myeloma (MM). We characterize the humoral and cellular immune responses in patients with MM before and after receiving the bivalent booster, including neutralizing assays to identify patterns associated with continuing vulnerability to current variants (XBB1.16, EG5) in the current post-pandemic era. We studied the humoral and cellular immune responses before and after bivalent booster immunization in 48 MM patients. Spike binding IgG antibody levels were measured by SARS-CoV-2 spike binding ELISA and neutralization capacity was assessed by a SARS-CoV-2 multi-cycle microneutralization assays to assess inhibition of live virus. We measured spike specific T-cell function using the QuantiFERON SARS-CoV-2 (Qiagen) assay as well as flow-cytometry based T-cell. In a subset of 38 patients, high-dimensional flow cytometry was performed to identify immune cell subsets associated with lack of humoral antibodies. We find that bivalent vaccination provides significant boost in protection to the omicron variant in our MM patients, in a treatment specific manner. MM patients remain vulnerable to newer variants with mutations in the spike portion. Anti-CD38 and anti-BCMA therapies affect the immune machinery needed to produce antibodies. Our study highlights varying immune responses observed in MM patients after receiving bivalent COVID-19 vaccination. Specifically, a subgroup of MM patients undergoing anti-CD38 and anti-BCMA therapy experience impairment in immune cells such DCs, B cells, NK cells and TFH cells, leading to an inability to generate adequate humoral and cellular responses to vaccination. National Cancer Institute (National Institutes of Health), National Institute of Allergy and Infectious Diseases (National Institutes of Health), NCI Serological Sciences Network for COVID-19 (SeroNet) and The Icahn School of Medicine at Mount Sinai.


Measurement of Newton's constant using a torsion balance with angular acceleration feedback.
We measured Newton's gravitational constant G using a new torsion balance method. Our technique greatly reduces several sources of uncertainty compared to previous measurements: (1) It is insensitive to anelastic torsion fiber properties; (2) a flat plate pendulum minimizes the sensitivity due to the pendulum density distribution; (3) continuous attractor rotation reduces background noise. We obtain G = (6.674215+/-0.000092) x 10(-11) m3 kg(-1) s(-2); the Earth's mass is, therefore, M = (5.972245+/-0.000082) x 10(24) kg and the Sun's mass is M = (1.988435+/-0.000027) x 10(30) kg.


Phosphoproteomic mapping reveals distinct signaling actions and activation of muscle protein synthesis by Isthmin-1.
The secreted protein isthmin-1 (Ism1) mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the PI3K-Akt pathway. However, while both Ism1 and insulin converge on these common targets, Ism1 has distinct cellular actions suggesting divergence in downstream intracellular signaling pathways. To understand the biological complexity of Ism1 signaling, we performed phosphoproteomic analysis after acute exposure, revealing overlapping and distinct pathways of Ism1 and insulin. We identify a 53% overlap between Ism1 and insulin signaling and Ism1-mediated phosphoproteome-wide alterations in ~450 proteins that are not shared with insulin. Interestingly, we find several unknown phosphorylation sites on proteins related to protein translation, mTOR pathway, and, unexpectedly, muscle function in the Ism1 signaling network. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets. As metabolic disorders such as diabetes are associated with accelerated loss of skeletal muscle protein content, these studies define a non-canonical mechanism by which this antidiabetic circulating protein controls muscle biology.


Biocompatible Polymer for Self-Humidification.
Lung supportive devices (LSDs) have been extensively utilized in treating patients diagnosed with various respiratory disorders. However, these devices can cause moisture depletion in the upper airway by interfering with the natural lubrication and air conditioning process. To remedy this, current technologies implement heated humidification processes, which are bulky, costly, and nonfriendly. However, it has been demonstrated that in a breath cycle, the amount of water vapor in the exhaled air is of a similar quantity to the amount needed to humidify the inhaled air. This research proposes to trap the moisture from exhaled air and reuse it during inhalation by developing a state-of-the-art hydrophilic/hydrophobic polymer tuned to deliver this purpose. Using the atom transfer radical polymerization (ATRP) method, a substrate was successfully created by incorporating poly (N-isopropyl acrylamide) (PNIPAM) onto cotton. The fabricated material exhibited a water vapor release rate of 24.2 ± 1.054%/min at 32 °C, indicating its ability to humidify the inhaled air effectively. These findings highlight the potential of the developed material as a promising solution for applications requiring rapid moisture recovery.


[An analysis of factors influencing maternal mortality in Southern Algeria].
Southern Algeria has the highest rate of maternal mortality in the country. An action-research study was conducted to identify the explanatory factors of this issue. Three methodological approaches were used: (i) an epidemiological data analysis of maternal mortality and an analysis of obstetric complications at the hospital of Tamanrasset; (ii) a socio-anthropological study conducted among women in Tamanrasset; and (iii) semi-structured interviews with health professionals aimed at understanding their beliefs and representations. RESULTS; The study identified three major factors influencing the decision to seek care: (i) the interpretation of illness by mothers; (ii) the origin of their decision to seek care based on their assessment of the range of available therapeutic options; and (iii) medical uncertainty, with mothers often forced to resort to a range of therapeutic options because of uncertainty and pressure from family and other local residents. A detailed analysis of the implementation of mobile healthcare services is required to provide local health services to the population.


ROBUSTNESS CONDITIONS FOR MIIV-2SLS WHEN THE LATENT VARIABLE OR MEASUREMENT MODEL IS STRUCTURALLY MISSPECIFIED.
Most researchers acknowledge that virtually all structural equation models (SEMs) are approximations due to violating distributional assumptions and structural misspecifications. There is a large literature on the unmet distributional assumptions, but much less on structural misspecifications. In this paper we examine the robustness to structural misspecification of the Model Implied Instrumental Variable, Two Stage Least Square (MIIV-2SLS) estimator of SEMs. We introduce two types of robustness: robust-unchanged and robust-consistent. We develop new robustness analytic conditions for MIIV-2SLS and illustrate these with hypothetical models, simulated data, and an empirical example. Our conditions enable a researcher to know whether, for example, a structural misspecification in the latent variable model influences the MIIV-2SLS estimator for measurement model equations and vice versa. Similarly, we establish robustness conditions for correlated errors. The new robustness conditions provide guidance on the types of structural misspecifications that affect parameter estimates and they assist in diagnosing the source of detected problems with MIIVs.


Bead-based multiplex detection of dengue biomarkers in a portable imaging device.
Dengue is one of the most rapidly spreading mosquito-borne viral diseases in the world. Differential diagnosis is a crucial step for the management of the disease and its epidemiology. Point-of-care testing of blood-borne dengue biomarkers provides an advantageous approach in many health care settings, and the ability to follow more than one biomarker at once could significantly improve the management of the disease. Bead-based multiplex technologies (suspension array) can measure multiple biomarker targets simultaneously by using recognition molecules immobilized on microsphere beads. The overarching objective of our work is to develop a portable detection device for the simultaneous measurement of multiple biomarkers important in dengue diagnosis, monitoring and treatment. Here, we present a bead-based assay for the detection of one of the four serotypes of dengue virus non-structural protein (DENV-NS1) as well as its cognate human IgG. In this system, the fluorescent microspheres containing the classification fluorophore and detection fluorophore are imaged through a microfluidic chip using an infinity-corrected microscope system. Calibration curves were plotted for median fluorescence intensity against known concentrations of DENV-NS1 protein and anti-NS1 human IgG. The limit of quantitation was 7.8 ng/mL and 15.6 ng/mL, respectively. The results of this study demonstrate the feasibility of the multiplex detection of dengue biomarkers and present its analytical performance parameters. The proposed imaging device holds potential for point-of-care testing of biomarkers on a highly portable system, and it may facilitate the diagnosis and prevention of dengue as well as other infectious diseases.


Joint time and time-frequency optimal detection of K-complexes in sleep EEG.
Automated detection of waveforms such as delta and K-complex in the EEG is an important component of sleep stage monitoring. The K-complex is a key feature that contributes to sleep stages assessment. However, its automated detection is still difficult due to the stochastic nature of the EEG. In this paper, we propose a detection structure which can be interpreted as joint linear filtering operations in time and time-frequency domains. We also introduce a method of obtaining the optimum detector from training data, and we show that the resulting receiver offers better performances than the one obtained via the Fisher criterion maximization. The efficiency of this approach for K-complexes detector design is explored. It results from this study that the obtained receiver is potentially the best one which can be found in the literature. Finally, it is emphasized that this methodology can be advantageously used to solve many other detection problems.


Medical Error Avoidance in Intraoperative Neurophysiological Monitoring: The Communication Imperative.
Error avoidance in medicine follows similar rules that apply within the design and operation of other complex systems. The error-reduction concepts that best fit the conduct of testing during intraoperative neuromonitoring are forgiving design (reversibility of signal loss to avoid/prevent injury) and system redundancy (reduction of false reports by the multiplication of the error rate of tests independently assessing the same structure). However, error reduction in intraoperative neuromonitoring is complicated by the dichotomous roles (and biases) of the neurophysiologist (test recording and interpretation) and surgeon (intervention). This "interventional cascade" can be given as follows: test → interpretation → communication → intervention → outcome. Observational and controlled trials within operating rooms demonstrate that optimized communication, collaboration, and situational awareness result in fewer errors. Well-functioning operating room collaboration depends on familiarity and trust among colleagues. Checklists represent one method to initially enhance communication and avoid obvious errors. All intraoperative neuromonitoring supervisors should strive to use sufficient means to secure situational awareness and trusted communication/collaboration. Face-to-face audiovisual teleconnections may help repair deficiencies when a particular practice model disallows personal operating room availability. All supervising intraoperative neurophysiologists need to reject an insular or deferential or distant mindset.


Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome.
In patients with acute respiratory distress syndrome (ARDS), the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network recommends a target partial pressure of arterial oxygen (Pao2) between 55 and 80 mm Hg. Prospective validation of this range in patients with ARDS is lacking. We hypothesized that targeting the lower limit of this range would improve outcomes in patients with ARDS. In this multicenter, randomized trial, we assigned patients with ARDS to receive either conservative oxygen therapy (target Pao2, 55 to 70 mm Hg; oxygen saturation as measured by pulse oximetry [Spo2], 88 to 92%) or liberal oxygen therapy (target Pao2, 90 to 105 mm Hg; Spo2, ≥96%) for 7 days. The same mechanical-ventilation strategies were used in both groups. The primary outcome was death from any cause at 28 days. After the enrollment of 205 patients, the trial was prematurely stopped by the data and safety monitoring board because of safety concerns and a low likelihood of a significant difference between the two groups in the primary outcome. Four patients who did not meet the eligibility criteria were excluded. At day 28, a total of 34 of 99 patients (34.3%) in the conservative-oxygen group and 27 of 102 patients (26.5%) in the liberal-oxygen group had died (difference, 7.8 percentage points; 95% confidence interval [CI], -4.8 to 20.6). At day 90, 44.4% of the patients in the conservative-oxygen group and 30.4% of the patients in the liberal-oxygen group had died (difference, 14.0 percentage points; 95% CI, 0.7 to 27.2). Five mesenteric ischemic events occurred in the conservative-oxygen group. Among patients with ARDS, early exposure to a conservative-oxygenation strategy with a Pao2 between 55 and 70 mm Hg did not increase survival at 28 days. (Funded by the French Ministry of Health; LOCO2 ClinicalTrials.gov number, NCT02713451.).


[Specificity of synthetic polyribonucleotides hydrolysis by endoribonuclease from cobra (Naja oxiana) venom].
An analysis of kinetic differences in homopolyribonucleotides hydrolysis by cobra venom endoribonuclease was carried out. It was concluded that the rate and intensity of hydrolysis as well as the length of the linear parts of the kinetic curves are correlated with the content of the nucleotide units with the C3'-endo conformation in the substrates. The structure factor was shown to predominate in some cases over the temperature factor. Protamine sulfate inhibits the enzyme by blocking its phosphodiether bonds. Study on the effects of divalent metal ions demonstrated the possibility that the enzyme-Me2+ complex is functionally active and that the ion-free polyribonucleotides are true substrates.


Allergic airway responses in obese mice.
Epidemiologic data indicate an increased incidence of asthma in the obese. To determine whether obese mice exhibit augmented pulmonary responses after allergen sensitization and challenge. Lean, wild-type (C57BL/6), obese ob/ob, and obese db/db mice were sensitized to ovalbumin (OVA), and then challenged with aerosolized OVA or phosphate-buffered saline (PBS). Changes in total pulmonary resistance (Rl) induced by intravenous methacholine were measured by forced oscillation. Blood was collected, bronchoalveolar lavage (BAL) was performed, and lungs were harvested for measurement of cytokine expression by real-time reverse transcription-polymerase chain reaction. OVA challenge increased baseline Rl in ob/ob, but not wild-type, mice, and airway responsiveness was greater in ob/ob than wild-type mice, regardless of the challenge. Compared with PBS, OVA challenge caused an increase in the number of BAL fluid (BALF) cells, an increase in lung Th2 cytokine expression, and an increase in serum IgE. Significantly fewer BALF cells were recovered from OVA-challenged ob/ob versus wild-type mice, whereas serum IgE levels were elevated significantly more in ob/ob versus wild-type mice. BALF and lung Th2 cytokine expression was not different in ob/ob versus wild-type mice. Airway responsiveness was greater in db/db versus wild-type mice, regardless of the challenge, and OVA caused airway hyperresponsiveness in db/db but not wild-type mice, despite reduced BALF cells in OVA-challenged db/db versus wild-type mice. These results demonstrate that obesity enhances OVA-induced changes in pulmonary resistance and serum IgE and that these changes are not the result of increased Th2 type airway inflammation.


Characteristics of Contemporary Randomized Clinical Trials and Their Association With the Trial Funding Source in Invasive Cardiovascular Interventions.
Changes in evidence-based practice and guideline recommendations depend on high-quality randomized clinical trials (RCTs). Commercial device and pharmaceutical manufacturers are frequently involved in the funding, design, conduct, and reporting of trials, the implications of which have not been recently analyzed. To evaluate the design, outcomes, and reporting of contemporary randomized clinical trials of invasive cardiovascular interventions and their association with the funding source. This cross-sectional study analyzed published RCTs between January 1, 2008, to May 31, 2019. The trials included those involving coronary, vascular and structural interventional cardiology, and vascular and cardiac surgical procedures. We assessed (1) trial characteristics, (2) finding of a statistically significant difference in the primary end point favoring the experimental intervention, (3) reporting of implied treatment advantage in trials without significant differences in primary end point, (4) existence of major discrepancies between registered and published primary outcomes, (5) number of patients whose outcomes would need to switch from a nonevent to an event to convert a significant difference in primary end point to nonsignificant, and (6) association with funding source. Of the 216 RCTs analyzed, 115 (53.2%) reported having commercial sponsorship. Most trials had 80% power to detect an estimated treatment effect of 30%, and 128 trials (59.3%) used composite primary end points. The median (interquartile range [IQR]) sample size was 502 (204-1702) patients, and the median (IQR) follow-up duration was 12 (1.0-14.4) months. Overall, 123 trials (57.0%) reported a statistically significant difference in the primary outcome favoring the experimental intervention; reporting strategies that implied an advantage were identified in 55 (65.5%) of 84 trials that reported nonsignificant differences. Commercial sponsorship was associated with a statistically significantly greater likelihood of favorable outcomes reporting (exponent of regression coefficient β, 2.80; 95% CI, 1.09-7.18; P = .03) and with the reporting of findings that are inconsistent with the trial results. Discrepancies between the registered and published primary outcomes were found in 82 trials (38.0%), without differences in trial sponsorship. A median (IQR) number of 5 (2.8-12.5) patients experiencing a different outcome would have change statistically significant results to nonsignificant. Commercial sponsorship was associated with a greater number of patients (exponent of regression coefficient β, 1.29; 95% CI, 1.00-1.66; P = .04). These results suggest that contemporary RCTs of invasive cardiovascular interventions are relatively small and fragile, have short follow-up, and have limited power to detect large treatment effects. Commercial support appeared to be associated with differences in trial design, results, and reporting.


The immunoreceptor tyrosine-based activation motif of Epstein-Barr virus LMP2A is essential for blocking BCR-mediated signal transduction.
The Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) blocks B-cell receptor (BCR) signal transduction in EBV-immortalized B lymphocytes in vitro. The cytoplasmic amino-terminal domain of LMP2A contains an immunoreceptor tyrosine activation motif (ITAM). ITAMs consist of paired tyrosine and leucine residues and play a central role in signal transduction of the BCR and the T-cell receptor (TCR). To investigate the importance of the LMP2A ITAM, two EBV recombinants were constructed, each containing a tyrosine-to-phenylalanine point mutation at amino acid 74 or 85 within the ITAM of LMP2A. Tyrosine phosphorylation, calcium mobilization, and induction of BZLF1 expression were no longer blocked in the LMP2A ITAM mutant LCLs following BCR cross-linking. In addition, the Syk protein tyrosine kinase (PTK) was unable to bind LMP2A in unstimulated LCLs infected with either of the LMP2A ITAM mutants. Analysis of Syk phosphorylation before and after BCR cross-linking in the LMP2A mutant ITAM LCLs compared with wild-type EBV LCLs indicates a specific role of the LMP2A ITAM on the LMP2A-mediated negative effect on the Syk PTK. These data indicate the importance of the LMP2A ITAM motif in the LMP2A-mediated block on BCR signal transduction and position the role of the Syk PTK as being central to the function of LMP2A.


Venous thromboembolism in cancer patients - risk scores and recent randomised controlled trials.
Cancer patients are at increased risk of developing venous thromboembolism (VTE). Guidelines recommend routine thromboprophylaxis in hospitalised acutely ill cancer patients and in myeloma patients receiving combination treatments including thalidomide or lenalidomide. Currently, thromboprophylaxis is not recommended in cancer outpatients. It is the aim of this review to give an overview of studies that applied scores for the risk assessment of cancer-related VTE. We will also discuss randomised controlled trials (RCTs) that investigated primary thromboprophylaxis in cancer patients. Recently, Khorana et al. published a practical and reproducible risk assessment score that includes clinical and laboratory parameters for the stratification of cancer patients according to their propensity to develop VTE. Patients assigned to the high-risk group are likely to benefit most from primary thromboprophylaxis. This score was validated in prospective and retrospective observational studies. In the Vienna Cancer and Thrombosis Study (CATS) the score was expanded by adding two biomarkers, and the prediction of VTE was considerably improved. In recent RCTs including cancer patients with different malignancies it was shown that thromboprophylaxis is safe and effective. However, VTE incidence rates were low. To date, no data is available from interventional studies applying thromboprophylaxis in cancer patients categorised into high-risk groups on the basis of risk assessment with scores. From the available literature we conclude that risk assessment for VTE is feasible in cancer patients; however, interventional studies to investigate the safety and efficacy of thromboprophylaxis in a high risk cancer population have yet to be performed.


Pure-breeding with sexed semen and crossbreeding with semen of double-muscled sires to improve beef production from dairy herds: Factors affecting heifer and cow fertility and the sex ratio.
Using sexed semen to produce purebred replacement heifers makes it possible to mate a large proportion of dairy cows to double-muscled sires and to quantitatively and qualitatively improve beef production and increase the income from dairy herds. Net profit first depends on changes in the farm's overall fertility rate. The objective of this study was to analyze the conception rate in herds using a combination of conventional dairy semen (for pure- and crossbreeding), X-sorted dairy semen (to produce purebred replacement heifers), and conventional beef semen (for terminal crossbreeding). Data were obtained from 50,785 inseminations of 15,580 dairy cows (78% Holstein-Friesian, 15% Brown Swiss, 2% Simmental, and 5% crossbreds) from 106 dairy farms (average milk yield 35.1 ± 9.4 kg/d, with 3.76 ± 0.83% fat and 3.32 ± 0.39% protein contents). To account for the main potential confounders, we used separate generalized linear mixed-effects models for cows and virgin heifers. The results showed that the odds ratio of conception improved (1.00 to 1.34) with an increase in the average milk yield of the herd but worsened (1.12 to 0.70) with an increase in the milk yield of individual cows within herd. The summer months showed a strong reduction in the odds ratio of conception in cows (0.56 in July and August) but not in virgin heifers. Multiparous cows had a lower odds ratio of conception (0.85) than primiparous cows (1.00). The order of insemination did not affect the fertility of the cows or heifers, whereas the odds ratio of conception improved with advancing lactation (1.00 to 2.12). The Simmental cows were more fertile than Holstein-Friesians (1.37 vs. 1.00), whereas the fertility of the heifers was not affected by breed. Taking all these possible confounders into account simultaneously, in pure-breeding the odds ratio of conception using sexed semen did not differ from that using conventional dairy semen in cows (0.90 vs. 1.00) or in virgin heifers (0.95 vs. 1.00). However, crossbreeding using conventional beef and dairy semen improved the odds ratio of conception (1.10 and 1.17, respectively) in cows (1.37 using beef semen) and heifers (1.25 using dairy semen). The proportion of newborn heifer calves was ≥90% using sexed dairy semen. The combined use of sexed semen, especially on heifers, to produce purebred replacement females and beef semen to produce terminal crossbred calves was shown to have the potential to increase overall herd fertility, which could be further improved using sexed dairy semen to produce dairy crossbreds instead of purebred replacement heifers.


Dual-input hybrid acousto-optic set-reset flip-flop and its nonlinear dynamics.
The characteristics of a dual-input hybrid acousto-optic device are investigated numerically and experimentally. The device, which operates as a set-reset flip-flop, uses the well-known bistable acousto-optic device with feedback to which two input beams are applied. The resulting flip-flop is analyzed numerically by use of nonlinear dynamical and nonlinear circuit-modeling techniques, and some of its properties are demonstrated experimentally.


Using seasonal genomic changes to understand historical adaptation to new environments: Parallel selection on stickleback in highly-variable estuaries.
Parallel evolution is considered strong evidence for natural selection. However, few studies have investigated the process of parallel selection as it plays out in real time. The common approach is to study historical signatures of selection in populations already well adapted to different environments. Here, to document selection under natural conditions, we study six populations of threespine stickleback (Gasterosteus aculeatus) inhabiting bar-built estuaries that undergo seasonal cycles of environmental changes. Estuaries are periodically isolated from the ocean due to sandbar formation during dry summer months, with concurrent environmental shifts that resemble the long-term changes associated with postglacial colonization of freshwater habitats by marine populations. We used pooled whole-genome sequencing to track seasonal allele frequency changes in six of these populations and search for signatures of natural selection. We found consistent changes in allele frequency across estuaries, suggesting a potential role for parallel selection. Functional enrichment among candidate genes included transmembrane ion transport and calcium binding, which are important for osmoregulation and ion balance. The genomic changes that occur in threespine stickleback from bar-built estuaries could provide a glimpse into the early stages of adaptation that have occurred in many historical marine to freshwater transitions.


Multifunctional cell membranes-based nano-carriers for targeted therapies: a review of recent trends and future perspective.
Nanotechnology has ignited a transformative revolution in disease detection, prevention, management, and treatment. Central to this paradigm shift is the innovative realm of cell membrane-based nanocarriers, a burgeoning class of biomimetic nanoparticles (NPs) that redefine the boundaries of biomedical applications. These remarkable nanocarriers, designed through a top-down approach, harness the intrinsic properties of cell-derived materials as their fundamental building blocks. Through shrouding themselves in natural cell membranes, these nanocarriers extend their circulation longevity and empower themselves to intricately navigate and modulate the multifaceted microenvironments associated with various diseases. This comprehensive review provides a panoramic view of recent breakthroughs in biomimetic nanomaterials, emphasizing their diverse applications in cancer treatment, cardiovascular therapy, viral infections, COVID-19 management, and autoimmune diseases. In this exposition, we deliver a concise yet illuminating overview of the distinctive properties underpinning biomimetic nanomaterials, elucidating their pivotal role in biomedical innovation. We subsequently delve into the exceptional advantages these nanomaterials offer, shedding light on the unique attributes that position them at the forefront of cutting-edge research. Moreover, we briefly explore the intricate synthesis processes employed in creating these biomimetic nanocarriers, shedding light on the methodologies that drive their development.


Comparison of Three Junctional Tourniquets Using a Randomized Trial Design.
Hemorrhage remains a leading cause of death in both civilian and military settings. Of preventable deaths from hemorrhage, a significant portion occurs from junctional wounds that are not amenable to traditional extremity tourniquets. Junctional tourniquets (JTQs) can potentially provide hemorrhage control by compressing the arteries at the junction of the trunk and extremities. The FDA has cleared 3 JTQ products: The Combat Ready Clamp (CRoC®), the Junctional Emergency Treatment Tool (JETT™), and the SAM® Junctional Tourniquet (SJT). However, little is known regarding which of these JTQs is superior in application time, effectiveness in pulse elimination, effectiveness during transport, and user preference. Active duty corpsmen (N = 49) were given standardized instruction and hands-on training with the CRoC®, JETT™, and SJT, then sequentially applied each JTQ unilaterally to a fellow study participant in a randomized order. Pulse elimination was determined by Doppler ultrasound at the dorsalis pedis immediately then reevaluated after a short transport. User preference data were collected following testing. Data were analyzed using repeated measures ANOVA and non-parametric statistics at p < 0.05. The CRoC® was significantly slower in application time than the JETT™ and SJT. Effectiveness was similar for CRoC®, JETT™, and SJT. Effectiveness during transport was significantly higher for SJT than for the JETT™, but no JTQ performed well during transport (24-48% effectiveness). SJT ranked first in perceived ease of use, stability, and reliability, and in user trust and overall preference. Participants provided cogent suggestions for product improvement. All JTQ devices performed poorly during transport. Combined, present findings highlight the potential of JTQ products for saving lives threatened by junctional wounds, but also highlight the need for specific product improvements towards fostering JTQ performance in patient transport.