Innovative design for a phase 1 trial with intra-patient dose escalation: The Crotoxin study.
Crotoxin has a broad antitumor activity but has shown frequent neurotoxic toxicity. To induce tolerance and limit this toxicity, we propose a new design with intra-patient dose escalation. A new Dose Limiting Toxicity definition was used. The concept of Target Ceiling Dose was introduced. Dose Limiting Toxicity was the inability to dose escalate twice. Target Ceiling Dose was the highest planned dose to be administered to a patient and could change for patients along time. Recommended Dose was defined similarly as in a (3 + 3) conventional design. This innovant design was used and the clinical trial is now closed for inclusions. Results will be presented later.


Silicon-based additive on heavy metal remediation in soils: Toxicological effects, remediation techniques, and perspectives.
Chemical fertilizer is gaining increasing attention and has been the center of much research which indicating complex beneficial and harmful effects. Chemical fertilizer might cause some environmental hazards to the biosphere, especially in the agricultural ecosystem. The application of silicon (Si) fertilizer in agriculture has been proved to be able to create good economic and environmental benefits. Si is the second most abundant earth crust element. Si fertilizer improves soil quality and alleviates biotic and abiotic crop stress. It is of great significance to understand the function of Si fertilizer in agricultural utilization and environmental remediation. This paper reviews the Si-based fertilizer in farmland use and summarizes prior research relevant with characterization, soil quality improvement, and pollution remediation effects. Its use in agriculture enhances plant silicon uptake, mediates plant salt and drought stress and remediates heavy metals such as Al, As, Cd, Cu, Zn and Cr. This article also summarizes the detoxification mechanism of silicon and its effects on plant physiological activity such as photosynthesis and transpiration. Fertilizer materials and crop fertilizer management were also considered. Foliar spraying is an effective method to improve crop growth and yield and reduce biotic or abiotic stress. Silicon nanoparticle material provides potential with great potential and prospects. More investigation and research are prospected to better understand how silicon impacts the environment and whether it is a beneficial additive.


Associations between oxytocin and empathy in humans: A systematic literature review.
This is a systematic review about the association between empathic behavior and oxytocin (OXT). Searches were conducted in the electronic databases PubMed, Web of Science, PsycINFO, SciELO, and LILACS using the search terms "oxytocin", "empathy", and "empathic". Forty-four studies were reviewed. Scarce findings point to a lack of association between baseline endogenous OXT levels and empathy traits, and for a trend towards a direct relationship between oxytocinergic reactivity and empathic functioning. The results showed that variations in empathy were related to polymorphisms in the OXT receptor gene, especially in rs53576, and that this relationship seems to mediated by individual, ethnic, and cultural characteristics. Most studies on the exogenous administration of OXT tested a single dose (24 IU) with positive effects mainly on the affective domain of empathy. At the neural level, findings were inconsistent. Taken together, the results of the studies reviewed support the existence of a relationship between OXT and empathy that is complex and multifaceted. Robust evidence is still needed to elucidate existing links. Future investigations could benefit from methodological improvements aimed at increasing the reproducibility and applicability of findings, as well as the systematic assessment of the effects of exogenous OXT considering dose and frequency of administration, genotyping, and hormonal availability at the peripheral and central levels. This should lead to significant progress in the understanding of the therapeutic possibilities of OXT in the domain of empathic behavior.


The reliability of in-training assessment when performance improvement is taken into account.
During in-training assessment students are frequently assessed over a longer period of time and therefore it can be expected that their performance will improve. We studied whether there really is a measurable performance improvement when students are assessed over an extended period of time and how this improvement affects the reliability of the overall judgement. In-training assessment results were obtained from 104 students on rotation at our university hospital or at one of the six affiliated hospitals. Generalisability theory was used in combination with multilevel analysis to obtain reliability coefficients and to estimate the number of assessments needed for reliable overall judgement, both including and excluding performance improvement. Students' clinical performance ratings improved significantly from a mean of 7.6 at the start to a mean of 7.8 at the end of their clerkship. When taking performance improvement into account, reliability coefficients were higher. The number of assessments needed to achieve a reliability of 0.80 or higher decreased from 17 to 11. Therefore, when studying reliability of in-training assessment, performance improvement should be considered.


Musculoskeletal manifestations of thyroid disease.
The relationship between thyroid disorders and rheumatic diseases is significant.Thyroid diseases not only emulate rheumatic disease with findings such as myopathy or arthropathy but also frequently manifest with primary rheumatologic complaints that the practitioner should be wary of, such as calcium pyrophosphate deposition disease. There is increasing recognition of the prevalence of autoimmune thyroid diseases in patients with connective tissue disorder, highlighting a common mechanism for the disease pathogenesis, which requires further inquiry.


A possible common origin of "Y-negative" human XX males and XX true hermaphrodites.
We have studied nine patients aged 1 month to 16 years with 46, XX karyotypes and testicular tissue. Some of these patients were followed through puberty. Phenotypically, two presented normal and seven abnormal external genitalia (AG). Among this latter group, four showed hypospadias and three true hermaphroditism (TH). The endocrine data were similar in all three groups: testosterone levels were within normal limits during puberty, decreasing in adulthood; gonadotrophin levels were above the control values at mid puberty. Histologies of the two sub groups of AG patients were identical up to 5 years of age and presented differences when compared with controls, regardless of the ovarian part of the ovotestis. However, in patients older than 8 years, germ cells disappeared and dysgenesis became obvious. In one patient, the ovarian zone of the gonad was detected only after complete serial sections of the removed gonad were examined. Southern blot analysis with Y-DNA probes displayed Y-specific material for the classic 46 XX males and a lack of such sequences for all patients with AG and TH. Based on these findings, we postulate that 46, XX males with AG and 46, XX TH may represent alternative manifestations of the same genetic defect. These data together with those concerning familial cases of 46, XX males with AG and 46, XX TH suggest an autosomally (or pseudoautosomally) determined mechanism.


Complete m6A and m4C methylomes for group B streptococcal clinical isolates CJB111, A909, COH1, and NEM316.
Group B Streptococcus (GBS) is known to colonize the female reproductive tract and causes adverse pregnancy outcomes and neonatal disease. DNA methylation is a common mechanism for both phage defense and transcriptional regulation. Here, we report the m6A and m4C methylomes of four clinical GBS isolates, CJB111, A909, COH1, and NEM316.


A Study of Gene Expression, Structure, and Contractility of iPSC-Derived Cardiac Myocytes from a Family with Heart Disease due to LMNA Mutation.
Genetic mutations to the Lamin A/C gene (LMNA) can cause heart disease, but the mechanisms making cardiac tissues uniquely vulnerable to the mutations remain largely unknown. Further, patients with LMNA mutations have highly variable presentation of heart disease progression and type. In vitro patient-specific experiments could provide a powerful platform for studying this phenomenon, but the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) introduces heterogeneity in maturity and function thus complicating the interpretation of the results of any single experiment. We hypothesized that integrating single cell RNA sequencing (scRNA-seq) with analysis of the tissue architecture and contractile function would elucidate some of the probable mechanisms. To test this, we investigated five iPSC-CM lines, three controls and two patients with a (c.357-2A>G) mutation. The patient iPSC-CM tissues had significantly weaker stress generation potential than control iPSC-CM tissues demonstrating the viability of our in vitro approach. Through scRNA-seq, differentially expressed genes between control and patient lines were identified. Some of these genes, linked to quantitative structural and functional changes, were cardiac specific, explaining the targeted nature of the disease progression seen in patients. The results of this work demonstrate the utility of combining in vitro tools in exploring heart disease mechanics.


Interfacing clinical laboratory instruments with a computer system.
This paper describes a number of methods of interfacing clinical laboratory instruments with a computer system. The instrument interface portion of the Laboratory Data Acquisition System, an IBM Installed User Program, is described, as is the use of the IBM 7406 Device Coupler. Emphasis is placed on establishing a standard interface for all new instruments. A method of adding the standard interface to older instruments using the IBM 7406 Device Coupler is discussed.


Higher glucose fluctuation is associated with a higher risk of cardiovascular disease: Insights from pooled results among patients with diabetes.
The relationship between glucose fluctuation and the risk of cardiovascular disease (CVD) in patients with diabetes remains elusive. Glycated hemoglobin (HbA1c) variability is a key parameter of glucose fluctuation. PubMed, Cochrane Library, Web of Science, and Embase were searched up to 1 July 2022. Studies reporting associations of HbA1c variability (HbA1c-SD), coefficient of variation of HbA1c (HbA1c-CV), and HbA1c variability score [HVS] with the risk of CVD among patients with diabetes were included. We used three different insights (a high-low value meta-analysis, a study-specific meta-analysis, and a non-linear dose-response meta-analysis) to explore the relationship between HbA1c variability and CVD risk. A subgroup analysis was also performed to screen the potential confounding factors. A total of 14 studies with 254 017 patients with diabetes were eligible. The highest HbA1c variability was significantly associated with increased risks of CVD (HbA1c-SD, risk ratio [RR] 1.45; HbA1c-CV, RR 1.74; HVS, RR 2.46; all p < .001) compared to the lowest HbA1c variability. The RRs of CVD for per HbA1c variability were significantly >1 (all p < .001). The subgroup analysis for per HbA1c-SD found a significant exposure-covariate interaction in the types of diabetes (p = .003 for interaction). The dose-response analysis showed a positive association between HbA1c-CV and CVD risk (P for nonlinearity <.001). Our study suggests that the higher glucose fluctuation is significantly associated with the higher CVD risk in diabetes patients based on HbA1c variability. The CVD risk associated with per HbA1c-SD might be higher among patients type 1 diabetes than patients with type 2 diabetes.


Oculomotor Prediction: A Window into the Psychotic Mind.
Psychosis - an impaired contact with reality - is a hallmark of schizophrenia. Many psychotic symptoms are associated with disruptions in agency - the sense that 'I' cause my actions. A failure to predict sensory consequences of one's own actions may underlie agency disturbances. Such predictions rely on corollary discharge (CD) signals, 'copies' of movement commands sent to sensory regions prior to action execution. Here, we make a case that the oculomotor system is a promising model for understanding CD in psychosis, building on advances in our understanding of the behavioral and neurophysiological correlates of CD associated with eye movements. In this opinion article, we provide an overview of recent evidence for disturbed oculomotor CD in schizophrenia, potentially linking bizarre and disturbing psychotic experiences with basic physiological processes.


Lessons for deprescribing from a nonessential medication hold policy in US nursing homes.
At the height of the COVID-19 pandemic, a large nursing home chain implemented a policy to temporarily hold potentially unnecessary medications. We describe rates of held and discontinued medications after a temporary hold policy of potentially unnecessary or nonessential medications. This retrospective cohort study uses electronic health record (EHR) data on 3247 residents of 64 nursing homes operated by a multistate long-term care provider. Medications were documented in the electronic medication administration record. Overall medication held and discontinued incidences are reported. Hierarchical Bayesian modeling is used to determine individual probabilities for medication discontinuation within each facility. In total, 3247 residents had 5297 nonessential medications held. Multivitamins were most likely to be held, followed by histamine-2 receptor antagonists, antihistamines, and statins. At the end of the hold policy, 2897 of 5297 (54%) were permanently discontinued, including probiotics (73%), histamine-2 receptor antagonists (66%), antihistamines (64%), and statins (45%). Demographics, cognitive and functional impairment were similar between residents with medications who were discontinued versus continued. For most medications, more than 50% of the variance in whether medications were discontinued was explained by facility rather than resident-level factors. A temporary medication hold policy implemented during the CoVID-19 pandemic led to the deprescribing of a plurality of 'nonessential' medications. This type of organization-wide initiative may be an effective mechanism for altering future prescribing behaviors to reduce the use of unnecessary medications.


How phenol stresses anammox for the treatment of ammonia-rich wastewater: Phenomena, microbial community evolution and molecular modeling.
Phenol is a biotoxic organic compound and found in large quantities in ammonia-rich wastewater discharged from coking and petrochemical industries. In this work, phenol was fed to the system of anaerobic ammonia oxidation (anammox), and the possible inhibitory mechanism was speculated using the characterization of granular sludge, analysis of microbial community and molecular docking simulations. The results showed that phenol (0-300 mg/L) did not significantly inhibit anammox. However, phenol did activate denitrification, which increased the nitrogen removal rate (NRR) by 0.94 kg N/(m3·d). Moreover, when phenol concentration reached t400 mg/L, the NRR was inhibited by 70%, while the extracellular polymeric substance (EPS) of granular sludge was reduced. Phenol resulted in the reduction of Candidatus_Kuenenia and promoted the proliferation of phenol-degrading denitrifying bacteria, Azoarcus and Thauera. Molecular docking indicated that phenol, 2-nitrophenol and 4-nitrophenol could bind the nitrite reductase (NirS), which prevented the first step of the anammox reaction.


A case report of cavernous sinus thrombosis after trauma.
Cavernous sinus thrombosis is a rare but well-documented complication of sinus disease, propagated by intracranial spread of infection via valveless veins of the midface, with facial cellulitis as an uncommon source of infection. We present a case of significant intracranial thromboses secondary to nasal dorsal abscess after trauma that was successfully treated with bedside drainage of the abscess in addition to broad-spectrum antibiotics, anticoagulation, and steroids, and remains asymptomatic with seven months follow-up.


Promoting the promoter.
Recent evolutionary studies clearly indicate that evolution is mainly driven by changes in the complex mechanisms of gene regulation and not solely by polymorphism in protein-encoding genes themselves. After a short description of the cis-regulatory mechanism, we intend in this review to argue that by applying newly available technologies and by merging research areas such as evolutionary and developmental biology, population genetics, ecology and molecular cell biology it is now possible to study evolution in an integrative way. We contend that, by analysing the effects of promoter sequence variation on phenotypic diversity in natural populations, we will soon be able to break the barrier between the study of extant genetic variability and the study of major developmental changes. This will lead to an integrative view of evolution at different scales. Because of their sessile nature and their continuous development, plants must permanently regulate their gene expression to react to their environment, and can, therefore, be considered as a remarkable model for these types of studies.


A case of Bordetella trematum and Kerstersia gyiorum infections in a patient with congestive dermatitis.
Bordetella trematum and Kerstersia gyiorum are rare gram-negative bacilli that are not frequently detected in human infections. In this report, we describe a case of a 48-year-old man who presented to our hospital with an infected wound on his leg. Discharges from the cracks of the granulation were collected and evaluated in our microbiology laboratory. Gram staining of the specimen showed polymorphonuclear leukocytes and abundant gram-negative bacilli. Three types of colonies were isolated on blood agar and were identified as B. trematum and Alcaligenes faecalis using VITEK MS. Moreover, K. gyiorum and B. trematum were identified and confirmed via 16S ribosomal RNA (rRNA) gene sequencing. The patient successfully recovered following application of meropenem antibacterial therapy and surgical debridement. This is the first reported case of complex wound infection caused by both B. trematum and K. gyiorum. Identification of B. trematum has recently been made possible by routine bacterial identification using matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS). However, K. gyiorum isolation is still rare, and species identification requires 16S rRNA sequencing. Thus, this case highlighted the importance of using multiple methods, such as MALDI-TOF MS and 16S rRNA gene sequencing, for identification of rarely isolated species from clinical specimens.


Effects of Combined Rapid Maxillary Expansion and Facemask Therapy on the Mandibular Dental Arch in Mixed Dentition.
The aim of this study was to evaluate changes in the mandibular dental arch and incisor alignment induced by combined bonded Rapid Maxillary Expansion (RME) and Face Mask (FM) therapy in the mixed dentition stage in which leeway space was used throughout the treatment. This retrospective study evaluates pretreatment (T0) and posttreatment (T1) cephalometric radiographs and orthodontic models of 25 patients (mean age: 10.75±2.64), in mixed dentition, having skeletal Class 3 anomaly (ANB<0) with maxillary retrognatism (SNA=77.2±0.68) and bilateral posterior crossbite treated with bonded Hyrax RME-FM. Mean treatment duration was 10.4 months. Dental model measurements were performed using the 3Shape OrthoAnalyzerTM 2013-1 program. Changes in the mandibular incisor and first molar positions were determined on cephalometric radiographs. Statistical evaluation was done with a paired t-test. A significant increase of 1.2 mm was found in intermolar width (p<0.001) in the mandibular dental arch. There was a significant decrease (1.4 mm) (p<0.001) in arch depth and an increase in arch length discrepancy (1.7mm)(p<0.01). There was a significant increase (0.8mm) (p<0.05) in the incisors' irregularity score (LII). IMPA showed a significant decrease (p<0.05). Clinicians should be aware that mandibular crowding tends to increase during this type of combined therapy.


Evaluating the influence of setup uncertainties on treatment planning for focal liver tumors.
A mechanism has been developed to evaluate the influence of random setup variations on dose during treatment planning. The information available for studying these factors shifts from population-based models toward patient-specific data as treatment progresses and setup measurements for an individual patient become available. This study evaluates the influence of population as well as patient-specific setup distributions on treatment plans for focal liver tumors. Eight patients with focal liver tumors were treated on a protocol that involved online setup measurement and adjustment, as well as ventilatory immobilization. Summary statistics from these three-dimensional conformal treatments yielded individual and population distributions of position at initial setup for each fraction. A convolution model for evaluation of the influence of random setup variation on calculated dose distributions has been previously described and investigated for application to focal liver radiotherapy by our department. Individual patient doses based on initial setup positions were calculated by convolving the calculated dose distribution with an anisotropic probability distribution function representing the individual patient's random variations. A separate convolution using population-averaged random variations was performed. Individual beam apertures were then adjusted to provide plans that ensured proper dose to the clinical target volume following convolution with population distributions, as well as individual patient position uncertainty models. Individual patient setup distributions for the course of treatment had random setup variations (sigma) that ranged from 2.5 to 5.7 mm (left-right), 2.1 to 8.3 mm (anterior-posterior), and 4.1 to 10.8 mm (cranial-caudal). The population random components were 4.2 mm (left-right), 4.1 mm (anterior-posterior), and 7.0 mm (cranial-caudal) at initial setup. The initial static planned dose distribution overestimated the volume of liver irradiated to high doses, because inclusion of setup uncertainties generally blurred the resulting doses, shifting the higher-dose region of normal liver dose-volume histograms to lower doses. Furthermore, the population-based dose convolution tended to predict a higher risk of radiation damage to the liver (based on an in-house parameterization of the Lyman normal tissue complication probability model) than the individual patient calculations. For an individual plan, application of different individual random variations yielded change in effective volume differences with a 3% range. Plan adjustment to account for random setup variations generally resulted in a lower change in effective volume than initial planning using a planning target volume followed by calculation of delivered dose based on random offsets. This study hints at the factors that most strongly influence planning of liver treatments taking into account geometric variations. Given a setup verification methodology that rapidly reduces systematic offsets, the importance of realistic incorporation of geometric variations as an initial step in treatment planning, as well as possible plan refinement, is demonstrated.


Intravenous Thrombolysis Improves the Prognosis of Patients with Acute Ischemic Stroke and Chronic Kidney Disease.
Chronic kidney disease (CKD) is associated with a higher mortality rate and a poor prognosis among patients with acute ischemic stroke (AIS) who receive intravenous thrombolysis (IVT); however, it is still unclear whether IVT improves the prognosis of patients with AIS and CKD. We conducted this study to evaluate the impact of IVT in patients with AIS and CKD. We analyzed patients with AIS and CKD in 3 stroke centers who met the indications for IVT between January 2015 and January 2020. The patients were grouped into an IVT group and a non-IVT group according to whether patients received IVT. After propensity score matching at a 1:1 ratio, symptomatic intracranial hemorrhage (sICH) and the modified Rankin Scale (mRS) score at 3 months were compared to assess the safety and efficacy of IVT in patients with AIS with CKD. A total of 888 patients were enrolled: 763 in the IVT group and 125 in the non-IVT group. After matching, 250 patients were analyzed, and no significant differences were found in sICH between the 2 groups. However, the IVT group had a better 90-day mRS (0-2) score (70.4% vs. 57.6; p = 0.048) than the non-IVT group. IVT improved the 3-month prognosis and did not increase the occurrence of sICH among patients with AIS with CKD.


Night sweats (nocturnal hyperhidrosis) causing wrinkled (pruney) hands in a patient with SARS-CoV-2 infection.
We report the case of a 28-year-old female who developed severe night sweated on the ninth day of SARS-CoV-2 infection with wrinkling of the fingers and palms.


Bronchial and arterial sleeve resection after induction therapy for lung cancer.
Lobectomy with reconstruction of the bronchus and pulmonary artery is a viable therapeutic option for patients with centrally located non-small cell lung cancer. Preoperative chemotherapy or chemoradiotherapy may represent an additional risk factor for postoperative complications because of increased difficulty in surgical dissection and potential impairment of bronchial healing. Although limited data are available in the literature in this setting, a few published studies have reported the possibility of performing even complex bronchovascular reconstructions after neoadjuvant treatment with no increased morbidity and mortality. This article discusses the main technical details and data from the literature.


Yoga for the treatment of depression: Five questions to move the evidence-base forward.
Yoga-based practices, derived from ancient Eastern mind-body practices, have grown in popularity in the West over the past several decades. Increasing evidence supports the antidepressant effects of yoga-based interventions (YBIs). However, despite yoga's promise as a potential treatment for depression, the literature to date is marked by substantial methodological limitations, which remain a barrier to the integration of YBIs into conventional clinical care. We highlight five key areas of study that need further investigation to fill crucial gaps in the literature-base to advance yoga research and yoga's potential as an effective evidence-based treatment for depression.


In vitro exposed magnesium oxide nanoparticles enhanced the growth of legume Macrotyloma uniflorum.
Nanoparticles interact with plants to induce a positive, negative, or neutral effect on their growth and development. In this study, we document the positive influence of magnesium oxide (MgO) nanoparticles (NPs) on the morpho-biochemical parameters of Macrotyloma uniflorum (horse gram). Horse gram is a protein and polyphenol-rich legume crop. It is an important part of the human diet and nutrition. When exposed to MgO-NPs, a significant increment in the shoot-root length, fresh biomass, and chlorophyll content of horse gram was evident. Furthermore, there was a 4-20 and 18-127% increase in the accumulation of carbohydrate and protein content on MgO-NP exposure. The antioxidant potential was enhanced by 5-19% on NP treatment as a result of the increase in the accumulation of total polyphenolics. Total phenols and flavonoids were enhanced by 7-20 and 50-84% in the presence of MgO-NPs. The enzyme activity of SOD, CAT, and APX was also enhanced in MgO-NP-exposed horse gram. The observed alterations were also justified by the Pearson correlation. Overall, the MgO-NP-induced morpho-biochemical alterations in horse gram indicated their probable role as a nano-fertilizer. However, it further warrants the need to extensively investigate the responses of various other plant types to MgO-NPs before industry scale application.


[Food supplements on the domestic market in Hungary: nutritional assessment of the ingredients, risks and benefits, the role of food supplements in human nutrition].
Food supplements are foods that are concentrated sources of nutrients such as vitamins and minerals and other substances with a physiological or nutritional effect. Since joining to the European Union, the distribution of food supplements in Hungary has not been bound to pre-market authorisation; products can be placed to the market after a formal notification at the National Institute for Food and Nutrition Science. Distribution, ingredients, and all information on the label are determined by numerous regulations but at the same time, the lack of harmonized legislation at Community level may cause a lot of problems. In the second part of the review authors introduce the evaluation process of components from the point of view of nutritional and physiological effects and the possible role of food supplements in human nutrition.


Modulation of the formation of the human C-3 amplification convertase of complement by polyelectrolytes.
Heparin in the fluid phase inhibits generation of the C3 amplification convertase of complement C3b,Bb. The anticomplementary activity requires the presence of O-sulfate groups on the molecule and is suppressed when the negative charges of heparin are neutralized with positive charges on polycations. In the absence of heparin, polycations inhibit generation of the cell-bound or fluid phase amplification convertase at final concentrations of 1 to 2 x 10(-8) M for poly-L- lysine 50,000 (PLL). PLL is more active on the D-dependent convertase C3b,Bb than in preventing generation of C3b,B; it does not alter the stabilizing effect of properdin. As for heparin, the major site of the inhibitory action of polycations is on the binding capacity of C3b for B. The low affinity interaction of C3b and B is a privileged site for potential pharmacologic modulation of the amplification convertase of complement by polyelectrolytes.


A de novo recombination in the ABO blood group gene and evidence for the occurence of recombination products.
We have encountered a paternity case where exclusion of the putative father was only observed in the ABO blood group (mother, B; child, A1; putative father, O), among the many polymorphic markers tested, including DNA fingerprints and microsatellite markers. Cloning a part of the ABO gene, PCR-amplified from the trio's genomes, followed by sequencing the cloned fragments, showed that one allele of the child had a hybrid nature, comprising exon 6 of the B allele and exon 7 of the O1 allele. Based on the evidence that exon 7 is crucial for the sugar-nucleotide specificity of A1 and B transferases and that the O1 allele is only specified by the 261G deletion in exon 6 of the consensus sequence of the A1 allele, we concluded that the hybrid allele encodes a transferase with A1 specificity, resulting, presumably, from de novo recombination between the B and O1 alleles of the mother during meiosis. Screening of random populations demonstrated the occurrence of four other hybrid alleles. Sequencing of intron VI from the five hybrid alleles showed that the junctions of the hybrid alleles were located within intron VI, the intron VI-exon 7 boundaries, or exon 7. Recombinational events seem to be partly involved in the genesis of sequence diversities of the ABO gene.


Bilateral nephroblastomatosis.
Bilateral nephromegaly with a histological picture of diffuse Wilms' tumor or so-called bilateral nephroblastomatosis is a rare condition. We present an additional case documented by urography. To our knowledge, this is the first report of diffuse nephroblastomatosis recognized at 2 hours of age. A few cases are reported but urographic documentation is available in only 4 of those and in our own. The review of the urographic findings reveals features which seem seem to be nearly pathognomonic of this condition. Urographic appearance similar to that of adult type polycystic disease without the typical radiolucent cysts, should raise the suspicion of a diffuse bilateral process in the kidneys. Exclusion of other infiltrative diseases, like leukemia and glycogen storage disease, should lead to radiologic diagnosis of nephroblastomatosis. Renal biopsy is then indicated.


Brain evolution: getting better all the time?
Recent studies on bats, goats and hominids suggest that some mammalian brains may have undergone dramatic evolutionary reductions in size. These studies emphasise the importance of selective pressures upon mammalian brain evolution and the need to integrate studies of neuroanatomy, neurophysiology and behaviour.


Orphan Drug Pricing and Costs: A Case Study of Kalydeco and Orkambi.
A common narrative is that high prices are necessary for "orphan drugs" because of the fewer patients. In the context of state health insurance systems, the high prices create significant challenges because of limited budgets. This study carefully examines both costs and revenues of two drugs for cystic fibrosis (ivacaftor and lumacaftor), showing that, for this important example, prices are not high because of fewer patients. The study then explores the justifications usually given for high orphan drug prices, including the need to support research and development for new drugs. Each of these standard justifications is shown to be inadequate; instead, it appears that the exercise of market power in the presence of insurance is the dominant driver of high prices. Insurers need to re-examine how they address high-priced drugs.


Trends in vascular risk factors, stroke performance measures, and outcomes in patients with first-ever ischemic stroke in Taiwan between 2000 and 2012.
With the aging of the population in Taiwan, the financial burden of stroke on the healthcare system is expected to rise. We aimed to investigate the trends in vascular risk factors, adherence to stroke performance measures, and stroke outcomes based on a nationwide representative sample. Adult patients hospitalized for first-ever ischemic stroke between 2000 and 2012 were identified from a nationwide administrative database. The study period was divided into 1-year intervals. The Cuzick test and the Cochran-Armitage test were used to determine the significance of changes over time. Trends in stroke outcomes as a function of year were assessed using logistic regression, controlling for age, sex, comorbidity, and stroke severity. A total of 11,462 patients (mean age 67.3years, female 40.9%) were hospitalized. Between 2000 and 2012, the prevalence of hypertension, diabetes mellitus, hyperlipidemia, and atrial fibrillation increased while the prevalence of coronary artery disease decreased. The proportion of patients taking antihypertensive or antidiabetic medication prior to stroke decreased, whereas the proportion of patients taking lipid lowering medication increased. Adherence to the five selected performance measures significantly improved. A significant decreasing trend in the proportion of recurrent stroke or all-cause death within one year was observed regardless of whether adjustment for age, sex, comorbidity, and stroke severity was made. Despite the rising prevalence of vascular risk factors, improved adherence to stroke performance measures was accompanied by better stroke outcomes.


A dual electrophysiologic test for atrial antireentry and ventricular antifibrillatory studies. Effects of bethanidine, procainamide, and WY-48986.
We have developed a dual electrophysiologic test that allows measurement of both antireentry and antifibrillatory activities of potential antiarrhythmics in the same anesthetized dog. The reentry portion of the model was created surgically by a Y-shaped crushing around the tissue between the superior and inferior vena cava and tissue parallel to the AV groove. The pacing-induced tachycardia that results from circus movements around the tricuspid ring is very persistent in duration and regular in cycle length. The antifibrillatory activities were assessed by determination of the ventricular fibrillation threshold (VFT) using train-stimuli method. Control VFT was measured every 15-20 min in duplicate and followed by induction of atrial reentry. A drug was infused to intervene the atrial tachycardia. After the conversion of the arrhythmia (either by drug regimens or pacing), postdrug VFT was measured, again in duplicate. Bethanidine (20 mg/kg), procainamide (30 mg/kg), and WY-48986 (10 mg/kg), a Class III antiarrhythmic, were evaluated in this dual test. Bethanidine and procainamide prolonged the cycle length of atrial reentry to a greater extent than WY-48986. The atrial arrhythmias were consistently terminated by procainamide and WY-48986 whereas bethanidine converted the tachycardias in one of the five dogs studied. All three agents elevated VFT with bethanidine producing higher values than procainamide and WY-48986. In conclusion, the dual electrophysiologic testing system offers both economic and scientific advantages for the study of modes of action of antiarrhythmic agents.


Risk factors for second hip fractures among elderly patients.
Hip fractures following falls by the elderly, which increase with age, are increasing in number annually. The incidence of refracture (second hip fractures) has been reported to be 5%-10% in Japan and is expected to increase with the aging of the population in the future. Therefore, through a retrospective cohort study, we attempted to clarify the risk factors associated with second hip fractures. A total of 400 patients were consecutively treated for hip fracture at a single orthopedic hospital between January 2001 and December 2007. We excluded 16 subjects: 11 patients who died within a year after a hip fracture and 5 who were <50 years of age. The remaining 384 patients, consisting of 64 men and 320 women, were chosen as the study subjects. The mean age of the subjects at the time of the initial fracture was 83.1 +/- 9.0 years (range 51-102 years). Age, sex, interval between the two fractures, body mass index (BMI), length of bed-rest periods and of rehabilitation periods, living place after an initial fracture, and complicating diseases were determined from medical records. Furthermore, effectors of second hip fractures were extracted using the Cox proportional hazard model. In all, 384 patients were observed for 1140.0 person-years (mean: 3.0 +/- 1.4 years per patient) following the initial hip fracture. During the observation period, 49 second hip fractures were identified, giving an overall incidence of 0.043 per person-year. The second fracture occurred within 3 years in 85.7% (42 patients). Dementia and respiratory disease were recognized as being significantly related to refracture. Using a Cox proportional hazard model, dementia showed a significant influence, with the hazard ratio (HR) 1.87 [95% confidence interval (CI) 1.02-3.41; P = 0.042]. Respiratory diseases also were associated with second hip fracture (HR 4.41, 95% CI 2.33-8.34; P < 0.001). In this study, 85.7% of refractures occurred within 3 years of the first fracture, with dementia and respiratory disease being the complicating factors that influenced refracture.


Efficacy of percutaneous image-guided biopsy for diagnosis of intrahepatic cholangiocarcinoma.
To evaluate the efficacy of percutaneous biopsy for diagnosing intrahepatic cholangiocarcinoma (IHCCA). Retrospective review of biopsy and pathology databases from 2006 to 2019 yielded 112 patients (54F/58 M; mean age, 62.9 years; 27 cirrhotic) with IHCCA who underwent percutaneous biopsy. Data regarding the lesion, biopsy procedure technique, and diagnostic yield were collected. If biopsy was non-diagnostic or discordant with imaging, details of repeat biopsy or resection/explant were gathered. A control group of 100 consecutive patients (56F/44 M; mean age, 63 years, 5 cirrhotic) with focal liver lesions > 1 cm was similarly assessed. Mean IHCCA lesion size was 6.1 ± 3.6 cm, with dominant lesion sampled in 78% (vs. satellite in 22%). 95% (n = 106) were US guided and 96% were core biopsies (n = 108), typically 18G (n = 102, 91%), median 2 passes. 18 patients (16%) had discordant/ambiguous pathology results requiring repeat biopsy, with two patients requiring 3-4 total attempts. A 4.4% minor complication rate was seen. Mean time from initial biopsy to final diagnosis was 60 ± 120 days. Control group had mean lesion size of 2.9 ± 2.5 cm and showed a non-diagnostic rate of 3.3%, both significantly lower than that seen with CCA, with average time to diagnosis of 21 ± 28.8 days (p = 0.002, p = 0.001). IHCCA is associated with lower diagnostic yield at initial percutaneous biopsy, despite larger target lesion size. If a suspicious lesion yields a biopsy result discordant with imaging, the radiologist should recommend prompt repeat biopsy to prevent delay in diagnosis.


Effect of peripheral axotomy on gene expression of NIDD in rat neural tissues.
Peripheral nerve lesion-induced production of neuronal nitric oxide synthase (nNOS) was implicated to influence a range of postaxotomy processes necessary for neuronal survival and nerve regeneration (Zochodne et al., Neuroscience, 91:1515-1527, 1999; Keilhoff et al., Journal of Chemical Neuroanatomy, 24:181-187, 2002, Nitric Oxide, 10:101-111, 2004). Protein-protein interactions represent an important mechanism in the control of NOS spatial distribution or activity (Alderton et al., Biochemical Journal, 357:593-615, 2001; Dedio et al., FASEB Journal, 15:79-89, 2001; Zimmermann et al., Proceedings of the National Academy of Sciences, 99:17167-17172, 2002). As one of the nNOS-binding proteins, nNOS-interacting DHHC domain-containing protein with dendritic mRNA (NIDD) has recently been identified to increase nNOS enzyme activity by targeting nNOS to the synaptic plasma membrane in a postsynaptic density protein 95/discs-large/zona occlusens-1 domain dependent manner (Saitoh et al., Journal of Biological Chemistry, 279:29461-29468, 2004). In this paper, we established a rat model with peripheral axotomy to investigate the gene expression patterns of NIDD in neural tissues using TaqMan quantitative real-time polymerase chain reaction and in situ hybridization combined with immunofluorescence. It revealed that NIDD mRNA was upregulated after sciatic nerve transection with the similar expressing styles as that of the nNOS in the injured nerves, corresponding dorsal root ganglia, and lumbar spinal cord. These findings imply that NIDD may be involved in the different pathological conditions including nerve regeneration, neuron loss or survival, and even pain process, possibly via regulating the enzyme nNOS activity.


Prospects for the clinical management of human cytomegalovirus infections.
Infection of susceptible populations by human cytomegalovirus (HCMV) is a significant public health problem in Western societies. Vaccination with live attenuated strains of HCMV has demonstrated some degree of clinical benefit but objections based on the possibility of these viruses becoming latent and their potential oncogenicity must be considered. Our knowledge of the biology and immunology of HCMV, although advancing rapidly, is still a long way short of being able to predict candidate subunit vaccines based on virus encoded proteins or glycoproteins. Treatment of the disease by injection of antibodies awaits a breakthrough and chemicals effective in the control of other human herpes viruses are disappointingly ineffective against HCMV. Clearly, prophylaxis is preferable to therapy and it is in the design of new effective vaccines that endeavours must be channelled so that we can control complications associated with severe clinical infection with this virus.


Prevalence of psychological distress, as measured by the Kessler 6 (K6), and related factors in Japanese employees.
The aim of this study was to examine the prevalence of and related factors for psychological distress among employees. The employees in Akita prefecture, Japan, were invited to complete the Kessler 6 (K6). A value of 13 or higher on the K6 scale indicated high psychological distress. Furthermore, we identified the relationships among the prevalence of high psychological distress, socio-demographic status, and employment-related variables. The data of 1,709 employees indicated that 10.8% of the employees had high psychological distress; the proportion of psychological distress found in the present study was high compared to that found in previous studies. The identified socio-demographic and occupation-related factors included young age groups associated with a high risk and clerical or administrative tasks associated with a low risk of psychological distress. The data of this study can be used as K6 benchmark values, which enhance the significance of future corporate health risk appraisal surveys.


Biopolymer-modified graphite oxide nanocomposite films based on benzalkonium chloride-heparin intercalated in graphite oxide.
Heparin is a potent anticoagulant agent that interacts strongly with antithrombin III to prevent the formation of fibrin clots. In the present work, poly(dimethylsiloxane)(PDMS)/graphite oxide-benzalkonium chloride-heparin (PDMS/modified graphite oxide) nanocomposite films were obtained by the solution intercalation technique as a possible drug delivery system. The heparin-benzalkonium chloride (BAC-HEP) was intercalated into graphite oxide (GO) layers to form GO-BAC-HEP (modified graphite oxide). Nanocomposite films were characterized by XRD, SEM, TEM, ATR-FTIR and TGA. The modified graphite oxide was observed to be homogeneously dispersed throughout the PDMS matrix. The effect of modified graphite oxide on the mechanical properties of the nanocomposite film was investigated. When the modified graphite oxide content was lower than 0.2 wt%, the nanocomposites showed excellent mechanical properties. Furthermore, nanocomposite films become delivery systems that release heparin slowly to make the nanocomposite films blood compatible. The in vitro studies included hemocompatibility testing for effects on platelet adhesion, platelet activation, plasma recalcification profiles, and hemolysis. Results from these studies showed that the anticoagulation properties of PDMS/GO-BCA-HEP nanocomposite films were greatly superior to those for no treated PDMS. Cell culture assay indicated that PDMS/GO-BCA-HEP nanocomposite films showed enhanced cell adhesion.


[Quality of buffy-coat-derived platelet concentrates prepared using automated system terumo automated centrifuge and separator integration (TACSI)].
Platelet recovery, and viability, and function is strongly dependent on the method of the preparation of platelet concentrate (PC). The glucose consumption, decrease of pH, release of alpha granules during storage in platelet concentrate impair their clinical effectiveness. To compare of the quality of buffy-coat-derieved platelet concentrates prepared using automatic system terumo automated centrifuge and separator integration (TACSI) and stored over 7 days. PCs were prepared from buffy coats using manual method (group I), or automatic system TACSI (group II). Fifteen PCs prepared from the 5 buffy coats each were stored over 7 days in 22-24 degrees C and tested. Samples were taken from the PCs container on days 1 and 7. The following laboratory tests were performed: number of platelets, platelets derived microparticles, CD62P expression, platelet adhesion, pH, glucose, lactate dehydrogenase activity. We have observed higher expression of CD62P in PCs prepared using manual method compared to the PCs produced automatically Platelet recovery was significantly higher in PCs prepared using automatic systems compare to manual method. Compared to manual methods, automatic system for preparation of buffy coats, is more efficient and enable production of platelets concentrates of higher quality.


Skeletal Anomalies in Senegalese Sole (Solea senegalensis, Kaup) Fed with Different Commercial Enriched Artemia: A Study in Postlarvae and Juveniles.
The high incidence of skeletal anomalies in Senegalese sole (Solea senegalensis) still constitutes a bottleneck constraining its production. There are diverse commercially available products for the enrichment of live preys, but few reports of their influence on skeletogenesis in Senegalese sole. This study evaluated the presence of vertebral anomalies in postlarvae and juvenile Senegalese sole fed with Artemia spp. metanauplii enriched with four commercial products (EA, EB, EC, and ED) in a fish farm. The most frequent alterations consisted of deformations of the neural/haemal arches and spines and fusions and deformations of hypurals, epural, or parhypural. The correspondence analysis ordered fish from each age in separated semiaxis, indicating the presence of different anomaly patterns for the two sampled stages. The results showed only very light changes in the frequency of vertebral abnormalities among tested enrichment products, i.e., individuals from EC and EA lots displayed less vertebral body anomalies and/or vertebral column deviations at 31 and 105 days after hatching, respectively. The existence of a large shared malformation pattern in all the experimental groups leads to impute to the rearing conditions as the main driving factor of the onset of such group of anomalies, probably masking some dietary effect.


Design of waveguide grating with ultrafast tunable index contrast.
A long-period waveguide grating (LPWG) with a tunable index contrast is proposed. The design features a simple configuration that consists of a two-mode waveguide formed on periodically poled lithium niobate with an angle with respect to its domain wall and a traveling-wave electrode. In the design, the electrical traveling wave introduces a periodic change in the refractive index of waveguide, which functions as a long-period waveguide grating that couples between symmetric and anti-symmetric core modes. The index contrast of grating can be controlled by the traveling-wave intensity. For application to ultrafast device, structural parameters satisfying velocity and impedance matching conditions are numerically calculated.


Association between the weekday on which coronary artery bypass graft surgery is performed and the 30-day mortality: A nationwide cohort study in South Korea.
Postoperative mortality associated with elective coronary artery bypass graft (CABG) surgery may reportedly increase as the weekday of surgery approaches the weekend. We aimed to investigate the potential effect of the weekday of CABG surgery on the 30-day mortality. This population-based cohort study analyzed data obtained from the South Korea national health insurance service database. The cohort included all adult patients diagnosed with ischemic heart disease (International Classification of Diseases-10 codes I20*-I25*) who underwent isolated and elective CABG surgery from January 2012 to December 2017. Of the 13,556 patients included in the analysis, 595 (4.4%) died within 30 days after CABG surgery. In a multivariable Cox model, the 30-day mortality of patients who underwent CABG surgery later in the week (Wednesday-Friday) was not significantly associated with the weekday of surgery as similar to those who underwent surgery early in the week (Monday-Tuesday) (hazard ratio [HR]: 1.14, 95% confidence interval [CI]: 0.97-1.34; p = .109). Multivariable sensitivity analysis revealed that CABG surgery on Friday was associated with a 1.40-fold higher hazard of 30-day mortality (HR: 1.40; 95% CI: 1.09-1.80; p = .008) than CABG surgery on Monday. This South Korean population-based cohort study revealed that relative to surgery early in the week (Monday-Tuesday), CABG surgery later in the week (Wednesday-Friday) was not associated with higher 30-day mortality. However, using surgery on Monday as a reference, CABG surgery on Friday was associated with higher 30-day mortality. Future studies must confirm these findings.


Candida albicans tenosynovitis of the hand.
Invasive fungal infections of the hand are extremely rare and usually require an immunocompromised host. We report the first known case of Candida albicans tenosynovitis of the hand presenting as a mass in a boy with Buckley's immunodeficiency. Treatment was successful after radical synovectomy of both the flexor and extensor aspects of the hand after he failed to respond to combined amphotericin B and 5-fluorouracil therapy. Fungal tenosynovitis should be considered when swelling and decreased range of motion occur in the hands or digits of an immunocompromised host, especially if pain is not a prominent symptom.


Lifelong Learning in Psychiatry and the Role of Certification.
In the early twentieth century, the medical profession focused on the development of specialties and specialty/subspecialty training. Parallel to this development was the establishment of certifying boards, which can evaluate and attest to a physician's mastery of a set of knowledge and skills; the goal is to provide assurance to patients and the public of a certain guarantee of quality of care. In the early decades of "board certification," the examination was a one-time, relatively high-stakes process that assessed knowledge, and often certain skills and clinical reasoning.


Cranioplasty with a frozen and autoclaved bone flap.
27 cases of cranioplasty with autogenous bone grafts stored in a deep-freezer and autoclaved before use are reported. The results of follow-up for an average period of one year were satisfactory from the standpoint of brain protection and cosmetic reconstruction. A small area of absorption of grafted bone was observed in two cases on the follow-up skull roentgenograms. No serious complications were seen except in one case, whose bone flap had to be removed due to an epidural abscess. Experiments revealed that deep-freezing and autoclaving had only minimal effects on bone structure, although osteocytes degenerated. Autogenous bone flap after deep-freezing is a useful material for cranioplasty but sterilization before use is indispensable. Autoclaving is a simple method for sterilization of the flap, available in any operating theatre. It does not increase the risk of postoperative complications such as infection or absorption.


The interplay of KRAS mutational status with tumor laterality in non-metastatic colorectal cancer: An international, multi-institutional study in patients with known KRAS, BRAF, and MSI status.
Although the prognostic relevance of KRAS status in metastatic colorectal cancer (CRC) depends on tumor laterality, this relationship is largely unknown in non-metastatic CRC. Patients who underwent resection for non-metastatic CRC between 2000 and 2018 were identified from institutional databases at six academic tertiary centers in Europe and Japan. The prognostic relevance of KRAS status in patients with right-sided (RS), left-sided (LS), and rectal cancers was assessed. Of the 1093 eligible patients, 378 had right-sided tumors and 715 had left-sided tumors. Among patients with RS tumors, the 5-year overall (OS) and recurrence-free survival (RFS) for patients with KRASmut versus wild-type tumors was not shown to differ significantly (82.2% vs. 83.2% and 72.1% vs. 76.7%, respectively, all p > .05). Among those with LS tumors, KRAS mutation was associated with shorter 5-year OS and RFS on both the univariable (OS: 79.4% vs. 86.1%, p = .004; RFS: 68.8% vs. 77.3%, p = .005) and multivariable analysis (OS: HR: 1.52, p = .019; RFS: HR: 1.32, p = .05). KRAS mutation status was independently prognostic among patients with LS tumors, but this association failed to reach statistical significance in RS and rectal tumors. These findings confirm reports in metastatic CRC and underline the possible biologic importance of tumor location.


UPL5 modulates WHY2 protein distribution in a Kub-site dependent ubiquitination in response to [Ca2+]cyt-induced leaf senescence.
The translocation of proteins between various compartments of cells is the simplest and most direct way of an/retrograde communication. However, the mechanism of protein trafficking is far understood. In this study, we showed that the alteration of WHY2 protein abundance in various compartments of cells was dependent on a HECT-type ubiquitin E3 ligase UPL5 interacting with WHY2 in the cytoplasm, plastid, and nucleus, as well as mitochondrion to selectively ubiquitinate various Kub-sites (Kub 45 and Kub 227) of WHY2. Plastid genome stability can be maintained by the UPL5-WHY2 module, accompany by the alteration of photosystem activity and senescence-associated gene expression. In addition, the specificity of UPL5 ubiquitinating various Kub-sites of WHY2 was responded to cold or CaCl2 stress, in a dose [Ca2+]cyt-dependent manner. This demonstrates the integration of the UPL5 ubiquitination with the regulation of WHY2 distribution and retrograde communication between organelle and nuclear events of leaf senescence.


Metabolism of C-terminal pentapeptide of gastrin in the rat. Part IV. Catabolic pathways of the N-terminal BOC-14C-glycine fragment.
The catabolism of the 14C-labelled pentagastrin was investigated in rats. The following results were found: -- the labelled BOC-glycine fragment is split off the pentagastrin in the small intestine -- it is absorbed through the intestinal wall, and -- enters first the portal and then the systemic circulation.


Comparison of the sensitivity of the protein A plaque assay and the immunofluorescence assay for detection of immunoglobulin producing cells.
This paper reports a comparative study on the sensitivity of the protein A plaque assay and the cytoplasmic immunofluorescence assay for detection of immunoglobulin (Ig) producing cells in cell suspensions of murine lymphoid organs. The protein A plaque assay was found to detect as many or several times more Ig producing cells than the immunofluorescence assay, depending on the age and antigenic load of the mice, and upon the Ig class and organ studied.


Performance of a novel sternal synthesis device after median and faulty sternotomy: mechanical test and early clinical experience.
Reinforcement of chest closure may be required in patients with multiple risk factors of wound dehiscence. Performance of a light, size-adaptable closure reinforcement device (DSS: Sternal Synthesis Device; Mikai SpA, Vicenza, Italy) is presented. A longitudinal median or paramedian incision was performed in artificial sternal models: closure was accomplished with simple interrupted steel wires or reinforced with the DSS. Forces required for separation of the rewired sternal halves during a monotonic tensile test were analyzed. A high velocity traction cycles test was also adopted to simulate the impact of coughing. After median incision, ultimate load values inducing break of the sternum models were 580 +/- 35 N (Newton) in controls; failure of the test occurred at 1,200 +/- 47 N in the reinforced group (p = 0.0002). More lateral displacement of sternal halves at increasing forces was observed in controls (p = 0.0001). After paramedian incision, ultimate load values inducing break of the constructs were lower in controls (220 +/- 20 N vs 500 +/- 25 N, p = 0.001), which also showed more lateral displacement of sternal halves than the reinforced group (p = 0.002). At the high velocity traction cycles test, the number of cycles required to break the models was lower in controls (2,250 +/- 35 vs 3,855 +/- 48 cycles, p = 0.0001). Preliminary clinical experience in 45 patients showed ease of implantation and low risk of complications. The proposed sternal reinforcement device provides substantial sternal support at electromechanical testing after median and faulty sternotomy and may hopefully prevent sternal wires migration and bone fractures in high risk patients.


Association between metformin and neurodegenerative diseases of observational studies: systematic review and meta-analysis.
Aging becomes a growing global concern with an increased risk of neurodegenerative diseases (NDs) that mainly consist of cognitive decline and Parkinson disease (PD). As the most commonly prescribed antidiabetic drug, metformin has been shown to have inconsistent roles in the incidence of NDs. We performed a systematic review and meta-analysis of observational studies to evaluate the effect of metformin exposure on onset of NDs. The observational studies that investigated the associations between metformin and the incidence of NDs were searched in MEDLINE, Embase and Cochrane Library databases. A random-effect model was performed using STATA to calculate the combined ORs. In total, 23 comparisons out of 19 studies with 285 966 participants were included. Meta-analysis found there was no significant effect on incidence of all the subtypes of NDs with metformin exposure (OR 1.04, 95% CI 0.92 to 1.17). However, metformin monotherapy was associated with a significantly increased risk of PD incidence compared with non-metformin users or glitazone users (OR 1.66, 95% CI 1.14 to 2.42). Metformin has failed to demonstrate a beneficial effect on NDs. In addition, it may increase the risk of PD development. In light of current results, how metformin would impact NDs, especially the potential risk of PD, needs to be scrutinized. The underlying mechanisms are vital to achieve some more profound understanding on the regimen. CRD 42019133285.


School self-efficacy is affected by gender and motor skills: findings from an Italian study.
Perceived school self-efficacy (SE) is an important variable in students' activities as it affects their motivation and learning. Further, self-efficacy might represent a good predictor of performance, persistence and perseverance. Motor skills and other physical health determinants are extensively debated and linked to cognitive function in children of developmental age. However, inconclusive evidence supports a definitive relationship between perceived school SE and motor skills among schoolchildren. We conducted a cross-sectional study on 6-11-year-old schoolchildren to evaluate the extent by which perceived school SE and physical health determinants were related. A SE questionnaire and motor performance battery tests were administered to primary school pupils recruited from 154 sampled schools of northwest Italy. Perceived SE at school was assessed via 12 items from the Caprara's questionnaire. Motor performance scores were obtained from motor skill tests: 4 × 10 m shuttle run test, SRT; standing broad jump, SBJ; six-minute walking test, 6MWT. A total of 3,962 children (M = 2,019; F = 1943) were studied and 68% were normal weight. Overall, a 58% of the sample perceived a high SE, while, as to gender differences, a greater percentage of females perceived high levels of school SE with respect to any other level (χ2 = 38.93, p < 0.0001). Results from multinomial logistic regression analysis revealed that: (i) females perceived higher SE compared to males; (ii) children who performed better in SRT and 6MWT showed higher levels of perceived school SE; (iii) no significant effect was registered for the body weight. Alternative strategies are encouraged to enhance SE through physical education: structured interventions might enhance both complex motor skills and high-order cognitive skills, like SE, in young children.


NPT520-34 improves neuropathology and motor deficits in a transgenic mouse model of Parkinson's disease.
NPT520-34 is a clinical stage, small molecule being developed for the treatment of Parkinson's disease and other neurodegenerative disorders. The therapeutic potential of NPT520-34 was first suggested by findings from cell-based assays of alpha-synuclein clearance. As reported here, NPT520-34 was subsequently evaluated for therapeutically relevant actions in a transgenic animal model of Parkinson's disease that overexpresses human alpha-synuclein and in an acute lipopolysaccharide-challenge model using wild-type mice. Daily administration of NPT520-34 to mThy1-alpha-synuclein (Line 61) transgenic mice for 1 or 3 months resulted in reduced alpha-synuclein pathology, reduced expression of markers of neuroinflammation, and improvements in multiple indices of motor function. In a lipopolysaccharide-challenge model using wild-type mice, a single dose of NPT520-34 reduced lipopolysaccharide-evoked increases in the expression of several pro-inflammatory cytokines in plasma. These findings demonstrate the beneficial effects of NPT520-34 on both inflammation and protein-pathology end points, with consequent improvements in motor function in an animal model of Parkinson's disease. These findings further indicate that NPT520-34 may have two complementary actions: (i) to increase the clearance of neurotoxic protein aggregates; and (ii) to directly attenuate inflammation. NPT520-34 treatment may thereby address two of the predominate underlying pathophysiological aspects of neurodegenerative disorders such as Parkinson's disease.


Native gel analysis for mammalian microRNPs assembled from pre-microRNAs.
MicroRNAs (miRNAs) are an important class of small RNAs that regulate gene expression posttranscriptionally through the microRNP (miRNP)/RNA-induced silencing complex (RISC). The core component of miRNPs is an Argonuate protein that directly binds to a miRNA. In mammals, most miRNPs are assembled through the miRNA loading complex (miRLC), which is composed of Dicer, Ago, and TRBP. miRLC processes miRNA precursors (pre-miRNAs) into miRNA duplexes and loads miRNA duplexes to Ago. Here, we describe a native gel analysis system for detecting miRNPs assembled with pre-miRNAs from mammalian lysates that ectopically express Ago2. The methods presented here provide a powerful tool for further dissecting miRNP assembly pathways in mammals.


High rates of ocular complications in a cohort of Haitian children and adolescents with diabetes.
Ophthalmic complications of pediatric diabetes are rare, and rates are unknown in Haitian youth. To determine the prevalence and predictors of diabetic retinopathy (DR) and cataracts in a cohort of Haitian youth with insulin-treated diabetes. We performed a cross-sectional retrospective review of pediatric patients with diabetes from a pediatric chronic disease center in Haiti, from December 1, 2012 to November 1, 2016. Data collection included demographic and anthropometric information, total daily insulin dose and result of eye examination by a local ophthalmologist. Of 67 patients (54% female, mean age at diagnosis 14.6 ± 3.9 years, mean diabetes duration 3.3 ± 3.0 years, mean HbA1c 84 ± 22 mmol/mol (9.8% ± 2.0%), mean current insulin requirement 0.49 ± 0.28 IU/kg/day), DR was diagnosed in 10/57 (18%) and cataracts in 10/62 (16%), at a mean age of 19.0 ± 4.3 and 19.1 ± 3.3 years, respectively. Diabetes duration was 4.9 ± 5.4 and 3.0 ± 1.5 years at the time of diagnosis of DR and cataracts, respectively. Age at complication, insulin requirement, sex, body mass index, family history, mean HbA1c and diabetes duration were not significant predictors of an ocular complication. In this cohort of Haitian youth, DR and cataracts occur prematurely. Low-insulin requirements years after diagnosis, possibly allowing for prolonged undetected hyperglycemia prediagnosis, may explain complication risk. The phenotypes of diabetes in pediatric populations of African ancestry may be distinct. Ophthalmologic evaluation should possibly start at diagnosis, and screening guidelines may need to be adapted.


Widespread labeling and genomic editing of the fetal central nervous system by in utero CRISPR AAV9-PHP.eB administration.
Efficient genetic manipulation in the developing central nervous system is crucial for investigating mechanisms of neurodevelopmental disorders and the development of promising therapeutics. Common approaches including transgenic mice and in utero electroporation, although powerful in many aspects, have their own limitations. In this study, we delivered vectors based on the AAV9.PHP.eB pseudo-type to the fetal mouse brain, and achieved widespread and extensive transduction of neural cells. When AAV9.PHP.eB-coding gRNA targeting PogZ or Depdc5 was delivered to Cas9 transgenic mice, widespread gene knockout was also achieved at the whole brain level. Our studies provide a useful platform for studying brain development and devising genetic intervention for severe developmental diseases.


Evaluation of salivary function in patients with burning mouth syndrome.
To investigate salivary function in patients with primary burning mouth syndrome (BMS) compared with control and to evaluate salivary hypofunction using salivary gland scintigraphy (SGS). A total of 33 patients with primary BMS and 30 control subjects were enrolled in our study. The severity of the pain and the burning sensation on a 10-cm visual analog scale (VAS) and the Oral Health Impact Profile-14 (OHIP-14) were assessed. Unstimulated and stimulated salivary flow rates (SFRs) were measured. (99m) Tc pertechnetate SGS was used to evaluate salivary gland function. Unstimulated SFR in patients with BMS was significantly lower than that in the control group (0.11 ± 0.15 vs 0.21 ± 0.16 ml min(-1) , P = 0.014). There was no significant difference in stimulated SFR between the two groups. The VAS scores for oral pain and burning sensation, the total OHIP-14 score, and salivary gland function by salivary scintigraphy were not significantly different between BMS patients with normal flow rate and hyposalivation. Patients with primary BMS exhibited a significant decrease in unstimulated SFR compared with control group. In addition, we could not find any difference in salivary gland function between BMS patients with or without hyposalivation.


Oral findings in coeliac disease and Sjögren's syndrome.
Both coeliac disease (CD) and Sjogren's syndrome (SS) have an autoimmune background and increased risk of oral mucosal and dental abnormalities. Individuals suffering concomitantly from CD and SS could even be at a higher risk. Oral mucosal and dental abnormalities were examined in 20 patients with CD + SS (mean age 61 years) and compared with age- and sex-matched controls with either CD or SS. Oral mucosal changes were most common in SS (80%), followed by CD + SS (65%) and CD (40%). Coeliac-type dental enamel defects were found in 89% in CD + SS and in 88% in CD compared with only 25% in SS (P < 0.001). The median number of teeth was six in the CD + SS, 24 in the CD and 22 in the SS group. The DMF index was higher (P < 0.005) in the CD + SS than in the CD group. CD + SS was characterized by higher salivary flow rate (P < 0.001) and lower inflammatory focus score in the salivary glands (P < 0.01) than SS. The co-occurrence of CD and SS should be recognized because of its effects on dental and oral mucosal health. A lower salivary gland inflammatory focus score and higher salivary flow rate in CD + SS than in SS suggests that a gluten-free diet treatment may alleviate autoimmune inflammation.


Foundation officers, evaluation, and ethical problems: a pilot investigation.
Ethical problems encountered by foundation officers in their evaluation-related work were identified via an email survey of a sample of Council on Foundations member organizations. Of the respondents who had worked with evaluators, one-third indicated that they had faced ethical challenges. Most challenges fell into one of four categories: Evaluation Findings, Internal Functioning of the Foundation, Authorship/Ownership/Dissemination of the Evaluation, and Evaluator-Focused Issues. Conflicts of interest involving a variety of stakeholders were reported. The potential for foundation officers to define "ethical problems" differently from evaluators is raised, and the role that attributional processes can play in descriptions of the sources of ethical conflicts is addressed. The study's findings underscore the practical importance of developing an in-depth understanding of the views of ethical problems held by both foundation officers and evaluators.


Pre-column derivatization of free bile acids for high-performance liquid chromatographic and gas chromatographic-mass spectrometric analysis.
Pentachlorophenyl (PCP) esters of five free bile acids (FBA) were obtained by reacting the FBA and Kovacs' complex (KC) in a 1:8 molar ratio in acetone at 65 degrees C, and were purified by column chromatography on silica gel. The esters were crystallized from benzene-hexane, derivatized as trimethylsilyl ethers for gas chromatography on a DB-1 capillary column and for gas chromatography-mass spectrometry with a DB-5 column, and mass spectrometry (MS) in the electron-impact (EI) positive-ion mode at 70 eV. The reaction is specific for FBA even in the presence of glycine and taurine conjugates of bile acids. The PCP esters were treated with benzylamine in chloroform or methanol to produce N-benzyl derivatives of FBA. The N-benzylamides were separated by high-performance liquid chromatography (HPLC) on a 4-microns Nova-Pak C18 column, studied by thermospray-LC-MS, and in the direct insertion probe-EI positive-ion mode.


Relation between renal and hepatic excretion of drugs: XIII. Pharmacokinetics of new antiarrhythmic drug Bonnecor in rats with normal and impaired excretory functions.
The clearance of 14C-Bonnecor, a weak organic cation, was measured in anaesthetized rats during 6 h after administration. The drug and its labelled metabolites are excreted both via kidney and liver. The renal excretion dominates especially following high doses. After bile duct ligation the renal excretion of Bonnecor increases significantly whereas in nephrectomized rats the biliary excretion of this substance is distinctly reduced. Plasma protein binding ratios amount to 60-70%. Renal removal of Bonnecor and the formed metabolites is in part a result of glomerular filtration. Increased urinary excretion of 14C-Bonnecor-activity under conditions of forced diuresis indicates the involvement of tubular reabsorption in renal handling of the drug and its metabolites. These in vivo results could be confirmed in experiments on renal cortical slices indicating a distinct tubular transport of the drug and its metabolites. In the kidney the aerobic accumulation of Bonnecor is very effective. Surprisingly, under anaerobic incubation conditions, uptake of Bonnecor into renal tissue remains relatively high indicating a distinct binding of Bonnecor within the tubular cells. In the liver the accumulation of Bonnecor is lower compared to the kidney. Furthermore, enterohepatic circulation of Bonnecor and its metabolites was checked. In animals with intact biliary tract, renal removal of 14C-Bonnecor-activity from the organism is significantly higher than in rats with bile duct cannulation. Reinfusion of bile increased renal excretion of 14C-Bonnecor-activity additionally. Both results indicate an effective intestinal reabsorption and enterohepatic circulation of this drug.


[Rare location of an epidermoid cyst in the forefoot region with nerve compression syndrome. Contribution to the differential diagnosis of Morton's metatarsalgia (author's transl)].
The case of a rare location of an epiderman cyst in the forefoor region is reported. Very intense pain on pressure or tension in the plantar region of the second and third metatarsals suggested a metatarsalgia and the existing diffuse swelling a synovitis. Surgical revision revealed an epidermoid cyst the size of a hazelnut which pressed the N. digitalis plantaris communis against the head of the third metartarsal.


Copper activation of organophosporus compounds detoxication by chicken serum.
Avian species contain low levels of enzymes that hydrolyze organophosphorus compounds (OPs), and chickens are used as a model of OPs delayed neurotoxicity. For both reasons, we studied the ability of chicken tissue for OP detoxication. A significant activating effect of Cu2+ on the hydrolysis of O-hexyl O-2,5-dichlorophenyl phosphoramidate (HDCP) was observed in hen plasma and the microsomal fractions of the liver, brain, and mainly in hen serum, by spectrophotometric and chiral chromatography methods. The concentration of 1 mM of Cu2+ or Zn2+ showed 200% and 168% activation, respectively, in hen plasma compared with the Ca2+-dependent hydrolysis, whereas these cations had an inhibitory effect on soluble liver and brain fractions. An increase of 1.5 to 19.5 fold in HDCP hydrolyzing activity was obtained for the 30-250 μM Cu2+ range when using chicken serum instead of hen plasma. This Cu2+-dependent hydrolysis in chicken serum was stereoselective for the R-(+)-HDCP isomer, which proved the opposite to the Ca2+-dependent stereoselective hydrolysis of the S-(-)-HDCP isomer reported in rat and rabbit serum. The level of copper needed to exert this effect should be further evaluated for its suitability for potential therapeutic and biotechnological applications.


Management of septic arthritis after arthroscopic anterior cruciate ligament reconstruction using a standard surgical protocol.
To report the incidence of septic arthritis after anterior cruciate ligament (ACL) reconstruction and management of this complication using a specific treatment protocol. All primary ACL reconstructions performed in our institution between January 2002 and January 2014 were included in this study. Time to presentation, clinical symptoms, and culture results of all infected patients were analyzed. According to our protocol, an arthroscopic debridement and irrigation of the knee joint was performed immediately after a diagnosis of infection was made. In case of recurrence, knee irrigation with hardware and graft removal and later re-implantation was performed. Patients were evaluated with the Lysholm knee score, International Knee Documentation Committee (IKDC) Form, KT 1000 arthrometer and radiographic evaluation. Postoperative septic arthritis occurred in seven of 1242 patients (0.56%). After initial arthroscopic debridement, infection recurred in six out of seven cases (85%). Graft and hardware removal was performed in these patients. Graft re-implantation was performed in four patients at an average five months after infection. At the final follow-up (mean 6.3years) all patients had full range of motion, while in patients with graft re-implantation the mean Lysholm score was 92, and the mean IKDC score was 87. Radiographs demonstrated that three patients had normal knees and one patient had a grade one, knee arthritis according to Kellgren-Lawrence classification. Management of septic arthritis after ACL reconstruction using a specific surgical protocol which includes graft removal in case of infection recurrence with later re-implantation, can provide good and excellent results. Level IV, case series.


Unilateral ovarian and fallopian tube agenesis.
The unilateral agenesis of the ovary and fallopian tube is an extremely uncommon event with only few cases described in literature. Here, we report a case of a 30-year-old woman admitted to our Unit for increasing pelvic pain. In the suspect of a corpus luteum hemorrhage, we performed a laparoscopy identifying the rare anomaly. Together with the predisposing genetic and/or environmental factor not yet discovered, two are the hypotheses explaining the absence of one or both the adnexes, the mechanical hypothesis, i.e., the asymptomatic torsion of both Fallopian tube and ovary with consequent organs' ischemia and atresia and the embryological hypothesis, i.e., the congenital absence of the adnexes.


Evaluation of post partum depression in a tertiary hospital.
To evaluate the association of different factors with postpartum depression. A prospective study conducted in the Department of Obstetrics and Gynecology, Medical College, Kolkata. Six thousand patients, 4-7 days postpartum, were interrogated using Edinburgh Postnatal Depression Scale (EPDS). Sociodemographic factors (age, parity, literacy, socioeconomic status, marital status and family structure), history of psychiatric disorder and abuse, mode of delivery and obstetric outcome were recorded. The results were analyzed statistically using Chi-square test. Incidence of PPD was 25%. Significant association of PPD was seen with poor socioeconomic group (P < 0.05), literacy (P < 0.001), nuclear family structure (P < 0.05), single mother (P < 0.001), past history of psychiatric illness (P < 0.001), history of abuse (P < 0.05), and poor obstetric outcome (P < 0.001). Age, parity and method of delivery showed no association. EPDS should be used routinely to screen for PPD among high risk cases.


Stimulus-responsive liposomes for biomedical applications.
Liposomes are amphipathic lipidic supramolecular aggregates that are able to encapsulate and carry molecules of both hydrophilic and hydrophobic nature. They have been widely used as in vivo drug delivery systems for some time because they offer features such as synthetic flexibility, biodegradability, biocompatibility, low immunogenicity, and negligible toxicity. In recent years, the chemical modification of liposomes has paved the way to the development of smart liposome-based drug delivery systems, which are characterized by even more tunable and disease-directed features. In this review, we highlight the different types of chemical modification introduced to date, with a particular focus on internal stimuli-responsive liposomes and prodrug activation.


A possible association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and the personality trait of harm avoidance in Japanese healthy subjects.
Catechol-O-methyltransferase (COMT) is an enzyme that degrades various biogenic amines, which have been hypothesized to be associated with personality traits. We investigated a possible relationship between the COMT Val158Met polymorphism and personality traits assessed by the Temperament and Character Inventory (TCI) in 139 healthy subjects in a Japanese population. The number of Met alleles of the COMT Val/Met genotype tended to relate to harm avoidance (HA) scores parametrically, while no significant difference was observed between genotype groups in either novelty seeking, reward dependence, persistence, self-directedness, cooperativeness or self-transcendence. These results suggest that the Val/Met polymorphism of the COMT gene may play a role in HA in Japanese population.


A comparative study on the concentrations of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THCCOOH) in head and pubic hair.
In this study, the concentrations of 11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid (THCCOOH) in pubic, axillary and beard hair were measured and the correlation between the concentrations of THCCOOH in head and pubic hair from same cannabis users were evaluated. The papers on body hair analysis for THCCOOH were rarely found although police officers submit body hair as a complimentary specimen to forensic laboratories in case cannabis users had no hair. Head, pubic, axillary, and beard hair were collected. All hair samples were cut into 0.5mm segments and decontaminated with methanol, digested with 1 mL of 1M NaOH at 85 °C for 30 min and extracted in 2 mL of n-hexane:ethyl acetate (9:1) two times after adding 1 mL of 0.1N sodium acetate buffer (pH = 4.5) and 200 μL of acetic acid followed by derivatization with 50 μL of PFPA and 25 μL of PFPOH for 30 min at 70 °C. The extracts were analyzed using gas chromatography tandem mass spectrometry operating in negative chemical ionization mode (GC/MS/MS-NCI). We determined the concentrations of THCCOOH in both pubic and head hair. The concentrations of THCCOOH in pubic hair were higher than those in head hair. We also evaluated the concentrations of THCCOOH in body hair (pubic, axillary and beard hair) and head hair according to the positive/negative urine test results. There was no statistically significant difference in the concentrations of THCCOOH in head and body hair according to urine results.


Duplex arteriography prior to femoral-popliteal reconstruction in claudicants: a proposal for a new shortened protocol.
The standard preoperative duplex arteriography (DA) from the aorta to the pedal vessels is time consuming and may be unnecessary in patients presenting with calf claudication alone. The feasibility of a shortened protocol was evaluated. Of 286 femoral-popliteal reconstruction based on DA during the last 4A years, 79 (28%) were primary operations for calf claudication. Eliminating the aortoiliac portion of the test except for the distal external iliac artery and limiting the scanning of the infrapopliteal vessels to one or two arteries in the leg would significantly shorten the exam. To confirm the adequacy of the inflow tract, we relied on the common femoral artery Doppler waveform analysis and the intraoperative graft pressure upon completion of the bypass. Of the 79 primary femoral-popliteal bypasses, 53 (67%) had triphasic common femoral artery waveform and the remaining 26 had monophasic or biphasic waveforms. Three (6%) of the 53 femoral-popliteal bypasses in the former group had significant pressure gradients measured intraoperatively and were treated with iliac angioplasties and stents for unsuspected stenoses in 2 cases and a covered stent for a common iliac aneurysm in 1 case. Three, two, and one infrapopliteal vessel runoff was observed in 24 (45%), 16 (30%), and 9 (17%) extremities, respectively. Four patients (8%) had significant stenoses (>50%) or occlusion of all three infrapopliteal arteries. Eighty-one percent of the patients would have completed the short protocol had we scanned the peroneal artery initially. An additional 8% would have required scanning of a second vessel (anterior tibial) and only 11%, scanning of all three infrapopliteal vessels. The time interval for completion of short-protocol DA was significantly less than the time for the standard DA (16.2 A+/- 5.2A min vs. 35.1 A+/- 10.6 min) ( p < 0.01). We believe that the proposed short DA protocol combined with intraoperative graft pressure measurements can be used in 94% of the patients who have a patent popliteal artery (>/= 7 cm). It is a totally noninvasive approach that is particularly suitable for vascular technologists and surgeons who wish to start utilizing DA instead of contrast arteriography prior to infrainguinal reconstructions. However, the short protocol does not avert the need for completion arteriography of the inflow arteries and readiness to perform endovascular procedures to correct lesions not suspected by common femoral artery waveform analysis.


Drug shortage-associated increase in catheter-related blood stream infection in children.
Ethanol lock therapy (ELT) has been shown to reduce the incidence of catheter-related blood stream infections (CRBSI) in intestinal failure (IF) patients. Dosing and frequency remains undefined. Scrutiny of pharmaceutical facilities by the Food and Drug Administration led to the voluntary shutdown of the sole supplier of ethanol, resulting in a nationwide shortage. To conserve supply, we reduced ELT frequency from a daily regimen. We examined the impact that reduction in ELT frequency had on CRBSI in pediatric IF patients. We retrospectively reviewed our parenteral nutrition-dependent IF children. Primary outcome measure was CRBSI per 1000 catheter days after ELT frequency reduction. Data were compared (paired t test) to the same group over 1 year before ethanol shortage and to historical controls. During the shortage 13 outpatients received ELT. Eight met study criteria. Mean ± SD age was 9.1 ± 7.8 years. Mean CRBSI rate per 1000 catheter days was 0.7 ± 1.3 before ELT shortage. This increased to 6.2 ± 2.5 after frequency reduction (P < .001). This CRBSI rate was similar to historical IF children not on ELT (8.0 ± 5.4). Seven children developed CRBSI after frequency reduction, 6 requiring hospitalization, 2 to the ICU. Mean length of stay (15.5 days) averaged $104,783(± 111,034) in hospital charges. Organisms included Gram-negatives (6), methicillin-resistant Staphylococcus aureus (1), and Candida spp (1). ELT frequency reduction resulted in complete failure in CRBSI prophylaxis. The nationwide shortage of this drug has been costly both financially and in patient morbidity.


Is it possible to improve diagnostic and prognostic criteria of preterm labour?
Preterm labour is a frequent cause of admission to hospital during pregnancy. However, in most cases, preterm labour is diagnosed with reference to clinical criteria only. Since the clinical assessment of uterine contractions and of cervical changes is highly subjective, few of the patients admitted to the hospital with suspected preterm labour will ultimately deliver preterm. There is a need for sensitive methods of detecting patients who are genuinely at high risk of preterm birth, but on the other hand, specific methods of reducing unnecessary treatments or hospital admissions are also required. Recently, a few techniques such as ultrasonographic measurement of cervical length and fetal fibronectin have been introduced into clinical practice with the aim of improving prediction of the risk of actual preterm delivery. In the future, the assessment of cervical status may be based not only on anatomical changes, but also on functional criteria. New techniques are being developed for evaluation of the mechanical properties of the cervix (cervical distensibility), noninvasive measurement of its collagen content (light-induced fluorescence of cervical collagen), or even direct assessment of the changes in cervical water content (magnetic resonance imaging). Correlations have been found between these measurements and the risk of preterm birth, but clinical studies are still needed to allow better assessment of the predictive value of these new methods in clinical practice.


Minimally instrumented SHERLOCK (miSHERLOCK) for CRISPR-based point-of-care diagnosis of SARS-CoV-2 and emerging variants.
The COVID-19 pandemic highlights the need for diagnostics that can be rapidly adapted and deployed in a variety of settings. Several SARS-CoV-2 variants have shown worrisome effects on vaccine and treatment efficacy, but no current point-of-care (POC) testing modality allows their specific identification. We have developed miSHERLOCK, a low-cost, CRISPR-based POC diagnostic platform that takes unprocessed patient saliva; extracts, purifies, and concentrates viral RNA; performs amplification and detection reactions; and provides fluorescent visual output with only three user actions and 1 hour from sample input to answer out. miSHERLOCK achieves highly sensitive multiplexed detection of SARS-CoV-2 and mutations associated with variants B.1.1.7, B.1.351, and P.1. Our modular system enables easy exchange of assays to address diverse user needs and can be rapidly reconfigured to detect different viruses and variants of concern. An adjunctive smartphone application enables output quantification, automated interpretation, and the possibility of remote, distributed result reporting.


Free radical induced polymerization of synthetic peptides into polymeric immunogens.
Free radical induced polymerization of vinyl monomers such as the acryloyl peptides described here is a facile and rapid reaction used routinely, for example, in the polymerization of acrylamide and bisacrylamide for the assembly of polyacrylamide gels. The technology allows the incorporation of many of the same or different peptide determinants into a single polymer chain. In this study large polymers containing multiple copies of peptides representing T- and B-cell determinants of influenza haemagglutinin were constructed. The determinants retained antigenicity after the polymerization procedure and the polymers were highly immunogenic; the levels of antibody obtained after a single dose of polymeric immunogen were at least as great as those achieved only after repeated doses of the equivalent monomeric peptide. The technology has a wide range of potential applications, not the least significant of which is the construction of designer immunogens for third generation vaccine candidates.


Thymus influence on the conversion of 19S to 7S antibody formation in the response to TNP-Brucella.
Serially transferred LAF spleen cells show a deficient 7S PFC response to TNP-Brucella when Tx as compared to normal irradiated intermediate hosts are used. This defect can be corrected by combining the spleen cells with lymph node cells from the Tx intermediate hosts. It is concluded that T helper cells, residing primarily in lymph node, are needed for efficient 19S leads to 7S conversion in the immune response.


The Effect of Root Canal Preparation Size and Taper of Middle Mesial Canals on Fracture Resistance of the Mandibular Molar Teeth: An In Vitro Study.
The aim of the present study was to investigate the influence of root canal preparation size and taper of middle mesial (MM) canals on fracture resistance of mandibular molars. Fifty-five mandibular molar teeth having an MM canal were selected based on the cone-beam computed tomographic analysis. After the decoronation and distal root separation procedure, the lengths of the mesial roots were standardized to 13 mm. The specimens were randomly distributed into 5 groups (n = 11). Mesiobuccal and mesiolingual canals were prepared up to size 30.06 using VDW.ROTATE rotary files (VDW, Munich, Germany). The MM canal was prepared up to size 25.04, 25.06, 30.04, and 30.06, respectively. No preparation was done in the MM canal in the control group. After the irrigation protocol, the canals were obturated with the single-cone technique. A thin layer of silicone-coated specimens was embedded in acrylic resin and subjected to a fracture strength test by a universal testing machine. A vertical force was applied to the roots until they fracture. Statistical analysis was performed with 1-way analysis of variance and post hoc Duncan tests (P = .05). There was no significant difference between group 25.04 and the control group, but the fracture strengths of these groups were found to be significantly higher than that of groups 25.06, 30.04, and 30.06 (P < .05). Within the limitations of this study, we concluded that increasing the apical diameter and taper in the MM canal reduces the fracture strength of mandibular molar teeth. Among the tested instrumentation sizes, fracture strength decreased significantly when greater than 25.04 instrumentation sizes were chosen.


Patient-Reported Outcomes in a Randomized Trial of Closed-Loop Control: The Pivotal International Diabetes Closed-Loop Trial.
Background: Closed-loop control (CLC) has been shown to improve glucose time in range and other glucose metrics; however, randomized trials >3 months comparing CLC with sensor-augmented pump (SAP) therapy are limited. We recently reported glucose control outcomes from the 6-month international Diabetes Closed-Loop (iDCL) trial; we now report patient-reported outcomes (PROs) in this iDCL trial. Methods: Participants were randomized 2:1 to CLC (N = 112) versus SAP (N = 56) and completed questionnaires, including Hypoglycemia Fear Survey, Diabetes Distress Scale (DDS), Hypoglycemia Awareness, Hypoglycemia Confidence, Hyperglycemia Avoidance, and Positive Expectancies of CLC (INSPIRE) at baseline, 3, and 6 months. CLC participants also completed Diabetes Technology Expectations and Acceptance and System Usability Scale (SUS). Results: The Hypoglycemia Fear Survey Behavior subscale improved significantly after 6 months of CLC compared with SAP. DDS did not differ except for powerless subscale scores, which worsened at 3 months in SAP. Whereas Hypoglycemia Awareness and Hyperglycemia Avoidance did not differ between groups, CLC participants showed a tendency toward improved confidence in managing hypoglycemia. The INSPIRE questionnaire showed favorable scores in the CLC group for teens and parents, with a similar trend for adults. At baseline and 6 months, CLC participants had high positive expectations for the device with Diabetes Technology Acceptance and SUS showing high benefit and low burden scores. Conclusion: CLC improved some PROs compared with SAP. Participants reported high benefit and low burden with CLC. Clinical Trial Identifier: NCT03563313.


French Registry on Acute ST-elevation and non ST-elevation Myocardial Infarction 2010. FAST-MI 2010.
AIM OF FAST-MI 2010: To gather data on characteristics, management and outcomes of patients hospitalised for acute myocardial infarction (AMI) at the end of 2010 in France. To provide cardiologists and health authorities national and regional data on AMI management every 5 years. Metropolitan France. 213 academic (n=38), community (n=110), army hospitals (n=2), private clinics (n=63), representing 76% of centres treating AMI patients. Inclusion from 1 October 2010. Consecutive patients included during 1 month, with a possible extension of recruitment up to one additional month (132 centres); 4169 patients included over the entire recruitment period, 3079 during the first 31 days; 249 additional patients declining participation (5.6%). Consecutive adults with ST-elevation and non-ST-elevation AMI with symptom onset ≤48 h. Patients with AMI following cardiovascular procedures excluded. Web-based collection of 385 items (demographic, medical, biologic, management data) recorded online from source files by external research technicians; case-record forms with automatic quality checks. Centralised biology in voluntary centres to collect DNA samples and serum. Long-term follow-up organised centrally with interrogation of municipal registry offices, patients' physicians, and direct contact with the patients. Data management in Toulouse University. Université Paris Descartes, Université de Toulouse, Université Pierre et Marie Curie-Paris 06, Paris. In-hospital events; cardiovascular events, hospital admissions and mortality during follow-up. Linkage with Institute for National Statistics. Available for research to any participating clinician upon request to executive committee (email@example.com).