The Use of Remote Consultations and Associated Factors in Rheumatology: A Large Retrospective Cohort Study of Follow-Up Consultations Before, During, and After COVID-19.
To investigate the use of remote consultations (RCs) and the influence of consultation, health care provider (HCP), and patient characteristics on the choice for remote or face-to-face consultation. A monocenter retrospective cohort study was conducted on follow-up consultations of patients with rheumatic diseases from January 1, 2019 to January 16, 2023, using data from electronic health records. Trends in the proportion of RCs before, during, and after COVID-19 were studied. Cross-classified multilevel logistic regression models were built to account for clustering of consultations (level 1) within both patients and HCPs (level 2). The influence of consultation, patient, and HCP characteristics on the type of consultation was assessed. 157,028 consultations of 30,215 unique patients seen by 64 HCPs were included in the data set. After an initial sharp increase in RC use at the beginning of the COVID-19 pandemic, the proportion of RCs decreased toward a seemingly steady state at around 30%. 90% of the variance in the use of RCs can be attributed to the consultation level, whereas 4% and 6% can be attributed to the patient and HCP level. Longer consultation durations and time since last consultation decreased the odds for a RC, as did higher patient age, shared care, and longer disease duration. Higher travel distance, consultation density, and patient digital access increased the odds for a RC. The COVID pandemic resulted in a structural increase in the use of RCs. Although several patient characteristics are associated with the type of consultation, most variance resulted from consultation characteristics compared with patients and HCPs.


Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-HT1A and TRPV1 receptor mechanisms.
Cocaine abuse continues to be a serious health problem worldwide. Despite intense research there is currently no FDA-approved medication to treat cocaine use disorder. The recent search has been focused on agents targeting primarily the dopamine system, while limited success has been achieved at the clinical level. Cannabidiol (CBD) is a U.S. FDA-approved cannabinoid for the treatment of epilepsy and recently was reported to have therapeutic potential for other disorders. Here we systemically evaluated its potential utility for the treatment of cocaine use disorder and explored the underlying receptor mechanisms in experimental animals. Systemic administration (10-40 mg/kg) of CBD dose-dependently inhibited cocaine self-administration, shifted a cocaine dose-response curve downward, and lowered break-points for cocaine self-administration under a progressive-ratio schedule of reinforcement. CBD inhibited cocaine self-administration maintained by low, but not high, doses of cocaine. In addition, CBD (3-20 mg/kg) dose-dependently attenuated cocaine-enhanced brain-stimulation reward (BSR) in rats. Strikingly, this reduction in both cocaine self-administration and BSR was blocked by AM630 (a cannabinoid CB2 receptor antagonist), WAY100135 (a 5-HT1A receptor antagonist), or capsazepine (a TRPV1 channel blocker), but not by AM251 (a CB1 receptor antagonist), CID16020046 (a GPR55 antagonist), or naloxone (an opioid receptor antagonist), suggesting the involvement of CB2, 5-HT1A, and TRPV1 receptors in CBD action. In vivo microdialysis indicated that pretreatment with CBD (10-20 mg/kg) attenuated cocaine-induced increases in extracellular dopamine (DA) in the nucleus accumbens, while CBD alone failed to alter extracellular DA. These findings suggest that CBD may have certain therapeutic utility by blunting the acute rewarding effects of cocaine via a DA-dependent mechanism.


Molecular evidence for partial inactivation of Y loops in T(X:Y)56 males from D. hydei.
Using loop-specific DNA clones, we established that the T(X:Y)56 (Hackstein and Hennig 1982) chromosome, formerly thought to be deleted for the Yshort arm and the associated 'nooses' loops is actually an XYS X YL combination. It carries, adjacent to the translocation junction, the complete and uninterrupted set of the two dysfunctional 'nooses' domains. The morphologically altered and functionally defective loops are transcribed at about 50% of the normal rate. Transcripts in one of the two 'nooses' domains are preferentially underrepresented and their distribution in the spermatocyte nucleus is distorted, presumably as a consequence of a spreading effect. No alteration in transcript size or in the correct strand selection, and no variegation of transcription on the single spermatocyte level, were observed. In another translocation T(X:Y)97, in which 'tubular ribbons' were reported to be inactivated (Hess 1970), complete elimination of DNA sequences is observed. A possible mechanism for the position effect inactivation of Y loops in X:Y translocations is discussed briefly.


Leaf curl diseases of two solanaceous species in Southwest Arabia are caused by a monopartite begomovirus evolutionarily most closely related to a species from the Nile Basin and unique suite of betasatellites.
The complete genome of 2780 bases was amplified using rolling circle amplification, and cloned, and sequenced for two distinct strains of the monopartite begomovirus Tomato leaf curl Sudan virus (ToLCSDV). The two strains shared 86-91% identity with the previously described ToLCSDV from the Nile Basin, and 90-91% identity with one another. One strain was cloned from symptomatic tomato plants from Tihamah (ToLCSDV-YE[YE:Tih:05]) while the other was cloned from symptomatic tobacco plants collected from Wadi Hadramaut (ToLCSDV-YE[YE:Had:89]). A distinct full-length betasatellite molecule (1352 bases) was cloned from the respective field-infected tomato and tobacco plants. Agro-inoculation of tomato and Nicotiana benthamiana plants with cloned partial tandem repeats of ToLCSDV-YE[YE:Tih11:05]) and the associated betasatellite, Tomato leaf curl Yemen betasatellite (ToLCYEB-[Tih:tom:137:05]), resulted in the reproduction of leaf curl disease symptoms in test plants like those observed in the field-infected plants. The betasatellite contributed to symptom severity in N. benthamiana test plants when it was co-inoculated with ToLCSDV-YE, compared to the milder symptoms that were observed in tobacco plants infected with the helper virus alone.


Identification and functional characterization of the Arabidopsis Snf1-related protein kinase SnRK2.4 phosphatidic acid-binding domain.
Phosphatidic acid (PA) is an important signalling lipid involved in various stress-induced signalling cascades. Two SnRK2 protein kinases (SnRK2.4 and SnRK2.10), previously identified as PA-binding proteins, are shown here to prefer binding to PA over other anionic phospholipids and to associate with cellular membranes in response to salt stress in Arabidopsis roots. A 42 amino acid sequence was identified as the primary PA-binding domain (PABD) of SnRK2.4. Unlike the full-length SnRK2.4, neither the PABD-YFP fusion protein nor the SnRK2.10 re-localized into punctate structures upon salt stress treatment, showing that additional domains of the SnRK2.4 protein are required for its re-localization during salt stress. Within the PABD, five basic amino acids, conserved in class 1 SnRK2s, were found to be necessary for PA binding. Remarkably, plants overexpressing the PABD, but not a non-PA-binding mutant version, showed a severe reduction in root growth. Together, this study biochemically characterizes the PA-SnRK2.4 interaction and shows that functionality of the SnRK2.4 PABD affects root development.


[Nursing: management with a bound to values].
Management is an activity that crosses every area of a hospital. Bioethics gives health care management the basic criteria to promote the common good, to respect everyone and to overcome the economistic paradigm. This article is based on an ongoing study in hospitals in the northern zone, within the PhD in Bioethics. It aims to disseminate the results obtained in the socio-professional group of nurses who perform management functions, regardless of the implemented management model or level of performance. We aim to understand if the system of human values and the ethics of hospital managers influence the decision on health care, while contributing to the identification of a "Profile of ethical skills to manage health units". Methodologically, this research is identified as an exploratory-descriptive and transversal study with a quantitative approach. When collecting data, we used the Ethicality Questionnaire of Hospital Management, developed and validated, with a good level of internal consistency (Cronbach's alpha = .74). It's a self-report instrument consisting of six dimensions (costs and ethics; weighting ethics; ethical decision, responsibility and quality; economic constraint and ethics, and ways to limit costs) and a total of 37 items, with a 5-point Likert-type scale response. We focused solely on the results of the group of professional nurses, given its predominance in the study (191 elements corresponding to 45,4%). The results that reveal the nurses' opinion suggest that there is an integration of values such as responsibility, respect for human dignity and equity, among others, highlighting the consideration of ethical issues in management practices in nursing. The ethical intentionality to manage with binding to values will have as a final and visible result the expression of a holistic care to the person.


Formulation of diets for slow-growing broilers slaughtered at different ages on carcass characteristics and composition of commercial cuts.
This study was conducted to examine the effects of a diet formulated with industrial amino acids and a commercial vitamin-mineral mixture on the characteristics of carcass and meat cuts of slow-growing broilers slaughtered at different ages. The experiment involved 600 one-day-old male and female white Naked Neck chicks. The chicks were allotted randomly to a 2 × 3 factorial arrangement consisting of two diets and three slaughter ages, in a completely randomized experimental design with five replicates of 20 birds each. The experimental period was 84 days. Six chicks were selected and slaughtered on the first day, and then at 56, 70 and 84 days of age 10 birds unit was selected and slaughtered per experimental period. Weight and yield of carcass, abdominal fat and breast, thigh and drumstick meat were determined. Additionally, moisture, protein, fat and mineral matter contents and protein and fat deposition in the breast, drumstick and thigh muscles were determined. The diet did not influence the yields of carcass, abdominal fat, or meat cuts or the nutritional composition of meat. Slaughter age influenced the yields of breast and thigh meat and abdominal fat; the protein content of breast meat; and the moisture, crude protein, fat, and mineral matter contents of drumstick and thigh meat. There was an interaction effect between diet and slaughter age for protein deposition in breast meat. The age factor influenced fat deposition in the drumstick muscles. Protein deposition in the thigh muscles was influenced by the diet. Moreover, a difference was observed between the ages for protein and fat deposition in the thigh muscle. In conclusion, the use of a commercial mixture in the diet results in decreased protein deposition in the breast and thigh muscles, although this difference does not affect the characteristics of carcass or meat cuts. Birds slaughtered at 70 days exhibit similar carcass characteristics to those of birds slaughtered at 84 days, indicating the possibility of an earlier slaughter age.


The effect of individualized diet challenges consisting of allergenic foods on TNF-alpha and IL-1beta levels in patients with rheumatoid arthritis.
To investigate the effect of individualized diet challenges consisting of allergenic foods, defined by the skin prick test (SPT), on tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in patients with rheumatoid arthritis (RA). Twenty patients with a positive SPT response for food extracts and 20 with a negative SPT response were enrolled. None of the patients had active disease. All patients were fasted for the most common allergenic foods for 12 days and then allocated to two groups according to SPT results. Food challenges were performed with allergenic foods in the prick-positive group (PPG) and with corn and rice in the prick-negative group (PNG) for a period of 12 days. Then, allergenic foods were excluded from the PPG patients' diet and corn and rice were removed from the PNG patients' diet. Clinical examinations were performed after fasting (baseline), at the end of the challenge phase and at the end of the re-elimination phase. Stiffness, pain, tender and swollen joint counts, health assessment questionnaire (HAQ), Ritchie's articular index, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum TNF-alpha and IL-1beta levels were measured. TNF-alpha (P < 0.01), IL-1beta (P < 0.05), ESR (P < 0.05) and CRP (P = 0.001) levels and all of the clinical variables, except HAQ, were increased with food challenges in the PPG. These increases were also recorded after the re-elimination phase. In the PNG, no significant change was seen in any of the variables, except pain (P < 0.05). During the study, important differences were observed for most of the variables between the two groups. Thirteen (72%) patients in the PPG and three (18%) in the PNG experienced disease exacerbation with challenges. This aggravation continued after elimination. Our results suggest that individualized dietary revisions may regulate TNF-alpha and IL-1beta levels in selected patients with RA.


Patients' experiences of the PICC insertion procedure.
Peripherally inserted central catheters (PICCs) are a type of central venous access device used to deliver a variety of intravenous therapies, including chemotherapy. PICCs may be placed by interventional radiologists, anaesthetists or, as is increasingly common, by specialist nurses in the hospital setting. However, little is known about how patients feel regarding the PICC insertion procedure. The aim of this study was to interview patients who had undergone a recent PICC insertion in the chemotherapy day unit to identify their experiences. On analysis of the qualitative data obtained from the semi-structured interview, five themes emerged: the context of cancer; expectations; levels of pain and anxiety; coping strategies; and explanation. The findings of this study support some previously described elements of procedural experiences; however, new understanding has provided implications for practice in the areas of expectations, allaying anxiety levels, supporting individual coping strategies and providing explanation. The major limitation of the study was the homogenous sample of oncology patients with a clear link between the patient experience of the PICC insertion and the context of cancer. The main recommendation for further research would be to repeat this study with a broader patient population.


Deep and brainstem cavernomas: a consecutive 8-year series.
The goal of this study was to provide epidemiological and clinical data on the management of cavernomas of the basal ganglia and brainstem from a long-term series at one institution. All 68 patients who were referred to the authors' department between 1992 and 2000 for deep cavernomas were evaluated by clinic examinations, review of neuroimaging examinations, and review of charts and operative notes. Twenty-nine patients underwent microsurgical procedures, which carried a 69% risk of transitory neurological deterioration. Radical excision was achieved in 25 of these patients, as determined by a review of neuroimages; the remaining four patients all experienced new hemorrhages that led to increased morbidity or even to mortality. Surgical results were better if surgery was performed early, within 1 month posthemorrhage, than if operations were postponed. In selected patients, deep lesions not reaching a pial surface could be safely removed from the thalamus, basal ganglia, or medulla oblongata. Of five patients who underwent gamma knife surgery, two experienced hemorrhages, one at 2 and the other at 5 years following treatment. Patients who did not undergo surgery had a yearly incidence of hemorrhage that was 2% in cases of incidental cavernomas and 7% in symptomatic ones. Over the long term, outcomes were worse following conservative treatment or shunt insertion surgery than after microsurgery of symptomatic cavernomas. Incidental cavernomas carried a low risk of neurological deterioration. Surgery should follow generally accepted indications, but only with the confidence that total removal can be safely achieved. Surgery that is performed within 10 to 30 days following ictus may be preferable to delayed surgery.


[LASIK results of IntraLase femtosecond laser to correct myopia: efficacy, security and predictability].
To evaluate LASIK results obtained with the IntraLase femtosecond laser to correct myopia. This was a prospective, single masked observer study. Flaps were created with the IntraLase femtosecond laser (FS). All laser procedures were performed by the same surgeon using the Technolas 217 excimer laser (Bausch & Lomb). We have analysed the uncorrected visual acuity (UCVA) at 1 day, 1 week, 1 month and 3 months after surgery and best spectacle-corrected visual acuity (BSCVA) after 3 months. 485 eyes with myopia were treated and their results evaluated. The mean preoperative sphere was of -3.9 D (SD 2.0) and a mean astigmatism of -0.9 D (SD 0.9) with BSCVA 1.1 (SD 0.1). The UCVA results were 0.94 (SD 0.1) at the first day postoperatively visit, 0.96 (SD 0.1) at first week, 1.00 (SD 0.1) at one month and 1.00 (SD 0.2) at 3 months. The refractive error at 3 months was -0.02 D (SD 0.3) and -0.1 D (SD 0.3) of myopia and astigmatism respectively. At 3 months 96.9% of eyes were within +/-1.00D and 93.6% of the eyes were within + 0.50 D. LASIK to correct myopia is a safe, effective and predictable procedure using IntraLase FS to create the flap.


Prevalence of Punctate Keratopathy of West Indians in a Colombian Referral Center and a New Name Proposed: Rice´s Keratopathy.
To perform a prevalence study of Punctate Keratopathy of West Indians in Colombian individuals and to propose a new name for the condition. Prospective, population-based epidemiological study. All patients evaluated between November 1 and December 31, 2012, in the Centro Oftalmológico Virgilio Galvis and Fundación Oftalmológica de Santander (FOSCAL), Floridablanca, Colombia, with clinical findings of white corneal opacities corresponding to Punctate Keratopathy of West Indians were identified. Careful slit-lamp examination was performed for clinical diagnosis and findings were reported in the electronic medical record indicating number and location of the lesions. Prevalence was calculated for the total population, and for gender and age groups. Furthermore a literature review was performed and a new name for the condition proposed. In the whole group of patients, prevalence was 1.0%. No one case was diagnosed in a patient younger than 21 year-old. No one lesion was located within 2.5 mm of the corneal apex. 96% of affected patients had unilateral involvement. 58.5% of eyes had a single corneal lesion; 7% of eyes had 6 or 7 corneal lesions. The condition heretofore known as Punctate Keratopathy of West Indians was present in 1% of our patients in Colombia (South America). Thus, this non-infectious, non-inflammatory, asymptomatic ailment of unknown etiology is not restricted to people of Antillean descent, or who have lived in these islands. We propose the new name "Rice's keratopathy". Age and male gender were independent risk factors for the presence of the keratopathy.


Dynamics of manual skill: a computerized analysis of single peg movements and stochastic resonance hypothesis of cerebral laterality.
Hand skill was analyzed using a computerized peg moving task. The durations of single hand movements (PMTs) were accurately measured in right-hand (RH) and left-hand (LH) writers. One trial consisted of 10 movements of the right hand and 10 movements of the left hand. Each participant performed five trials. Women showed significantly higher percentage than men in right-handedness; men showed higher percentage than women in left-handedness. This sex difference completely disappeared after taking the same height range in participants. The mean RH- and LH-PMTs decreased in 5 successive trials, even within a single trial during 10 successive hand movements, indicating a learning effect of repeated hand movements. The LH- minus RH-PMTs exhibited fluctuations within a single trial between positive (faster right hand) and negative (faster left hand) values. LH-RH PMTs were significantly greater than zero, in favor of right hand, in RH-writers, but not significantly different from zero in LH-writers, exhibiting a true fluctuating asymmetry. Participants with no familial sinistrality (FS-) were preponderantly right-handed (ca. 90%), those with left-handed mother and right-handed father (FS+1) showed stochastic distribution of hand preference (50:50). Participants with right-handed mother and left-hander father (FS+2) were not different from FS- individuals. LH-RH PMT was significantly greater than zero in FS- participants, almost equal to zero in FS+1 participants, and greater than zero in FS+2 participants exhibiting greater asymmetry than that in FS- participants. These results suggest a genetic inheritance of direction and degree of handedness, being a a X-linked trait originating from mother's genotype. It was suggested that fluctuating asymmetries may reflect interactions between stochastic resonance phenomena within right and left brains. This property of brain may genetically transmitted from mother's X chromosome; a net effect of stochastic interactions between hemispheres may result in right- or left-handedness, a predominantly unidirectional coupling creating right-handedness, in favor of left brain, and a stochastic bi-directional coupling between hemispheres would be a main trait of left-handers. This new "stochastic resonance hypothesis of cerebral laterality" concerns with stochastic fluctuations in hand-skill asymmetry and inter-hemispheric coupling through corpus callosum, and seems to be important for new developments in handedness research.


Components of reproductive isolation between the monkeyflowers Mimulus lewisii and M. cardinalis (Phrymaceae).
Evolutionists have long recognized the role of reproductive isolation in speciation, but the relative contributions of different reproductive barriers are poorly understood. We examined the nature of isolation between Mimulus lewisii and M. cardinalis, sister species of monkeyflowers. Studied reproductive barriers include: ecogeographic isolation; pollinator isolation (pollinator fidelity in a natural mixed population); pollen competition (seed set and hybrid production from experimental interspecific, intraspecific, and mixed pollinations in the greenhouse); and relative hybrid fitness (germination, survivorship, percent flowering, biomass, pollen viability, and seed mass in the greenhouse). Additionally, the rate of hybridization in nature was estimated from seed collections in a sympatric population. We found substantial reproductive barriers at multiple stages in the life history of M. lewisii and M. cardinalis. Using range maps constructed from herbarium collections, we estimated that the different ecogeographic distributions of the species result in 58.7% reproductive isolation. Mimulus lewisii and M. cardinalis are visited by different pollinators, and in a region of sympatry 97.6% of pollinator foraging bouts were specific to one species or the other. In the greenhouse, interspecific pollinations generated nearly 50% fewer seeds than intraspecific controls. Mixed pollinations of M. cardinalis flowers yielded >75% parentals even when only one-quarter of the pollen treatment consisted of M. cardinalis pollen. In contrast, both species had similar siring success on M. lewisii flowers. The observed 99.915% occurrence of parental M. lewisii and M. cardinalis in seeds collected from a sympatric population is nearly identical to that expected, based upon our field observations of pollinator behavior and our laboratory experiments of pollen competition. F1 hybrids exhibited reduced germination rates, high survivorship and reproduction, and low pollen and ovule fertility. In aggregate, the studied reproductive barriers prevent, on average, 99.87% of gene flow, with most reproductive isolation occurring prior to hybrid formation. Our results suggest that ecological factors resulting from adaptive divergence are the primary isolating barriers in this system. Additional studies of taxa at varying degrees of evolutionary divergence are needed to identify the relative importance of pre- and postzygotic isolating mechanisms in speciation.


pH-sensitive carboxymethyl chitosan hydrogels via acid-labile ortho ester linkage for potential biomedical applications.
Hydrogel systems with favorable biocompatibility and biodegradability are of much interest for application in biomaterials and tissue engineering. In this study, a new ortho ester-based acid-labile crosslink agent with dual-epoxy end groups was synthesized and crosslinked with carboxymethyl chitosan (CMCS) at different molar ratios to prepare a series of pH-sensitive hydrogels for drug delivering. Doxorubicin (DOX) was then readily loaded into the hydrogels and the in vitro release profiles indicated that the release rate increased rapidly while pH decreased from 7.4 to 5.0, which is consistent with the degradation rate of these hydrogels at corresponding pH conditions. In addition, results from MTT assay and flow cytometry demonstrated that these CMCS-based hydrogels and their degradation products have no cytotoxicity against SH-SY5Y and 293T cells. Therefore, the prepared acid-labile hydrogels could be applied in tumorous drug delivery systems and peritumoral implantation therapy by further optimization.


Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease.
Aortic disease, including dissection, aneurysm, and rupture, carries significant morbidity and mortality and is a notable cause of sudden cardiac death. Much of our knowledge regarding the genetic basis of aortic disease has relied on the study of individuals with Mendelian aortopathies and, until recently, the genetic determinants of population-level variance in aortic phenotypes remained unclear. However, the application of machine learning methodologies to large imaging datasets has enabled researchers to rapidly define aortic traits and mine dozens of novel genetic associations for phenotypes such as aortic diameter and distensibility. In this review, we highlight the emerging potential of genomics for identifying causal genes and candidate drug targets for aortic disease. We describe how deep learning technologies have accelerated the pace of genetic discovery in this field. We then provide a blueprint for translating genetic associations to biological insights, reviewing techniques for locus and cell type prioritization, high-throughput functional screening, and disease modeling using cellular and animal models of aortic disease.


A pilot surrogate end point biomarker trial of perillyl alcohol in breast neoplasia.
Efficient strategies to screen promising agents in early phase development are essential for rapid progress in breast cancer chemoprevention. We report our experience with the natural compound perillyl alcohol (POH) administered in a short-term surrogate end point biomarker (SEB) protocol, using the "window" between diagnostic and definitive surgery. Eligible patients included those with a diagnosis of atypical ductal hyperplasia, ductal carcinoma in situ, lobular carcinoma in situ, or invasive carcinoma (<3 cm in size) that required further surgery. Thirty-seven of 267 women screened were enrolled in the study (14%). Five women received single-dose POH (1.5 g/m2) 2 days before surgery, 16 received escalating doses of POH (1.2 g/m2 to 4.8 g/m2/day) for 2 days before surgery, and 16 served as untreated controls. Exploratory SEB analysis [estrogen receptor, progesterone receptor, proliferation, apoptosis, M6P/insulin-like growth factor (IGF)-2R, IGF1, IGF2 and transforming growth factor beta] was conducted before and after POH. Only a small portion of the population screened entered the study. Reasons for nonparticipation included protocol ineligibility, conflict of timing of surgery, miscellaneous logistical reasons, or patient's choice. POH administration was well tolerated and did not interfere with surgical management. The power to observe changes in candidate SEB was diminished by a 44% incidence of cases in which the index lesion was not present in the definitive surgical specimen. Preoperative POH exposure was safe and suitable for a more definitive phase II SEB study. Further investigations must overcome logistical obstacles to accrual, and they must focus on approaches to maximize tissue collection and to incorporate genomic analysis of target lesions.


Role of Oral and Gut Microbiota in Dietary Nitrate Metabolism and Its Impact on Sports Performance.
Nitrate supplementation is an effective, evidence-based dietary strategy for enhancing sports performance. The effects of dietary nitrate seem to be mediated by the ability of oral bacteria to reduce nitrate to nitrite, thus increasing the levels of nitrite in circulation that may be further reduced to nitric oxide in the body. The gut microbiota has been recently implicated in sports performance by improving muscle function through the supply of certain metabolites. In this line, skeletal muscle can also serve as a reservoir of nitrate. Here we review the bacteria of the oral cavity involved in the reduction of nitrate to nitrite and the possible changes induced by nitrite and their effect on gastrointestinal balance and gut microbiota homeostasis. The potential role of gut bacteria in the reduction of nitrate to nitrite and as a supplier of the signaling molecule nitric oxide to the blood circulation and muscles has not been explored in any great detail.


Immunotherapy-responsive dementias and encephalopathies.
The diagnosis of an autoimmune dementia requires the detection of objective improvements in cognitive decline (usually subacute in onset with a fluctuating course) after a course of immunotherapy. Serum and CSF antibody markers of autoimmunity (particularly those with neural antigen specificity) as well as other CSF markers of inflammation increase the suspicion for an autoimmune cause. The detection of neural autoantibodies should raise concern for a paraneoplastic etiology and may inform a targeted oncologic evaluation (eg, NMDA receptor antibodies are associated with teratoma). MRI, EEG, functional imaging, and neuropsychological evaluations provide objective evidence of neurologic dysfunction by which the success of immunotherapy may be measured. Most treatment information emanates from retrospective case series and expert opinion. Nonetheless, early intervention allows reversal of deficits in many patients. Chronic treatment is often required to maintain remission.


Programming With Varying Dietary Fat Content Alters Cardiac Insulin Receptor, Glut4 and FoxO1 Immunoreactivity in Neonatal Rats, Whereas High Fat Programming Alters Cebpa Gene Expression in Neonatal Female Rats.
Fetal programming refers to an intrauterine stimulus or insult that shapes growth, development and health outcomes. Dependent on the quality and quantity, dietary fats can be beneficial or detrimental for the growth of the fetus and can alter insulin signaling by regulating the expression of key factors. The effects of varying dietary fat content on the expression profiles of factors in the neonatal female and male rat heart were investigated and analyzed in control (10% fat), 20F (20% fat), 30F (30% fat) and 40F (40% fat which was a high fat diet used to induce high fat programming) neonatal rats. The whole neonatal heart was immunostained for insulin receptor, glucose transporter 4 (Glut4) and forkhead box protein 1 (FoxO1), followed by image analysis. The expression of 84 genes, commonly associated with the insulin signaling pathway, were then examined in 40F female and 40F male offspring. Maintenance on diets, varying in fat content during fetal life, altered the expression of cardiac factors, with changes induced from 20% fat in female neonates, but from 30% fat in male neonates. Further, CCAAT/enhancer-binding protein alpha (Cebpa) was upregulated in 40F female neonates. There was, however, differential expression of several insulin signaling genes in 40F (high fat programmed) offspring, with some tending to significance but most differences were in fold changes (≥1.5 fold). The increased immunoreactivity for insulin receptor, Glut4 and FoxO1 in 20F female and 30F male neonatal rats may reflect a compensatory response to programming to maintain cardiac physiology. Cebpa was upregulated in female offspring maintained on a high fat diet, with fold increases in other insulin signaling genes viz. Aebp1, Cfd (adipsin), Adra1d, Prkcg, Igfbp, Retn (resistin) and Ucp1. In female offspring maintained on a high fat diet, increased Cebpa gene expression (concomitant with fold increases in other insulin signaling genes) may reflect cardiac stress and an adaptative response to cardiac inflammation, stress and/or injury, after high fat programming. Diet and the sex are determinants of cardiac physiology and pathophysiology, reflecting divergent mechanisms that are sex-specific.


Multicentre European study of thalamic stimulation in parkinsonian and essential tremor.
Thalamic stimulation has been proposed to treat disabling tremor. The aims of this multicentre study were to evaluate the efficacy and the morbidity of thalamic stimulation in a large number of patients with parkinsonian or essential tremor. One hundred and eleven patients were included in the study and 110 were implanted either unilaterally or bilaterally. Patients were evaluated with clinical scales, before and up to 12 months after surgery. Upper and lower limb tremor scores were reduced in both groups. Eighty five per cent of the electrodes satisfied the arbitrary criteria of two point reduction in rest tremor reduction in the parkinsonian tremor group and 89% for postural tremor reduction in the essential tremor group. In the parkinsonian tremor group, limb akinesia and limb rigidity scores were moderately but significantly reduced. Axial scores were unchanged. In the essential tremor group, head tremor was significantly reduced only at 3 months and voice tremor was non-significantly reduced. Activities of daily living were improved in both groups. Changes in medication were moderate. Adverse effects related to the surgery were mild and reversible. Thalamic stimulation was shown to be an effective and relatively safe treatment for disabling tremor. This procedure initially applied in a very limited number of centres has been successfully used in 13 participating centres.


Definition of main pollen season using a logistic model.
This paper proposes a method to unify the definition of the main pollen season based on statistical analysis. For this, an aerobiological study was carried out in Porto region (Portugal), from 2003-2005 using a 7-day Hirst-type volumetric spore trap. To define the main pollen season, a non-linear logistic regression model was fitted to the values of the accumulated sum of the daily airborne pollen concentration from several allergological species. An important feature of this method is that the main pollen season will be characterized by the model parameters calculated. These parameters are identifiable aspects of the flowering phenology, and determine not only the beginning and end of the main pollen season, but are also influenced by the meteorological conditions. The results obtained with the proposed methodology were also compared with two of the most used percentage methods. The logistic model fitted well with the sum of accumulated pollen. The explained variance was always higher than 97%, and the exponential part of the predicted curve was well adjusted to the time when higher atmospheric pollen concentration was sampled. The comparison between the different methods tested showed large divergence in the duration and end dates of the main pollen season of the studied species.


Oral lesions in HIV+/AIDS adolescents perinatally infected undergoing HAART.
To assess the prevalence of the oral lesions related to HIV-infection (HIV-OL) in HIV+/AIDS adolescents (=13 years old), and the differences with HIV+/AIDS children (=3 - <13 years old) perinatally infected. 25 HIV+/AIDS adolescents and 62 HIV+/AIDS children, undergoing Highly Active Antiretroviral Therapy, were orally examined. HIV-OL was diagnosed in accordance with EC-Clearinghouse-World Health Organization. The patients were classifies with respect to their immune status in relation with the CD4+ cell counts as moderately immunodeficient; mildly immunodeficient and severely immunodeficient in accordance to the revised surveillance case definitions for HIV infection among adults, adolescents, and children aged <18 months and for HIV infection and AIDS among children aged 18 months to <13 years (CDC-USA). The virological status was established in relation to the copies of RNA-HIV-1/mL as follows: with undetectable viral load (UDVL); with low viral load and with high viral load. A chi-square test was performed (p<0.05 IC95%). The prevalence of HIV-OL in HIV+/AIDS adolescents was 20% while in HIV/AIDS children was 30.6% (p>0.05). Oral candidiasis was the most prevalent oral lesion in both groups. Association (p<0.05) of a high prevalence of HIV-OL and oral candidiasis with a high viral load was observed in both study groups. Adolescents perinatally HIV-infected have a high prevalence of HIV-OL. Oral Candidiasis still is the most frequent oral opportunistic infection. Oral lesions could have association to viral failure in HIV+/AIDS adolescents undergoing HAART.


Measuring quantitative serum human chorionic gonadotropin. Variations in levels between kits.
Human chorionic gonadotropin (hCG) may be used in the monitoring of early pregnancy. It may also be used as a tumor marker in the diagnosis and follow-up of gestational trophoblastic disease, choriocarcinoma and testicular carcinoma. The combination of maternal serum unconjugated estriol, alpha-fetoprotein and quantitative hCG has shown promise as an antepartum screen for Down syndrome. In the quantitative assessment of hCG, the calibrators used by various kits are standardized to one of two different standards, either the Second International Standard or the First International Reference Preparation (IRP), established by the World Health Organization in 1968 and 1975, respectively. The IRP is now considered the Third International Standard, and both terms may be used interchangeably. Confusion may exist in clinical situations if quantitative hCG levels determined by assays in different laboratories using different standards are compared or used simultaneously. Practitioners are advised to be aware of which calibration standard is utilized in their laboratory and to interpret the results accordingly.


Human mesenchymal stromal cells from adult and neonatal sources: a comparative in vitro analysis of their immunosuppressive properties against T cells.
Bone marrow-mesenchymal stromal cells (BM-MSCs) have immunosuppressive properties and have been used in cell therapies as immune regulators for the treatment of graft-versus-host disease. We have previously characterized several biological properties of MSCs from placenta (PL) and umbilical cord blood (UCB), and compared them to those of BM-the gold standard. In the present study, we have compared MSCs from BM, UCB, and PL in terms of their immunosuppressive properties against lymphoid cell populations enriched for CD3(+) T cells. Our results confirm the immunosuppressive potential of BM-MSCs, and demonstrate that MSCs from UCB and, to a lesser extent PL, also have immunosuppressive potential. In contrast to PL-MSCs, BM-MSCs and UCB-MSCs significantly inhibited the proliferation of both CD4(+) and CD8(+) activated T cells in a cell-cell contact-dependent manner. Such a reduced proliferation in cell cocultures correlated with upregulation of programmed death ligand 1 on MSCs and cytotoxic T lymphocyte-associated Ag-4 (CTLA-4) on T cells, and increased production of interferon-γ, interleukin-10, and prostaglandin E2. Importantly, and in contrast to PL-MSCs, both BM-MSCs and UCB-MSCs favored the generation of T-cell subsets displaying a regulatory phenotype CD4(+)CD25(+)CTLA-4(+). Our results indicate that, besides BM-MSCs, UCB-MSCs might be a potent and reliable candidate for future therapeutic applications.


Suppression of interleukin-12 production by human monocytes after preincubation with lipopolysaccharide.
Interleukin-12 (IL-12) is a potent proinflammatory and immunoregulatory cytokine skewing T lymphocytes to express a type 1 cytokine pattern. Optimal expression of IL-12 mRNA and bioactivity in vitro requires specific priming of monocytes by interferon-gamma (IFN-gamma) or granulocyte-macrophage colony-stimulating factor (GM-CSF) before lipopolysaccharide (LPS) stimulation. We show here for the first time that the production of IL-12 by IFN-gamma- or GM-CSF-primed human monocytes can be completely suppressed by preincubation with LPS (from Escherichia coli Serotype 055:B5) for 6 to 24 hours before the priming procedure. A dose-dependent suppression of IL-12p70 was measured on the levels of intracellular cytokine production and cytokine secretion. mRNA studies on the expression of p40 and p35 showed an LPS-induced downregulation of both subunits. The results of several different experimental approaches suggest that IL-12 downregulation was not due to endogenous IL-10, IL-4, prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), or nitric oxide (NO) production induced by LPS. Moreover, preincubation of monocytes with LPS did not lead to a downregulation of the CD14 antigen, which is an LPS receptor. LPS preincubation in this experimental setting did not result in a general hyporesponsiveness of the monocytes, as IL-6 production as well as IFN-gamma-induced upregulation of CD54 did not decline. Downregulation of IL-12 was not due to changes in mRNA stability. These findings show that the immunoregulatory important cytokine, IL-12, underlies itself a complex regulation.


Comparison of the characteristic features of Bonghan ducts, blood and lymphatic capillaries.
To show that the characteristic morphological and ultrastructural features of a Bonghan corpuscle and duct presented here are consistent with the description given in the early reports of Bonghan Kim. We compared the morphological aspects of Bonghan ducts with those of blood and lymphatic capillaries on the ultrastructural level to display the manifestly distinctive nature of the Bonghan system. The walls of the ductules were observed to be composed of a single layer of endothelial cells with characteristic rod-shaped nuclei and were not surrounded by a basal lamina or by accessory cells, such as pericytes or smooth muscle cells. The abluminal cell membranes of Bonghan ductules were not attached by anchoring filaments to the fibers of extracellular matrices as observed in lymphatic capillaries. The cytoplasmic processes of ductule endothelial cells appear to form overlapping and interdigitated interconnections which completely lack junctional elements. Although the cytoplasm of ductule endothelial cells contained a well-developed rough endoplasmic reticulum and many free ribosomes and polysomes, there was a relatively small number of pinocytotic vesicles and lacks specific organelles, such as Weibel-Palade bodies. The Bonghan corpuscles are specialized structures consisting of different types of immune cells randomly scattered as single cells in the matrix or clustered in follicle-like formations. Moreover, the Bonghan ductules in the corpuscle contain flowing immune cells and occasionally basophilic bodies.


Quality of life in patients with rheumatoid arthritis: does abatacept make a difference?
Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune disease that, in addition to causing joint damage, is associated with pain, fatigue, disability and functional loss, which can substantially decrease a patient's quality of life (QoL). Along with improvements in signs and symptoms, QoL benefits have become increasingly important in optimizing treatment outcomes in RA. Measurements of QoL have previously been under-used in all areas of medicine and only recently have clinical trials included them as a measure of treatment effectiveness. The existence of a positive relationship between improvements in signs and symptoms and concomitant improvements in QoL provides additional evidence that QoL measures are useful benchmarks for evaluating the effectiveness of treatment for RA. Furthermore, since these outcome measures evaluate the real-life, patient-centered benefits of RA therapies, they are likely to become increasingly central to the assessment of disease impact in clinical trials and practice, and to both drug approval and reimbursement decisions. This article reviews the impact of abatacept, a selective co-stimulation modulator, on the QoL of patients with active RA across a number of pivotal clinical trials. Firstly, an overview of the key QoL measurements used in abatacept clinical trials is provided, including those such as the Short Form-36, Health Assessment Questionnaire and Visual Analog Scale for pain, sleep and fatigue. We then present QoL data obtained in a wide range of patients with RA, including those with an inadequate response to either methotrexate or anti-tumor necrosis factor therapy, who have been treated with abatacept. Analysis of these data demonstrates that abatacept therapy has the potential to improve QoL across a range of patients with RA.


The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells.
Trastuzumab (herceptin) and pertuzumab (Omnitarg, 2C4) are recombinant humanized monoclonal antibodies that target different extracellular regions of the HER-2 tyrosine kinase receptor. We explored combination effects of these agents in the HER-2-overexpressing BT474 breast cancer cell line. Trastuzumab and 2C4 synergistically inhibited the survival of BT474 cells, in part, because of increased apoptosis. Trastuzumab increased 2C4-mediated disruption of HER-2 dimerization with the epidermal growth factor receptor and HER-3. Combination drug treatment reduced levels of total and phosphorylated HER-2 protein and blocked receptor signaling through Akt but did not affect mitogen-activated protein kinase. These results suggest that combining HER-2-targeting agents may be a more effective therapeutic strategy in breast cancer rather than treating with a single HER-2 monoclonal antibody.


The factors related to mother's beliefs and behaviors concerning the prevention of poisoning among children under the age of five, using the Health Belief Model.
Rezapur Shahkolai F, Bandehelahi K, Karimi Shahanjarini A, Farhadian M. The factors related to mother's beliefs and behaviors concerning the prevention of poisoning among children under the age of five, using the Health Belief Mode. Turk J Pediatr 2019; 61: 749-756. Poisoning is a major public health problem and children younger than five years of age are more likely to be exposed to injury events such as poisoning. The aim of this study is to investigate the factors associated with the mothers' beliefs and behaviors in relation to poisoning prevention among children under five years of age, considering the Health Belief Model (HBM). This cross-sectional study was conducted among 580 mothers with at least one child under the age of five that had been referred to a health center in Hamadan County, Iran, in 2017. The participants were selected randomly, using cluster sampling method. Data were collected through interviews, by trained interviewers, and using a questionnaire developed by the authors. This study showed the statistically significant relationship between mothers' behavior concerning the prevention of poisoning in children under the age of five years and the variables of the gender of children (P=0.014); mother's education level (P < 0.001) and occupation (P=0.001); and father's education level (P < 0.001) and occupation (P < 0.001). Moreover, mothers' related knowledge and, according to HBM constructs, mothers' perceived susceptibility (p < 0.001) and perceived severity (p= 0.004) regarding poisoning among their children, cues to action (p=0.041) and their self-efficacy (p=0.012) were more powerful predictors for prevention of poisoning among children under the age of five. This study indicates that the HBM, highlighting the four constructs can be helpful to design educational interventions for improving the behaviors of mothers regarding poisoning prevention among children under the age of five years.


Atovaquone-Proguanil in Combination With Artesunate to Treat Multidrug-Resistant P. falciparum Malaria in Cambodia: An Open-Label Randomized Trial.
Recent artemisinin-combination therapy failures in Cambodia prompted a search for alternatives. Atovaquone-proguanil (AP), a safe, effective treatment for multidrug-resistant Plasmodium falciparum (P.f.), previously demonstrated additive effects in combination with artesunate (AS). Patients with P.f. or mixed-species infection (n = 205) in Anlong Veng (AV; n = 157) and Kratie (KT; n = 48), Cambodia, were randomized open-label 1:1 to a fixed-dose 3-day AP regimen +/-3 days of co-administered artesunate (ASAP). Single low-dose primaquine (PQ, 15 mg) was given on day 1 to prevent gametocyte-mediated transmission. Polymerase chain reaction-adjusted adequate clinical and parasitological response at 42 days was 90% for AP (95% confidence interval [CI], 82%-95%) and 92% for ASAP (95% CI, 83%-96%; P = .73). The median parasite clearance time was 72 hours for ASAP in AV vs 56 hours in KT (P < .001) and was no different than AP alone. At 1 week postprimaquine, 7% of the ASAP group carried microscopic gametocytes vs 29% for AP alone (P = .0001). Nearly all P.f. isolates had C580Y K13 propeller artemisinin resistance mutations (AV 99%; KT 88%). Only 1 of 14 treatment failures carried the cytochrome bc1 (Pfcytb) atovaquone resistance mutation, which was not present at baseline. P.f. isolates remained atovaquone sensitive in vitro but cycloguanil resistant, with a triple P.f. dihydrofolate reductase mutation. Atovaquone-proguanil remained marginally effective in Cambodia (≥90%) with minimal Pfcytb mutations observed. Treatment failures in the presence of ex vivo atovaquone sensitivity and adequate plasma levels may be attributable to cycloguanil and/or artemisinin resistance. Artesunate co-administration provided little additional blood-stage efficacy but reduced post-treatment gametocyte carriage in combination with AP beyond single low-dose primaquine.


Molecular and morphological criteria for revision of the genus Microcoleus (Oscillatoriales, Cyanobacteria).
Ninety-two strains of Microcoleus vaginatus (=nomenclatural-type species of the genus Microcoleus Desmazières ex Gomont) and Phormidium autumnale Trevisan ex Gomont from a wide diversity of regions and biotopes were examined using a combination of morphological and molecular methods. Phylogenies based on the 16S rDNA and 16S-23S ITS (partial) demonstrated that the 92 strains, together with a number of strains in GenBank, were members of a highly supported monophyletic clade of strains (Bayesian posterior probability = 1.0) distant from the species-cluster containing the generitype of Phormidium. Similarity of the 16S rRNA gene exceeded 95.5% among all members of the Microcoleus clade, but was less than 95% between any Microcoleus strains and species outside of the clade (e.g., Phormidium sensu stricto). These findings, which are in agreement with earlier studies on these taxa, necessitate the revision of Microcoleus to include P. autumnale. Furthermore, the cluster of Phormidium species in the P. autumnale group (known as Group VII) must be moved into Microcoleus as well, and these nomenclatural transfers are included in this study. The main diacritical characters defining Microcoleus are related to the cytomorphology of trichomes, including: narrowed trichome ends, calyptra, cells shorter than wide up to more or less isodiametric, and facultative presence of sheaths. The majority of species are 4-10 μm in diameter. The possession of multiple trichomes in a common sheath is present facultatively in many but not all species.


Planning and production of grammatical and lexical verbs in multi-word messages.
Grammatical words represent the part of grammar that can be most directly contrasted with the lexicon. Aphasiological studies, linguistic theories and psycholinguistic studies suggest that their processing is operated at different stages in speech production. Models of sentence production propose that at the formulation stage, lexical words are processed at the functional level while grammatical words are processed at a later positional level. In this study we consider proposals made by linguistic theories and psycholinguistic models to derive two predictions for the processing of grammatical words compared to lexical words. First, based on the assumption that grammatical words are less crucial for communication and therefore paid less attention to, it is predicted that they show shorter articulation times and/or higher error rates than lexical words. Second, based on the assumption that grammatical words differ from lexical words in being dependent on a lexical host, it is hypothesized that the retrieval of a grammatical word has to be put on hold until its lexical host is available, and it is predicted that this is reflected in longer reaction times (RTs) for grammatical compared to lexical words. We investigated these predictions by comparing fully homonymous sentences with only a difference in verb status (grammatical vs. lexical) elicited by a specific context. We measured RTs, duration and accuracy rate. No difference in duration was observed. Longer RTs and a lower accuracy rate for grammatical words were reported, successfully reflecting grammatical word properties as defined by linguistic theories and psycholinguistic models. Importantly, this study provides insight into the span of encoding and grammatical encoding processes in speech production.


The immunogenicity and safety of Group B Streptococcal maternal vaccines: A systematic review.
To systematically review immunogenicity and safety data of maternal group B streptococcal (GBS) vaccines in published clinical trials until July 2023. EMBASE, MEDLINE, Cochrane Library and clinicaltrial.gov. databases were searched for clinical studies that reported immunogenicity and/or safety of GBS vaccine in non-pregnant adults, pregnant women and infants between 1st of January 1996 to 31st of July 2023. Pairs of reviewers independently selected, data extracted, and assessed the risk of bias of the studies. Discrepancies were resolved by consensus. (PROSPERO CRD42020185213). We retrieved 1472 records from the literature search; 20 studies and 6 sub-studies were included, involving 4440 non-pregnant participants and 1325 pregnant women with their newborns. There was a significantly higher IgG Geometric Mean Concentration (GMC) and IgG placental transfer ratios in vaccinated compared to placebo groups, with peak response 4-8 weeks after vaccination. Placental transfer ratio varied from 0.4 to 1.4 across five studies. The different clinical trials used different assays that limited direct comparison. There were no significant differences in the risk of serious adverse events (adjusted OR 0.73; 95 % CI 0.49-1.07), serious adverse events leading to withdrawal (adjusted OR 0.44; 95 % CI 0.13-1.51), and systemic illness or fever (adjusted OR 1.05; 95 % CI 0.26-4.19) between the vaccine and placebo groups. The published clinical trials show significant IgG GMC response in subjects receiving the conjugated capsular polysaccharide and surface subunit protein vaccines compared to placebo. In current clinical trials of experimental GBS maternal vaccines, there have been no observed serious adverse events of special interest directly linked to vaccination.


Polymer dynamics under confinement.
We review recent neutron scattering work and related results from simulation and complementary techniques focusing on the microscopic dynamics of polymers under confinement. Confinement is either realized in model porous materials or in polymer nanocomposites (PNC). The dynamics of such confined polymers is affected on the local segmental level, the level of entanglements as well as on global levels: (i) at the segmental level the interaction with the surface is of key importance. At locally repulsive surfaces compared to the bulk the segmental dynamics is not altered. Attractive surfaces slow down the segmental dynamics in their neighborhood but do not give rise to dead, glassy layers. (ii) Confinement generally has little effect on the inter-chain entanglements: both for weakly as well as for marginally confined polymers the reptation tube size is not changed. Only for strongly confined polymers disentanglement takes place. Similarly, in PNC at higher NP loading disentanglement phenomena are observed; in addition, at very high loading a transition from polymer caused topological constraints to purely geometrical constraints is observed. (iii) On the more global scale NSE experiments revealed important information on the nature of the interphase between adsorbed layer and bulk polymer. (iv) Polymer grafts at NP mutually confine each other, an effect that is most pronounced for one component NP. (v) Global diffusion of entangled polymers both in weakly and strongly attractive PNC is governed by the ratio of bottle-neck to chain size that characterizes the 'entropic barrier' for global diffusion.


Pediatric Continuous Renal Replacement Therapy (PCRRT) expert committee recommendation on prescribing prolonged intermittent renal replacement therapy (PIRRT) in critically ill children.
Recently, prolonged intermittent renal replacement therapies (PIRRT) have emerged as cost-effective alternatives to conventional CRRT and their use in the pediatric population has started to become more prominent. However, there is a lack of consensus guidelines on the use of PIRRT in pediatric patients in an intensive care setting. A literature search was performed on PubMed/Medline, Embase, and Google Scholar in conjunction with medical librarians from both India and the Cleveland Clinic hospital system to find relevant articles. The Pediatric Continuous Renal Replacement Therapy workgroup analyzed all articles for relevancy, proposed recommendations, and graded each recommendation for their strength of evidence. Of the 60 studies eligible for review, the workgroup considered data from 37 studies to formulate guidelines for the use of PIRRT in children. The guidelines focused on the definition, indications, machines, and prescription of PIRRT. Although the literature on the use of PIRRT in children is limited, the current studies give credence to their benefits and these expert recommendations are a valuable first step in the continued study of PIRRT in the pediatric population.


A Global Review on the Utility of Genetic Testing for Familial Hypercholesterolemia.
Familial hypercholesterolemia (FH) is a genetic disorder of cholesterol metabolism that affects an estimated 1/250 persons in the United States and abroad. FH is hallmarked by high low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. This review summarizes recent global evidence showing the utility of FH genetic testing across diverse populations. Clinical and other qualitative outcomes following FH genetic testing were improved FH diagnosis, treatment initiation or continued treatment, treatment modification, improved total or LDL cholesterol levels, education on lifestyle management, and genetic counseling. This summary of evidence should be considered by those seeking overall evidence and knowledge gaps on the utility of FH genetic testing from a global perspective and for certain ethnic and age populations. These findings can be used to inform insurance policies and coverage decisions for FH genetic testing, policy recommendations to reduce the clinical and public health burden of FH, clinical practice and guidelines to improve the management of FH populations, and ongoing research involving FH genetic testing. We conclude that further investigations are needed to examine: (1) non-clinical outcomes following FH genetic testing; (2) patient-reported outcomes following FH genetic testing to convey patient experiences, values, and goals; and (3) clinical outcomes following FH genetic testing in non-Caucasian and pediatric populations in the United States and abroad.


Predicting Posttraumatic Stress Disorder Among Survivors of Recent Interpersonal Violence.
A substantial minority of women who experience interpersonal violence will develop posttraumatic stress disorder (PTSD). One critical challenge for preventing PTSD is predicting whose acute posttraumatic stress symptoms will worsen to a clinically significant degree. This 6-month longitudinal study adopted multilevel modeling and exploratory machine learning (ML) methods to predict PTSD onset in 58 young women, ages 18 to 30, who experienced an incident of physical and/or sexual assault in the three months prior to baseline assessment. Women completed baseline assessments of theory-driven cognitive and neurobiological predictors and interview-based measures of PTSD diagnostic status and symptom severity at 1-, 3-, and 6-month follow-ups. Higher levels of self-blame, generalized anxiety disorder severity, childhood trauma exposure, and impairment across multiple domains were associated with a pattern of high and stable posttraumatic stress symptom severity over time. Predictive performance for PTSD onset was similarly strong for a gradient boosting machine learning model including all predictors and a logistic regression model including only baseline posttraumatic stress symptom severity. The present findings provide directions for future work on PTSD prediction among interpersonal violence survivors that could enhance early risk detection and potentially inform targeted prevention programs.


Implicit motives predict affective responses to emotional expressions.
We explored the influence of implicit motives and activity inhibition (AI) on subjectively experienced affect in response to the presentation of six different facial expressions of emotion (FEEs; anger, disgust, fear, happiness, sadness, and surprise) and neutral faces from the NimStim set of facial expressions (Tottenham et al., 2009). Implicit motives and AI were assessed using a Picture Story Exercise (PSE) (Schultheiss et al., 2009b). Ratings of subjectively experienced affect (arousal and valence) were assessed using Self-Assessment Manikins (SAM) (Bradley and Lang, 1994) in a sample of 84 participants. We found that people with either a strong implicit power or achievement motive experienced stronger arousal, while people with a strong affiliation motive experienced less arousal and less pleasurable affect across emotions. Additionally, we obtained significant power motive × AI interactions for arousal ratings in response to FEEs and neutral faces. Participants with a strong power motive and weak AI experienced stronger arousal after the presentation of neutral faces but no additional increase in arousal after the presentation of FEEs. Participants with a strong power motive and strong AI (inhibited power motive) did not feel aroused by neutral faces. However, their arousal increased in response to all FEEs with the exception of happy faces, for which their subjective arousal decreased. These differentiated reaction patterns of individuals with an inhibited power motive suggest that they engage in a more socially adaptive manner of responding to different FEEs. Our findings extend established links between implicit motives and affective processes found at the procedural level to declarative reactions to FEEs. Implications are discussed with respect to dual-process models of motivation and research in motive congruence.


Family process and content: comparing families of suicide attempters, human immunodeficiency virus positive patients and general population in southern iran, 2012.
Family is considered as the smallest social unit, which is the basis of forming a society and one of the effective factors for individual behaviors. When family pattern is useful, the family will be productive and otherwise it becomes nonproductive. This study aimed to investigate family process and content among families of suicide attempters, human immunodeficiency virus (HIV) positive patients, and general population in Shiraz, Southern Iran. This was a causal-comparative study. Our study population included three groups of single men, including suicide attempters, HIV positive patients and general population in Southern Iran. Our sample size was 180 male individuals including 60 suicide attempters referring to one of hospitals in Shiraz, 60 HIV positive patients referring to Behavioral Health Consultation Center, and 60 individuals from the general population who were selected using simple sampling method and were being investigated by Samani's family process and family content questionnaires. Data were being analyzed by ANCOVA and MANCOVA. The two clinical groups had a poorer situation than the general population (P < 0.001) in some dimensions of family process including decision-making and coping (P < 0.001), mutual respect, and communication (P = 0.02) when compared with the general population. HIV positive patients had significantly lower scores than suicide attempters in some dimensions of family content including financial resources, social position (P < 0.001), and place of residence (P = 0.04). The two clinical groups had a poor situation in most of the dimensions when compared with the general population (P < 0.001). The results of this study indicate the importance of education in the field of communication, decision-making and coping skills.


Regression models in clinical studies: determining relationships between predictors and response.
Multiple regression models are increasingly being applied to clinical studies. Such models are powerful analytic tools that yield valid statistical inferences and make reliable predictions if various assumptions are satisfied. Two types of assumptions made by regression models concern the distribution of the response variable and the nature or shape of the relationship between the predictors and the response. This paper addresses the latter assumption by applying a direct and flexible approach, cubic spline functions, to two widely used models: the logistic regression model for binary responses and the Cox proportional hazards regression model for survival time data.


Effect of Psychotherapy for Borderline Personality Disorder on Quality of Life: A Systematic Review and Meta-Analysis.
Whereas several meta-analyses have shown that psychotherapy is effective for reducing borderline personality disorder (BPD) pathology, the overall impact of psychotherapy for BPD on quality of life (QoL) remains as yet unclear. Because impaired QoL is associated with poor long-term outcomes after therapy for BPD, this seems a timely and relevant issue. The authors conducted a systematic review and meta-analysis of randomized controlled trials of psychotherapies for adults diagnosed with BPD that reported results of QoL at posttreatment. Fourteen trials were included (1,370 individuals with BPD). Psychotherapies for BPD relative to control conditions showed significant effect sizes for QoL (Cohen's d = 0.31; 95% CI [0.18, 0.44]), and for BPD pathology (d = 0.43; 95% CI [0.23, 0.64]). The effect on QoL was not significantly moderated by the effect on BPD pathology. Psychotherapies for BPD have a positive effect on QoL of patients with BPD. However, more studies are needed to examine the impact of psychotherapy on QoL and long-term outcome, including recovery.


Current status of treatment of metastatic colorectal cancer with special reference to cetuximab and elderly patients.
Elderly cancer patients often have co-morbidities and other characteristics that make the selection of optimal treatment more complex. The introduction of targeted therapies in colorectal cancer has further complicated this problem. This review will focus on the role of the EGFR antibody cetuximab in elderly patients. We have reviewed the available evidence in the literature to evaluate the results of therapy with cetuximab, alone or in combination with chemotherapy, with a focus on elderly patients with metastatic colorectal cancer (mCRC). In patients with mCRC, combination chemotherapy prolongs median survival to more than 18 months and even around 24 months in combination with cetuximab in selected patients. No prospective studies have evaluated cetuximab in elderly patients. However, subgroup analyses from randomized trials and retrospective analysis suggest that the efficacy of chemotherapy and cetuximab is maintained in fit elderly patients, but with slightly increased but acceptable toxicity. No prospective cetuximab studies have been conducted solely in a population of elderly patients. However, available data suggest that outcomes in the fit elderly mirror results observed in younger patients.


Glycine N-Thiocarboxyanhydride: A Key to Glycine-Rich Protein Mimics.
Glycine-rich proteins (GRPs) containing a high content of glycine residues (>30%) possess unique structural stability. However, the controllable synthesis of glycine-rich poly(amino acid)s (PAAs) to mimic GRPs has not been realized yet due to the poor solubility of polyglycine segments. We developed a novel method to synthesize glycine-rich PAAs via the controlled ring-opening copolymerization of glycine-N-thiocarboxyanhydrides (Gly-NTA) with sarcosine-N-carboxyanhydride and ε-Cbz-l-lysine-N-carboxyanhydride. The random copolymerization is evidenced by a kinetic study that shows that the propagation rate constant of Gly-NTA is close to those of comonomers. The copolymers exhibit predictable molecular weights between 4.5 and 24.6 kg/mol and tunable glycine incorporation, varying from 10.3 to 59.2%. Poly(Gly-r-Sar) samples with various glycine contents form nanoparticles or a hydrogel in water. Remarkably, the β-sheet folding of poly(Gly-r-Lys) remains intact in a neutral environment where the amine groups are protonated. Overall, the strategy paves the way to engineer glycine-rich PAAs and thereby expands their applications.


Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes.
Ketoconazole has recently been shown to interfere with steroidogenesis in patients and rat in vitro systems. In this study we attempted to elucidate the site of inhibition in the adrenal gland. Although ketoconazole impaired adrenocorticotropic hormone stimulated cyclic (c)AMP production, dibutyrl cAMP addition did not bypass the steroidogenic blockade indicating that the critical ketoconazole-inhibited step was distal to cAMP. Addition of radiolabeled substrates to isolated adrenal cells and analysis of products by high performance liquid chromatography demonstrated a ketoconazole block between deoxycorticosterone (DOC) and corticosterone. This 11-hydroxylase step is carried out by a P450-dependent mitochondrial enzyme. No restriction of progesterone or pregnenolone conversion to DOC was detected, steps carried out by non-P450-dependent microsomal enzymes. Inhibition of cholesterol conversion to pregnenolone by mitochondrial fractions indicated a second block at the side chain cleavage step, another mitochondrial P450-dependent enzyme. Adrenal malate dehydrogenase, a non-P450-dependent mitochondrial enzyme was not inhibited while renal 24-hydroxylase, a P450-dependent mitochondrial enzyme in another organ, was blocked by ketoconazole. We conclude that ketoconazole may be a general inhibitor of mitochondrial P450 enzymes. This finding suggests that patients receiving ketoconazole be monitored for side effects relevant to P450 enzyme inhibition. Further, we raise the possibility that this drug action may be beneficially exploited in situations where inhibition of steroidogenesis is a therapeutic goal.


Viscoelastic phase separation in soft matter and foods.
Phase separation is a fundamental phenomenon that produces spatially heterogeneous patterns in soft matter and foods. We argue that phase separation in these materials generally belongs to "viscoelastic phase separation", where the morphology is determined by the mechanical balance of not only the thermodynamic force (interface tension) but also the viscoelastic force. The origin of the viscoelastic force is dynamic asymmetry between the components of a mixture, which can be caused by either a size disparity or a difference in the glass transition temperature between the components. Such dynamic asymmetry quite often exists in foods, which are typically mixtures of big molecules (polymers, proteins, etc.) and liquids (water, oil, etc.). We show examples of mechanically driven pattern formation in foods, in which dynamic asymmetry plays crucial roles, including the formation of network and cellular patterns in foods (e.g., breads, sponge cakes, butter, chocolates, etc.) and crack pattern formation (dried foods, cooked meat, etc.). Collapsing of these structures upon heating or moisture uptake is also discussed. We also argue that heterogeneous gels are in general formed as a consequence of dynamical arrest of the viscoelastic phase separation. Finally we mention an intimate link of viscoelastic phase separation, where deformation fields are spontaneously generated by phase separation itself, to mechanical instability and fracture induced by externally imposed strain fields. Such mechanical instability and nonlinear rheology may be relevant to food processing and also to separation and fracture of foods. We propose that all these phenomena can be understood as mechanically driven inhomogeneization with the concept of dynamic asymmetry in a unified manner.


Membrane electrical parameters of normal human red blood cells.
The studies reported in this chapter indicate that the Na/K pump's contribution to Em of human red blood cells with normal cellular Na is no more than 0.1 to 0.2 mV. Estimates based on this magnitude of the electrogenic component and the pump current (taken as one-third the ouabain-sensitive Na efflux) indicate that Rm in these cells is about 1 to 2 X 10(5) ohm cm2.


Snow angels - the microbiology of freshly fallen snow: implications for immunocompromised patients.
The frequency of seasonal snowfall results in the transient covering of gardens/amenity sites/open public spaces, which encourages recreational interaction mainly with children. No data is available demonstrating the microbiological composition of such fallen snow and therefore a study was undertaken to examine the microbiology of snow from 37 sites, estimating (i) total viable count (TVC), (ii) identification of bacteria, and (iii) the presence of Pseudomonas aeruginosa. Mean TVC count of 8.3 colony-forming units (cfu)/ml snow melt water, 51.7 cfu/ml, 865 cfu/ml and 2,197 cfu/ml, was obtained for public amenity sites, domestic gardens, public open spaces and melting snow from public footpaths, respectively. No bacterial organisms (<10 cfu/ml) were detected in 5/14 (35.7%) open public spaces, 2/5 (40%) amenity sites and in 1/10 (10%) domestic gardens. Pseudomonas aeruginosa was not detected from any snow sample examined. Bacterial diversity consisted of 15 bacterial species (11 Gram-positive/four Gram-negative). The six Gram-positive genera identified from snow were Actinomyces, Bacillus, Brevibacillus, Micrococcus, Staphylococcus and Streptococcus. The four Gram-negative genera identified were Enterobacter, Pantoea, Pseudomonas and Xanthomonas. Bacillus licheniformis was the most commonly isolated organism from snow; it was isolated from every snow type. Snow may contain a diverse range of bacteria, many of which are capable of causing human infections.


Inhibition of hemopoietic growth factor-induced proliferation by adenosine diphosphate-ribosylation inhibitors.
The effects of adenosine diphosphate (ADP) ribosylation inhibitors on hematopoietic growth factor-induced proliferation were examined. Significant inhibition of interleukin-3 (IL-3), colony-stimulating factor 1, and lung conditioned media-induced clonal agar growth of normal murine hematopoietic cells by 10 mmol/L nicotinamide (NAM), 10 mmol/L 3-aminobenzamide (3AB), and 5 mmol/L N1-methylnicotinamide (1MN) was noted. Nicotinic acid, a related compound that does not inhibit ADP ribosylation, failed to inhibit the growth factor-mediated proliferation. NAM (10 mmol/L), 3AB (10 mmol/L), and 1MN (5 mmol/L) also prevented IL-3 and phorbol ester-stimulated 3H-thymidine incorporation into the IL-3-responsive FDC-P1 cell line. Exposure of FDC-P1 cells to 10 mmol/L NAM led to a significant decrease in nuclear poly-(ADP-ribose) levels. Exposure of FDC-P1 cells to 5 mmol/L 1MN did not affect the interaction of the phorbol ester receptor, protein kinase-C (PK-C), with the cell membrane as determined by assay of phorbol ester binding in cytosol and membrane preparations. Nor did it affect the catalytic activity of PK-C as determined by assaying the in vitro phosphorylation of histone H1 by cytosolic kinase preparations from FDC-P1 as well as EL4 thymoma cells. 1MN markedly enhanced the inhibitory effects of phorbol esters on DNA synthesis of EL4 cells even at concentrations (1.25 mmol/L) that had no effects on DNA synthesis in the absence of phorbol esters. Our findings demonstrate that (a) active ADP ribosylation inhibitors interfere with growth factor-induced proliferation of murine hematopoietic cells and (b) the inhibition occurs at a step that follows the activation and translocation of PK-C and is more closely linked to DNA synthesis.


Sperm, a source of estrogen.
This review article discusses a novel nontraditional site of estrogen synthesis and the potential targets of estrogen action within the male reproductive system. Our laboratories have recently demonstrated that developing spermatids in several species contain aromatase, the cytochrome P450 enzyme responsible for converting androgens into estrogens. The enzyme was localized by immunocytochemistry and the protein's presence was confirmed by Western blot analysis. Northern blot analysis and in situ hybridization were used to corroborate the presence of mRNA for aromatase. It appears that the aromatase message precedes the synthesis of the protein, and the protein remains in the spermatids several days after the message disappears. The enzyme is located along the tail of newly released sperm and is active in the epididymal sperm as well as in the developing germ cells of the testis. This unique discovery is the basis for our overall hypothesis that estrogen, synthesized by sperm, plays a role in the regulation of epididymal function proportional to the number of sperm being transported. The presence of an estrogen source within the ductal lumen is of special importance to the study of epididymal function because the regulatory mechanisms in this region remain unclear, particularly for the efferent ductules and initial segment regions, although estrogen receptors have been identified in the ductal epithelium. An understanding of the role that estrogen plays in the function of the epididymis may provide benefits in several areas including the treatment of abnormalities in epididymal function, the potential development of a male contraceptive, and insight into the causes of adult epididymal lesions induced by neonatal exposure to estrogenic compounds such as diethylstilbestrol.


Formaldehyde exposure during pregnancy.
Pregnancy is a particularly vulnerable time for exposure to indoor air pollutants, such as formaldehyde (FA), which is linked to spontaneous abortion, congenital malformations, and premature birth. To determine personal exposure to FA during pregnancy, and to identify the relationship between FA exposure levels and potential residential sources of FA. The study sample consisted of 140 pregnant women recruited from obstetrical clinics in Huntsville, Alabama. Formaldehyde exposure was measured by FA vapor monitor badges. Questionnaires were administered to participants to identify potential residential sources of FA. Urine cotinine, a surrogate for tobacco smoke exposure, was also used as an indicator of a possible source of residential exposure to FA. The mean level of FA exposure by vapor monitor badge was 0.04 parts per million (ppm) (SD = 0.06; range 0.003-0.54 ppm). Minimum risk levels of 0.03 and higher were found in 36.4% of participants. Exposure levels of FA were higher in spring than winter (p < 0.001). Exposure levels of FA were correlated with indoor temperature of dwellings (p < 0.02), installation of new carpet within last 5 years (p < 0.04), and use of nail polish (p < 0.01). No relationship was found between FA exposure and urine cotinine levels. Formaldehyde exposure may increase at various times in the lives of women; however, it is of particular concern during pregnancy because of perinatal risk to the exposed fetus.


Cellular and mucosal immune responses in the respiratory tract of Nigerian goats following intranasal administration of inactivated Recombinant Mannheimia hemolytica bacterine.
This experiment was conducted to evaluate the cellular and mucosal responses in the respiratory tract of Nigerian goats vaccinated intranasally with recombinant Mannheimia hemolytica bacterine. Twenty one goats were divided into five groups, five goats each in three vaccinated groups while three goats each in two other groups serve as positive and negative control. Group A was vaccinated once; group B was vaccinated twice at one week interval, and group D at twice at two weeks interval. Group C1 were the unvaccinated and challenged, while group C2 were unvaccinated and unchallenged. The bronchoalveolar lavage differential counts and bronchial associated lymphoid tissue (BALT) responses were measured using Giemsa stained thin smear of the cell fraction of the lavage and histomorphometry. ANOVA were employed and significance was at p>0.05. The post-challenge macrophage to neutrophil (M:N) ratio values of group B goats was the highest and the ratio differed from other groups which had much lower M:N values. The exposure in group B resulted in significant increase in number and size of BALTs as well as the number of lymphocytes in BALT than those of the other groups. This study showed that intranasal vaccination of the recombinant Mannheimia hemolytica bacterine twice at a week interval was more efficient in inducing strong mucosal and defensive cellular responses in the respiratory tract.


Receptors for human plasminogen on gram-negative bacteria.
A total of 188 strains representing 11 species of gram-negative bacteria were examined for the ability to interact with human plasminogen. Highly purified human plasminogen was labeled with 125I, and its uptake by different bacterial strains was measured. All 14 strains of Haemophilus influenzae and all 13 strains of Branhamella catarrhalis tested were positive with respect to plasminogen uptake. Also, eight species belonging to the family Enterobacteriaceae were tested, and of those, Proteus mirabilis demonstrated the most substantial uptake, with 28 of 39 strains taking up more than 10% of the plasminogen. Ten strains of Pseudomonas aeruginosa were also tested, of which seven showed uptake values higher than 10%. With H. influenzae and B. catarrhalis strains, Scatchard analysis indicated a two-phase receptor interaction, one more-avid receptor with a Kd of 6 to 8 nM and 2,000 to 2,500 sites per bacterium and a second receptor with a Kd of 50 to 80 nM and 9,000 sites per bacterium. With Pseudomonas aeruginosa strains, a single receptor interaction was detected with a Kd of 60 nM and the number of sites was estimated as 8,000 per bacterium. Scatchard analysis with strains of P. mirabilis indicated binding of a less-specific nature. However, plasminogen uptake by this species could be reduced by 50% by the addition of 2 mM unlabeled plasminogen. This estimate of Kd, as well as uptake studies with plasminogen fragments, suggests different properties of this receptor. With all receptor types, the addition of plasmin-aprotinin complex inhibited plasminogen uptake, which demonstrates that both forms of the molecule react with the same receptors. Plasminogen uptake could be eliminated by the addition of lysine or epsilon-aminocaproic acid, which suggests that the lysine-binding sites of the plasminogen molecule are involved in the receptor-ligand interaction.


Methodological considerations in estimating speed of cognitive operations.
Individuals infected with Human Immunodeficiency Virus (HIV) and having cognitive impairment have been described as having slow mentation. Data supporting this proposition come from a variety of sources, including Sternberg's (1966) item recognition memory task. The procedure nominally provides an index of speed of mental operations, independent from input/output demands. However, since the original use of this procedure in the 1960s, advances in cognitive psychology have revealed many of its limitations. The purpose of the present study was to examine the psychometric characteristics of this task. Each participant performed the Sternberg item recognition task twice, 6 mo apart. The stability of the estimate of the slope of regression equations and for zero intercept ranged from excellent (r = .87) to poor (r = .30), and the data from many individual subjects could not be reliably modelled using multiple linear regression techniques. These data, as well as those from previous research, demonstrate the limited practical use of this task in clinical samples. Furthermore, as cognitive psychological theory has advanced in the past 30 yr, the conceptual underpinnings of the procedure have essentially evaporated.


Setting research priorities for Type 1 diabetes.
Research priorities are often set by academic researchers or the pharmaceutical industry. The interests of patients, carers and clinicians may therefore be overlooked and research questions that matter may be neglected. The aims of this study were to collect uncertainties about the treatment of Type 1 diabetes from patients, carers and health professionals, and to collate and prioritize these uncertainties to develop a top 10 list of research priorities, using a structured priority-setting partnership of patients, carers, health professionals and diabetes organizations, as described by the James Lind Alliance. A partnership of interested organizations was set up, and from this a steering committee of 10 individuals was formed. An online and paper survey was used to identify uncertainties. These were collated, and the steering group carried out an interim priority-setting exercise with partner organizations. This group of uncertainties was then voted on to give a smaller list that went forward to the final priority-setting workshop. At this meeting, a final list of the top 10 research priorities was agreed. An initial 1141 uncertainties were described. These were reduced to 88 indicative questions, 47 of which went out for voting. Twenty-four were then taken forward to a final priority-setting workshop. This workshop resulted in a list of top 10 research priorities in Type 1 diabetes. We have shown that it is possible using the James Lind Alliance process to develop an agreed top 10 list of research priorities for Type 1 diabetes from health professionals, patients and carers.


A Fast and Accessible Method for the Isolation of RNA, DNA, and Protein To Facilitate the Detection of SARS-CoV-2.
Management of the coronavirus disease 2019 (COVID-19) pandemic requires widespread testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A main limitation for widespread SARS-CoV-2 testing is the global shortage of essential supplies, among them RNA extraction kits. The need for commercial RNA extraction kits places a bottleneck on tests that detect SARS-CoV-2 genetic material, including PCR-based reference tests. Here, we propose an alternative method we call PEARL (precipitation-enhanced analyte retrieval) that addresses this limitation. PEARL uses a lysis solution that disrupts cell membranes and viral envelopes while simultaneously providing conditions suitable for alcohol-based precipitation of RNA, DNA, and proteins. PEARL is a fast, low-cost, and simple method that uses common laboratory reagents and offers performance comparable to that of commercial RNA extraction kits. PEARL offers an alternative method to isolate host and pathogen nucleic acids and proteins to streamline the detection of DNA and RNA viruses, including SARS-CoV-2.


[Diagnosis of pulmonary embolism].
The diagnosis of pulmonary embolism (PE) is challenging because the symptoms are unspecific and an objective confirmation of the disease is required. Clinical symptoms and physical examination can be used to estimate the clinical probability of the disease used to interpret the results of the diagnostic tests. In patients with low or moderate clinical probability most quantitative D-dimer tests allow to exclude PE safely. A positive proximal venous ultrasound enables to confirm PE but the sensitivity is too low to exclude the diagnosis. In patients with a positive D-dimer test, multidetector spiral CT allows to confirm or exclude PE with confidence in most of the cases. Lung scanning is still useful in patients with renal impairment or allergy to contrast medium.


Measurement invariance versus selection invariance: is fair selection possible?
This article shows that measurement invariance (defined in terms of an invariant measurement model in different groups) is generally inconsistent with selection invariance (defined in terms of equal sensitivity and specificity across groups). In particular, when a unidimensional measurement instrument is used and group differences are present in the location but not in the variance of the latent distribution, sensitivity and positive predictive value will be higher in the group at the higher end of the latent dimension, whereas specificity and negative predictive value will be higher in the group at the lower end of the latent dimension. When latent variances are unequal, the differences in these quantities depend on the size of group differences in variances relative to the size of group differences in means. The effect originates as a special case of Simpson's paradox, which arises because the observed score distribution is collapsed into an accept-reject dichotomy. Simulations show the effect can be substantial in realistic situations. It is suggested that the effect may be partly responsible for overprediction in minority groups as typically found in empirical studies on differential academic performance. A methodological solution to the problem is suggested, and social policy implications are discussed.


Day and Night Fluctuations in GABA Biosynthesis Contribute to Drought Responses in Nicotiana tabacum L.
When synchronized with the light/dark cycle the circadian rhythm is termed a diurnal rhythm and this organizes an organism's daily life cycle in relation to the metabolic shifts during the day/night cycles. This is a complex task, particularly under stress conditions. Accurate maintenance of the diurnal rhythm becomes an issue under environmental extremes, such as drought due to the impairment of metabolism, redox balance, and structural integrity. In plants, the non-proteinogenic amino acid GABA accumulates to high levels in response to several stress factors but this is not always dependent on the activation of its biosynthesis. Here we propose a regulatory role to GABA during the diurnal rhythm in plants which is similar to its function in animals where it adjusts the circadian rhythm. Here we investigated whether GABA-biosynthesis was affected by drought stress during the diurnal cycle. For this, we took samples from leaves of N. tabacum plants subjected to PEG-mediated drought stress (-0.73 MPa) during the day and night cycle during a 24 hour period. Glutamate, GABA, and proline contents, along with GDH, GAD enzyme activities and transcript profiles were analyzed. Overall, we conclude that the oscillations in GABA biosynthesis during day and night cycle have an impact on drought stress responses which needs to be elucidated by further analysis.


Mitogenic properties of polyene antibiotics for murine B cells.
Two polyene antibiotics, nystatin and amphotericin B, were found to be mitogenic for mouse spleen cells as measured by induction of DNA synthesis and polyclonal antibody production. This effect was demonstrated on spleen cells from nude mice and anti-theta-treated spleen cells from normal mice. No effect was found on cortisone-resistant thymocytes or on spleen cells treated with anti-mouse bone marrow-derived lymphocyte antigen antiserum. Nor was there any effect on spleen cells passed through a nylon fiber column. Thus we conclude that nystatin and amphotericin B are murine B-cell mitogens.


Determination of optimum optoelectronic properties in vertically stacked MoS2/h-BN/WSe2 van der Waals heterostructures.
Current achievements show that inserting an insulator at the interface in van der Waals (vdW) heterostructures can improve the photoelectric conversion efficiency. However, the underlying mechanism of the intercalated insulator effect on photocarrier collection and recombination, etc., remains unclear at the atomic level. Herein, we investigate the influence of intercalated hexagonal boron nitride (h-BN) on the optoelectronic properties of MoS2/WSe2 vdW heterostructures based on the interface bond relaxation and detailed balance principles. It was found that the band offsets (barrier height) at the heterointerface decrease with increasing h-BN size and decreasing transition metal dichalcogenide (TMD) thickness. Moreover, the power conversion efficiency (PCE) in monolayer MoS2/11-layers h-BN/monolayer WSe2 can reach 3.23% and enhances with increasing thickness of TMDs. Also, the optimal thickness of h-BN in MoS2/h-BN/WSe2 decreases from 3.64 to 2.86 nm as the thickness of TMDs increases. Our results show that the PCE and open-circuit voltage of the MoS2/h-BN/WSe2 vdW heterostructure are obviously improved compared with the bilayer heterostructure without h-BN, and this further proves the feasibility of the intercalated insulator as a booster for highly efficient photovoltaic and optoelectronic nanodevices.


Recent advances in design and fabrication of upconversion nanoparticles and their safe theranostic applications.
Lanthanide (Ln) doped upconversion nanoparticles (UCNPs) have attracted enormous attention in the recent years due to their unique upconversion luminescent properties that enable the conversion of low-energy photons (near infrared photons) into high-energy photons (visible to ultraviolet photons) via the multiphoton processes. This feature makes them ideal for bioimaging applications with attractive advantages such as no autofluorescence from biotissues and a large penetration depth. In addition, by incorporating advanced features, such as specific targeting, multimodality imaging and therapeutic delivery, the application of UCNPs has been dramatically expanded. In this review, we first summarize the recent developments in the fabrication strategies of UCNPs with the desired size, enhanced and tunable upconversion luminescence, as well as the combined multifunctionality. We then discuss the chemical methods applied for UCNPs surface functionalization to make these UCNPs biocompatible and water-soluble, and further highlight some representative examples of using UCNPs for in vivo bioimaging, NIR-triggered drug/gene delivery applications and photodynamic therapy. In the perspectives, we discuss the need of systematically nanotoxicology data for rational designs of UCNPs materials, their surface chemistry in safer biomedical applications. The UCNPs can actually provide an ideal multifunctionalized platform for solutions to many key issues in the front of medical sciences such as theranostics, individualized therapeutics, multimodality medicine, etc.


Purification and characterization of recombinant human renin for X-ray crystallization studies.
The renin-angiotensin-aldosterone system (RAS) cascade is a major target for the clinical management of hypertension. Although inhibitors of various components of this cascade have been developed successfully, development of renin inhibitors has proven to be problematic. The development of these inhibitors has been hindered by poor bioavailability and complex synthesis. However, despite the challenges of designing renin inhibitors, the enzyme remains a promising target for the development of novel treatments for hypertension. X-ray crystallographic data could greatly assist the design and development of these inhibitors. Here we describe the purification and characterization of recombinant human renin for x-ray crystallization studies. A cDNA encoding the full length of native human preprorenin (406 amino acid residues) was introduced into the HEK-293 cell line. A clonal cell line expressing prorenin was generated and grown under serum free conditions in a hollow fiber bioreactor. Prorenin was constitutively secreted and purified directly from the conditioned medium. Concanavalin A chromatography effectively enriched and purified prorenin to 90% homogeneity in a single step. Prorenin was converted to active renin by trypsin digestion to remove the propeptide. Active renin was further purified using a cation exchange column followed by a gel filtration column. Biochemical characterization of the recombinant enzyme showed both binding and catalytic properties were essentially identical to previously reported activities for purified renin. Crystals were grown using this material in our X-ray structure studies, and high resolution diffraction was obtained. This present work describes a simple and efficient method for the generation and purification of active human renin. The protein is highly pure and is suitable for supporting structural biology efforts.