Propranolol and Weekly Paclitaxel in the Treatment of Metastatic Heart Angiosarcoma.
Heart angiosarcoma, the most frequent among cardiac malignancies, is an extremely rare vascular tumor known to carry a dismal prognosis. The spectrum of presenting symptoms depends on tumor's size, its anatomic location, and its invasiveness, whereas imaging techniques including cardiac magnetic resonance are critical in the differential diagnosis between malignant and benign neoplasms. Despite there are various available systemic therapeutic regimens for advanced cardiac angiosarcomas, yet, it still remains unclear which of them offers the best survival outcome in general. We present the uncommon case of metastatic right atrium angiosarcoma in a young male patient, in which the combination of propranolol and weekly paclitaxel, as first-line treatment, showed promising activity with manageable toxicity. Given the existing strong rationale for repurposing propranolol in oncology, this therapeutic approach merits further investigation in prospective studies with heart angiosarcoma patients.


Staphylococcus aureus α-Toxin Induces Inflammatory Cytokines via Lysosomal Acid Sphingomyelinase and Ceramides.
Staphylococcus aureus (S. aureus) infections are a major clinical problem and range from mild skin and soft-tissue infections to severe and even lethal infections such as pneumonia, endocarditis, sepsis, osteomyelitis, and toxic shock syndrome. Toxins that are released from S. aureus mediate many of these effects. Here, we aimed to identify molecular mechanisms how α-toxin, a major S. aureus toxin, induces inflammation. Macrophages were isolated from the bone marrow of wildtype and acid sphingomyelinase-deficient mice, stimulated with S. aureus α-toxin and activation of the acid sphingomyelinase was quantified. The subcellular formation of ceramides was determined by confocal microscopy. Release of cathepsins from lysosomes, activation of inflammasome proteins and formation of Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α) were analyzed by western blotting, confocal microscopy and ELISA. We demonstrate that S. aureus α-toxin activates the acid sphingomyelinase in ex vivo macrophages and triggers a release of ceramides. Ceramides induced by S. aureus α-toxin localize to lysosomes and mediate a release of cathepsin B and D from lysosomes into the cytoplasm. Cytosolic cathepsin B forms a complex with Nlrc4. Treatment of macrophages with α-toxin induces the formation of IL-1β and TNF-α. These events are reduced or abrogated, respectively, in cells lacking the acid sphingomyelinase and upon treatment of macrophages with amitriptyline, a functional inhibitor of acid sphingomyelinase. Pharmacological inhibition of cathepsin B prevented activation of the inflammasome measured as release of IL-1β, while the formation of TNF-α was independent of cathepsin B. We demonstrate a novel mechanism how bacterial toxins activate the inflammasome and mediate the formation and release of cytokines: S. aureus α-toxin triggers an activation of the acid sphingomyelinase and a release of ceramides resulting in the release of lysosomal cathepsin B and formation of pro-inflammatory cytokines.


Role of color Doppler imaging in early diagnosis and prediction of progression in glaucoma.
This longitudinal and prospective study analyzes the ability of orbital blood flow measured by color Doppler imaging (CDI) to predict glaucoma progression in patients with glaucoma risk factors. Patients with normal perimetry but having glaucoma risk factors and patients in the initial phase of glaucoma were prospectively included in the study and divided, after a five-year follow-up, into two groups: "Progression" and "No Progression" based on the changes in the Moorfields regression analysis (MRA) classification of Heidelberg retina tomograph (HRT). An orbital CDI was performed in all patients and the parameters obtained were correlated with changes in HRT. A logistic discrimination function (LDF) was calculated for ophthalmic artery (OA) and central retinal artery (CRA) parameters. Receiver operating characteristics curves (ROC) were used to assess the usefulness of LDFs to predict glaucomatous progression. A total of 71 eyes were included. End-diastolic velocity, time-averaged velocity, and resistive index in the OA and CRA were significantly different (P < 0.05) between the Progression and No Progression groups. The area under the ROC curves calculated for both LDFs was of 0.695 (OA) and 0.624 (CRA). More studies are needed to evaluate the ability of CDI to perform early diagnosis and to predict progression in glaucoma in eyes.


Biotic Interactions Are More Important than Propagule Pressure in Microbial Community Invasions.
Microbial probiotics are intended to improve functions in diverse ecosystems, yet probiotics often fail to establish in a preexisting microbiome. This is a species invasion problem. The relative importance of the two major factors controlling establishment in this context-propagule pressure (inoculation dose and frequency) and biotic interactions (composition of introduced and resident communities)-is unknown. We tested the effect of these factors in driving microbial composition and functioning following 12 microbial community invasions (e.g., introductions of many microbial invaders) in microcosms. Ecosystem functioning over a 30-day postinvasion period was assessed by measuring activity (respiration) and environment modification (dissolved organic carbon abundance). To test the dependence on environmental context, experiments were performed in two resource environments. In both environments, biotic interactions were more important than propagule pressure in driving microbial composition and community function, but the magnitude of effect varied by environment. Successful invaders comprised approximately 8% of the total number of operational taxonomic units (OTUs). Bacteria were better invaders than fungi, with average relative abundances of 7.4% ± 6.8% and 1.5% ± 1.4% of OTUs, respectively. Common bacterial invaders were associated with stress response traits. The most resilient bacterial and fungal families, in other words, those least impacted by invasions, were linked to antimicrobial resistance or production traits. Illuminating the principles that determine community composition and functioning following microbial invasions is key to efficient community engineering.IMPORTANCE With increasing frequency, humans are introducing new microbes into preexisting microbiomes to alter functioning. Example applications include modification of microflora in human guts for better health and those of soil for food security and/or climate management. Probiotic applications are often approached as trial-and-error endeavors and have mixed outcomes. We propose that increased success in microbiome engineering may be achieved with a better understanding of microbial invasions. We conducted a microbial community invasion experiment to test the relative importance of propagule pressure and biotic interactions in driving microbial community composition and ecosystem functioning in microcosms. We found that biotic interactions were more important than propagule pressure in determining the impact of microbial invasions. Furthermore, the principles for community engineering vary among organismal groups (bacteria versus fungi).


FoxA2 and p53 regulate the transcription of HSD17B1 in ovarian granulosa cells of pigs.
The oestrogens have been highly implicated in the fertility of female animals. It is widely known that the oestrogens are primarily synthetized by the ovarian granulosa cells (GCs), and the final and essential step of this process is to catalyse the oestrone to the more active oestradiol by the protein coded by hydroxysteroid 17-beta dehydrogenase 1 (HSD17B1) gene. However, the molecular mechanism regarding the transcription of HSD17B1 remains to be fully elucidated in ovarian GCs. In this study, the 5'-deletion, luciferase assay and chromatin immunoprecipitation (ChIP) were utilized to explore the molecular regulation of transcription of HSD17B1 with the porcine ovarian GCs as the cellular model. After the deletions with -2105 to -1754 bp, -1753 to -1429 bp, -1430 to -1081 bp and -1082 to -730 bp, the relative luciferase activity of HSD17B1 promoter did not change significantly, but the deletion of -731 to -332 bp significantly increased the relative luciferase activity of HSD17B1 promoter, and an insertion (GTTT) that might raise the transcription of HSD17B1 was identified at -401 bp of HSD17B1. These findings suggested the region from -731 to +38 bp was the core promoter of HSD17B1, and the region between -731 to -332 bp might be a silence element for HSD17B1. Furthermore, the forkhead box A2 (FoxA2) directly bound at -412 to -401 bp to negatively but p53 bound at -383 to -374 bp to positively regulate the transcription and translation of HSD17B1 in ovarian GCs. These findings will improve our understanding on HSD17B1-mediated oestrogens and provide useful information for further investigations into fertility of females.


Multiepitope synthetic peptide and recombinant protein for the detection of antibodies to Trypanosoma cruzi in patients with treated or untreated Chagas' disease.
A tetrapeptide and a recombinant protein, each representing 4 immunodominant epitopes of Trypanosoma cruzi, were tested by use of ELISA for the detection of serum antibodies. Sera from individuals with Chagas' disease, including persons untreated and successfully or unsuccessfully treated, were tested. These assays detected antibody in 100% of the parasitemias. The antibody reactivity decreased based on the success of treatment. Higher sensitivity was observed for tetrapeptide/recombinant protein assays than for lysate-based ELISA, and specificity was improved, particularly with Leishmania sera. The results indicate that multiepitope antigens provide a more sensitive and specific alternative to lysate for detection of anti-T. cruzi antibodies, as required for developing blood screening assays.


Stability and change of volume and intensity of physical activity as predictors of hypertension.
Controversy exists concerning intensity of physical activity and risk of hypertension. Also, the association between long-term changes in physical activity and hypertension is poorly known. Therefore we investigated how the stability and change of volume and intensity of physical activity are associated with the risk of hypertension in Finnish men and women. A total of 3,931 men and 4,381 women responded to three questionnaires on health and lifestyle. Baseline data were gathered from two questionnaires, in 1975 and 1981. The subjects were 24-51 years of age, healthy, and non-hypertensive at baseline (1981). At the end of the follow-up, in 1990, the subjects responded to a third questionnaire, according to which we assessed the cumulative incidence of hypertension between 1982 and 1990. The cumulative incidence of hypertension from 1982 to 1990 was 10.2% in men and 8.0% in women. In men, the risk of hypertension was higher among those who were persistently not participating in vigorous physical activity (i.e. in both 1975 and 1981) (odds ratio, 1.60; 95% confidence interval, 1.15 to 2.24; p=0.006) than among those persistently participating, when all confounding factors were adjusted for. Among those participating in vigorous activity only in 1975 or in 1981 the risk was not significantly increased compared with those participating persistently. Volume of physical activity was not associated with hypertension. In women, there was no association between physical activity and incidence of hypertension. Compared with inactivity, persistent vigorous physical activity predicts a low risk of hypertension in men.


Down-regulation of central dopamine receptors in schizophrenia.
CSF homovanillic acid (HVA) levels reflecting central dopamine release and apomorphine-stimulated human growth hormone (HGH) secretion reflecting central dopamine receptor activity were concomitantly determined in 20 schizophrenic patients. There was a strong negative correlation between HVA and HGH levels: high dopamine release was associated with lower HGH responses to dopamine receptor activation by apomorphine. Studies are reviewed which suggest that the presently observed relationship reflects release-mediated down-regulation of central D2 receptors, the dopamine receptor subtype associated with the antipsychotic properties of neuroleptic medication.


Physical and affective components of dyspnoea are improved by pulmonary rehabilitation in COPD.
Dyspnoea is a multidimensional experience of breathing discomfort, but its affective dimension is unfrequently assessed in people with chronic obstructive pulmonary disease (COPD). We evaluated the effectiveness of a home-based pulmonary rehabilitation (PR) programme on the physical and affective components of dyspnoea assessed by the Dyspnoea-12 (D-12) questionnaire. We also determined the baseline characteristics that contributed to the change in D-12 scores. In this retrospective study, 225 people with COPD (age, 65±11 years; forced expiratory volume in 1 s (FEV1), 35±15% of predicted value) were enrolled into a person-centric home-based PR, consisting of a weekly supervised 90 min home session during 8 weeks. D-12 questionnaire, health status, anxiety and depressive symptoms, exercise tolerance and general fatigue were assessed at baseline (M0), at the end of PR programme (M2), and 8 (M8) and 14 months (M14) after M0. Multivariable analysis of covariance (ANCOVA) models were performed to identify the baseline characteristics that contributed to the change in D-12 scores. Both physical and affective components of dyspnoea and all the other outcome measures were improved at M2, M8 and M14 compared with baseline (p<0.05). Baseline body mass index was the only significant independent predictor of the changes in physical dyspnoea score, while the change in the affective dimension of dyspnoea after PR was associated with FEV1, anxiety symptoms and exercise tolerance (6 min stepper test). However, since these variables had only a small impact on the changes in D-12 questionnaire scores, results from the ANCOVA analysis should be taken cautiously. Both physical and affective components of dyspnoea were improved, at short term and long term, by 8 weeks of individualised home-based PR. The present results support the importance of assessing dyspnoea as a multidimensional experience during PR, warranting replication by robustly designed randomised and controlled studies.


Dynamic chromatin accessibility modeled by Markov process of randomly-moving molecules in the 3D genome.
Chromatin three-dimensional (3D) structure plays critical roles in gene expression regulation by influencing locus interactions and accessibility of chromatin regions. Here we propose a Markov process model to derive a chromosomal equilibrium distribution of randomly-moving molecules as a functional consequence of spatially organized genome 3D structures. The model calculates steady-state distributions (SSD) from Hi-C data as quantitative measures of each chromatin region's dynamic accessibility for transcription factors and histone modification enzymes. Different from other Hi-C derived features such as compartment A/B and interaction hubs, or traditional methods measuring chromatin accessibility such as DNase-seq and FAIRE-seq, SSD considers both chromatin-chromatin and protein-chromatin interactions. Through our model, we find that SSD could capture the chromosomal equilibrium distributions of activation histone modifications and transcription factors. Compared with compartment A/B, SSD has higher correlations with the binding of these histone modifications and transcription factors. In addition, we find that genes located in high SSD regions tend to be expressed at higher level. Furthermore, we track the change of genome organization during stem cell differentiation, and propose a two-stage model to explain the dynamic change of SSD and gene expression during differentiation, where chromatin organization genes first gain chromatin accessibility and are expressed before lineage-specific genes do. We conclude that SSD is a novel and better measure of dynamic chromatin activity and accessibility.


[Comparative Analysis of Spectrophotometric Methods of the Protein Measurement in the Pectic Polysaccharide Samples].
For the assay to reliability of determination of the protein content in the pectic polysaccharide samples by absorbance in the ultraviolet and visible regions of the spectrum a comparison of the eleven techniques called Flores, Lovry, Bradford, Sedmak, Rueman (ninhydrin reaction) methods, the method of ultraviolet spectrophotometry, the method Benedict's reagent, the method Nessler's reagent, the method with amide black, the bicinchoninic reagent and the biuret method was carried out. The data obtained show that insufficient sensitivity of the seven methods from the listed techniques doesn't allow their usage for determination of protein content in pectic polysaccharide samples. But the Lowry, Bradford, Sedmak methods, and the method Nessler's reagent may be used for determination of protein content in pectic polysaccharide samples, and the Bradford method is advisable for protein contaminants content determination in pectic polysaccharide samples in case protein content is less than 15%, and the Lowry method--for samples is more than 15%.


Less disease severity of COVID-19 among smokers: An indication of investigating nicotine as preventive measure.
The study was aimed to mention the epidemiology of smoking in Pakistani COVID-19 infected patients along with the disease severity, oxygen dependency and fatality rate. A cross sectional epidemiological study was carried out on 555 confirmed cases of COVID-19 infection. The median age was 47±16 years. 59% were male and 41% were female. Most of the patients (97.5%) survived, while only 2.5% expired. 25.6% patients required the oxygen. Total 17 (3%) COVID-19 patients with age 20-75 years were identified as smokers. No mortality was observed in smokers. The 1.4% smokers presented with mild disease, 1.2% with moderate disease and 0.4% had severe disease. According to Chi-Square test, there existed an insignificant difference (p-value: 0.38649) between smokers and non-smokers in disease severity levels. Smoking is a precursor for countless diseases, but it behaved differently in COVID-19 infected patients, as its prevalence was significantly low. We found no significant variation of the disease severity among the smokers and non-smokers. Profound experiments should be conducted to recommend whether nicotine can be used as a protective agent to negate COVID-19 infection.


Transforming growth factor-beta 3 is required for secondary palate fusion.
Mice lacking TGF-beta 3 exhibit an incompletely penetrant failure of the palatal shelves to fuse leading to cleft palate. The defect appears to result from impaired adhesion of the apposing medial edge epithelia of the palatal shelves and subsequent elimination of the mid-line epithelial seam. No craniofacial abnormalities were observed. This result demonstrates that TGF-beta 3 affects palatal shelf fusion by an intrinsic, primary mechanism rather than by effects secondary to craniofacial defects.


Time to diagnosis and treatment of lung cancer: A systematic overview of risk factors, interventions and impact on patient outcomes.
Over half of patients with lung cancer are diagnosed at a stage when curative treatment is not possible, suggesting an earlier diagnosis could improve outcomes. This comprehensive overview summarises the evidence on 1) times to diagnosis and treatment, 2) their impact on patient outcomes, 3) risk factors and 4) interventions to reduce time intervals, and 5) key methodological issues in such studies. Eligible articles were relevant systematic or scoping reviews and meta-analyses, searched via PubMed, Embase, Web of Science, and Cochrane Library; published from database inception to 6 August 2020 (PROSPERO identifier: CRD42020203530). A total of 18 systematic and scoping reviews were included. Times to diagnosis and treatment significantly varied and were often longer than recommended in international guidelines. Results regarding the impact of time intervals on survival or tumour stage indicated mixed associations (positive, negative, or no); in each review, however, more studies reported either no or negative association. Risk factors were considerable, categorized at the disease, patient, healthcare provider and system levels. Interventions including fast-access diagnosis programs, patient navigation and multidisciplinary strategies were effective in reducing times to diagnosis and treatment. Methodological issues included large variations in interval definitions and summary measures, lack of addressing an important potential source of bias-the "waiting time paradox"-and few studies of trends over time of these intervals. The current evidence indicates that patients with lung cancer experience diagnosis and treatment delays given guidelines' recommendations, but there are inconsistent findings about the association between times to diagnosis and treatment and patient outcomes. This is partially due to variations in definitions of time intervals, and limitations in analytic approaches that fail to account for a potential waiting time paradox. The identified risk factors and effective interventions demonstrate the potential for improvements in addressing diagnostic and treatment delays, regionally and globally.


Effect of adrenalectomy in kindled rats.
It has previously been observed that adrenalectomy (ADX) increases the amplitude of transient Ca currents in CA1 hippocampal neurons. In the present study, the effect of ADX on cellular properties of CA1 neurons was investigated under conditions that challenge the CA1 network, i.e. in fully kindled rats, 5-6 weeks after the last kindling session. At this time, adrenally intact kindled rats showed, in comparison to non-kindled controls, a reduced population spike amplitude evoked in the CA1 area by Schaffer/commissural fiber stimulation, an increased amplitude of low-threshold, transient Ca currents and a decrease of the high-threshold, sustained Ca currents. As observed before, ADX in non-kindled rats increased the amplitude of transient Ca currents while sustained Ca currents were not affected. In kindled rats, ADX did not increase the transient Ca current amplitude beyond the level reached by kindling alone. The kindling-induced reduction of the sustained Ca current was partly normalized after ADX. Field responses of kindled rats were not affected by ADX. These data support the view that lack of adrenal hormones does not exacerbate but, to some extent, normalizes the kindling-induced changes in cellular properties and network function of the CA1 area. The hormonal effects on kindling may be reciprocal in nature, since kindling, in turn, was found to affect the stress response and the corticosteroid receptor mRNA expression in the hippocampus.


The management of the client with a leg ulcer: precarious nursing practice.
The management of clients who present at the doctor's surgery with leg ulcers follows an accepted but often perilous course. It is generally accepted custom and practice that the overall care of this client group is delegated to nurses without the medical practitioner first determining the nature of the underlying pathology. The usual arrangement of care for patients with leg ulcers is such that the development of chronic wounds is almost inevitable. The author, drawing on the medical and nursing literature and on the findings of her ongoing doctoral research, suggests that nurses in primary care should re-examine this area of practice and consider alternative approaches that would emphasize the unique contribution professional nursing practice could bring to this patient group.


Carotid intimal-medial thickness in active professional American football players aged 23 to 35 years.
Risk of cardiovascular disease and death in retired professional American football players may be higher than that in the general population. Previously published data have demonstrated that American football players have less glucose intolerance, less smoking, similar lipid profiles, and higher blood pressure despite a much larger body compared to the general population, although the presence of subclinical atherosclerosis in these subjects has not been evaluated. This study compared the prevalence of subclinical atherosclerosis in active professional American football players to that in age-, gender-, and race-matched controls derived from the Bogalusa Heart Study. Carotid intimal-medial thickness (CIMT) was used as an indicator of subclinical atherosclerosis in 75 active American football players (23 to 35 years old, 31 white, 44 African-American) as measured by B-mode ultrasonography at Mayo Clinic, Scottsdale, Arizona, on September 13 and 14, 2009. CIMT measurements of 75 athletes were compared to those of 518 matched controls who had CIMT determinations in 1995 and 1996. Two-group t tests determined population similarities between groups. In a generalized linear model, players (overall and by race) had lower CIMT values than controls after age and race adjustment (p <0.001 for all comparisons). Nonlinemen and linemen had lower CIMT values than controls (p < 0.001 and p = 0.004, respectively). In conclusion, active professional American football players, regardless of position, had mean CIMT values similar to or lower than those in a matched general population cohort, suggesting that if the prevalence of subclinical atherosclerosis is increased in retired professional American football players, this occurs after retirement.


[Consensus recommendations on minimally invasive removal of carious tissue from dentine].
The International Caries Consensus Collaboration (ICCC) presented recommendations on terminology, methods of carious tissue removal and managing cavitated carious lesions. It identified 'dental caries' as the disease that dentists should manage by controlling the activity of existing cavitated lesions by preserving as much hard tissue as possible, maintaining pulp sensibility and retaining functional teeth in the long-term. The ICCC recommended the level of hardness as the criterion for determining the clinical consequences of the process of demineralisation and defined new strategies for the selective removal of carious tissue. The starting point is to effectively remove the biofilm from cavitated carious lesions. Only when cavitated carious lesions are either non-cleansable or can no longer be sealed, are restorative interventions indicated, with due regard for the principles of a minimally invasive approach. Applying a restoration facilitates biofilm removal, guards the pulpodental complex and restores form, function and aesthetics.


Adjusting flow-mediated dilation for shear stress stimulus allows demonstration of endothelial dysfunction in a population with moderate cardiovascular risk.
Although normalization of brachial artery flow-mediated dilation (FMD) to individual shear stress (FMD:shear stress ratio) has been proposed to improve this measure of endothelial function, the clinical utility of FMD normalization has not yet been demonstrated. We tested (1) whether following conventional 5-min forearm occlusion, the FMD:shear stress ratio would discriminate a population with moderate cardiovascular risk (MR) from a low-risk (LR) population, and (2) whether the dose-response profile relating shear stress to FMD would be different between the 2 populations. Five different magnitudes of reactive hyperemia-induced shear stress were applied to 20 MR and 20 LR subjects by manipulating forearm cuff occlusion duration. Brachial artery diameters and velocities were measured via high-resolution ultrasound. To quantify the hyperemic stimulus, shear stress area under the curve was individually calculated for the duration of time-to-peak dilation. Following 5-min of forearm occlusion, FMD:shear stress ratio (p = 0.041), but not FMD (p = 0.286), discriminated MR from LR. The slope of the shear stress-FMD regression line was lower in MR compared to the LR (p < 0.001). The FMD:shear stress ratio distinguished reduced endothelial function in a population with MR. The dose-response profile of the shear stress-FMD relationship appears to differ between populations of distinct cardiovascular risk.


Two forms of implicit learning in childhood ADHD.
Attention deficit hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and hyperactivity mediated by frontal-striatal-cerebellar dysfunction. These circuits support implicit learning of perceptual-motor sequences but not visual-spatial context. ADHD and control children performed the Alternating Serial Reaction Time (ASRT) task, a measure of sequence learning, and the Contextual Cueing (CC) task, a measure of spatial contextual learning. Relative to controls, children with ADHD showed inconsistent ASRT learning but did not differ on CC learning. Thus, implicit sequence learning, a cognitive process mediated by frontal-striatal-cerebellar circuitry that is not under executive control, was atypical in ADHD.


Nosocomial pneumonia, including ventilator-associated pneumonia.
Patients with nosocomial pneumonia have evidence of immunosuppression. The most obvious defect in immunity is the loss of mechanical barriers with an endotracheal tube. Only a third of colonized patients on ventilators develop pneumonia, however, suggesting that altered immunity is more extensive. This subgroup of patients tends to get multiple synchronous and sequential infections. The exact mechanisms of this compromise of immunity remain to be fully elucidated. Both a temporary immunocompromised and a specifically predisposed subpopulation, however, can explain the clinical pattern. A temporary immunoparalysis clearly occurs and is associated with increased risk of infections. An underlying genetic predisposition may lead to a predisposed population. Genetic polymorphisms in pathogen recognition molecules increase the risk of nosocomial infections. Genetic variability in immune mediators increase severity of infections and mortality but have not been demonstrated as consistently to lead to infections. Adequate treatment of an initial infection is required for reversal of the temporary immunoparalysis, whereas specific immunomodulatory therapies can reverse the markers of immunoparalysis and may decrease the risk of infection.


Developmental origins of the world's largest flowers, Rafflesiaceae.
Rafflesiaceae, which produce the world's largest flowers, have captivated the attention of biologists for nearly two centuries. Despite their fame, however, the developmental nature of the floral organs in these giants has remained a mystery. Most members of the family have a large floral chamber defined by a diaphragm. The diaphragm encloses the reproductive organs where pollination by carrion flies occurs. In lieu of a functional genetic system to investigate floral development in these highly specialized holoparasites, we used comparative studies of structure, development, and gene-expression patterns to investigate the homology of their floral organs. Our results surprisingly demonstrate that the otherwise similar floral chambers in two Rafflesiaceae subclades, Rafflesia and Sapria, are constructed very differently. In Rafflesia, the diaphragm is derived from the petal whorl. In contrast, in Sapria it is derived from elaboration of a unique ring structure located between the perianth and the stamen whorl, which, although developed to varying degrees among the genera, appears to be a synapomorphy of the Rafflesiaceae. Thus, the characteristic features that define the floral chamber in these closely related genera are not homologous. These differences refute the prevailing hypothesis that similarities between Sapria and Rafflesia are ancestral in the family. Instead, our data indicate that Rafflesia-like and Sapria-like floral chambers represent two distinct derivations of this morphology. The developmental repatterning we identified in Rafflesia, in particular, may have provided architectural reinforcement, which permitted the explosive growth in floral diameter that has arisen secondarily within this subclade.


Using mu rhythm desynchronization to measure mirror neuron activity in infants.
The Mirror Neuron System hypothesis stating that observed actions are projected onto the observer's own action system assigns an important role to development, because only actions mastered by the observer can be mirrored. The purpose of the present study was to investigate whether there is evidence of a functioning mirror neuron system (MNS) in 8-month-old infants. High-density EEG was used to assess the mu rhythm desynchronization in an action observation task where the infants observed a live model. To reduce noise, ICA decompositions were used. The results show a higher desynchronization of the mu rhythm when infants observed a goal-directed action than when they observed a spatially similar non-goal-directed movement. The localizations of the sources are in agreement with those proposed by the MNS hypothesis. This indicates that the MNS is functioning at this age.


Ultrastructural and proapoptotic-like effects of kaempferol in Giardia duodenalis trophozoites and bioinformatics prediction of its potential protein target.
Kaempferol (KPF) is a flavonoid with antiparasitic activity including experimental giardiasis which mechanism of action is unknown. To analyse the cytotoxic effects of KPF on Giardia duodenalis trophozoites and to identify a likely parasite target of this compound. We used inhibitory concentrations of KPF (IC25, IC50 and IC100) and albendazole (ABZ) as reference drug. The ultrastructure of the trophozoites was analysed by transmission electron microscopy (TEM) whilst apoptosis/necrosis, production of reactive oxygen species (ROS) and cell cycle progression were assessed by flow cytometry (FCM) and confocal laser microscopy (CLM). Ligand-protein docking analyses were carried out using KPF structure from a drug library and crystal structure of a G. duodenalis aldose reductase (GdAldRed) homolog. KPF provoked appearance of perinuclear and periplasmic spaces devoid of cytosolic content and multilamellar structures. KPF induced proapoptotic death associated with partial arrest in the S phase without ROS production. Bioinformatics approaches predicted that GdAldRed is a viable KPF target (ΔG = -7.09 kCal/mol), exhibiting 92% structural identity and a similar coupling pattern as its human homolog. KPF exerted a proapoptotic effect on G. duodenalis trophozoites involving partial interruption of DNA synthesis without oxidative stress or structure damage to chromatin and cytoskeletal structures. GdAldRed is a likely target underlying its antigiardial activity.


Primary hyperparathyroidism caused by a parathyroid carcinoma in a 16-year-old male neutered cat with concurrent chronic kidney disease.
A 16-year-old domestic shorthaired cat with chronic kidney disease was presented with a subacute history of weakness and anorexia. Severe hypercalcaemia was identified and attributed to a cervical mass, diagnosed as a parathyroid carcinoma after surgery. Renal function, as evaluated by plasma creatinine, initially worsened during hypercalcaemia but fully returned to previously documented values two months post-operatively.


Analysis of 58 poly-/perfluoroalkyl substances and their occurrence in surface water in a high-technology industrial park.
Poly/perfluoroalkyl substances (PFASs) have some water solubility so that they are more liable to enter surface water. A comprehensive analysis method was established to analyze 17 classes of 58 PFASs in surface water by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) after automated solid phase extraction (SPE). The method showed acceptable recoveries and precision with recoveries of 60%-130% and RSD less than 30% with a few exceptions, and method detection limits (MDLs) of 0.004 ng/L-2.0 ng/L. It was investigated the surface water around Zhangjiang High-Technology Park in Shanghai. The concentration of ∑PFASs ranged from 115 ng/L to 600 ng/L. The main pollutant was perfluoro-3-methylheptanoic acid (P3MHpA), which is isopropyl isomer of perfluorooctanoic acid (PFOA), accounting 41.6% of ∑PFASs. It was detected in all samples and its level was far higher than that of PFOA with the maximum of 432 ng/L determined surrounding integrated circuits company. Short-chain perfluorocarboxylic acids (PFCAs) and PFOA were also major constituents accounting for 39.9% of ∑PFASs. Perfluorosulfonic acid (PFSAs (C4, 6, 8)) were detected in all samples, while most concentrations were below 10 ng/L. In addition, 1H,1H,2H,2H-perfluorooctane sulfonate (6:2) (6:2 FTS), 2,3,3,3-tetrafluoro-2-(1,1,2,2,3,3,3-heptafluoropropoxy)-propanoic acid (HFPO-DA) and 9-chlorohexadecafluoro-3-oxanonane-sulfonate (9Cl-PF3ONS) were also detected in all samples at low level. Long chain PFCAs and PFSAs and other classes of PFASs were also detected with low levels and/or low frequencies. The level of PFASs shows an increasing trend in surface water in Shanghai. The whole risk is low for residents from water exposure, while it should cautious to the emission of P3MHpA from integrated circuits and its potential risk.


AMPK-Dependent Mechanisms but Not Hypothalamic Lipid Signaling Mediates GH-Secretory Responses to GHRH and Ghrelin.
GH (growth hormone) secretion/action is modulated by alterations in energy homeostasis, such as malnutrition and obesity. Recent data have uncovered the mechanism by which hypothalamic neurons sense nutrient bioavailability, with a relevant contribution of AMPK (AMP-activated protein kinase) and mTOR (mammalian Target of Rapamycin), as sensors of cellular energy status. However, whether central AMPK-mediated lipid signaling and mTOR participate in the regulation of pituitary GH secretion remains unexplored. We provide herein evidence for the involvement of hypothalamic AMPK signaling, but not hypothalamic lipid metabolism or CPT-1 (carnitine palmitoyltransferase I) activity, in the regulation of GH stimulatory responses to the two major elicitors of GH release in vivo, namely GHRH (growth hormone-releasing hormone) and ghrelin. This effect appeared to be GH-specific, as blocking of hypothalamic AMPK failed to influence GnRH (gonadotropin-releasing hormone)-induced LH (luteinizing hormone) secretion. Additionally, central mTOR inactivation did not alter GH responses to GHRH or ghrelin, nor this blockade affected LH responses to GnRH in vivo. In sum, we document here for the first time the indispensable and specific role of preserved central AMPK, but not mTOR, signaling, through a non-canonical lipid signaling pathway, for proper GH responses to GHRH and ghrelin in vivo.


[Surgical treatment of the accessory navicular syndrome with simple excision].
To observe and evaluate the clinical effects of surgical treatment for the accessory navicular syndrome with simple excision. From November 2006 to December 2008, 23 patients (twenty-five feet) with accessory navicular syndrome received simple excision of the accessory navicular bone. The chief complains were intermittent pain of feet after running or walking. Physical examination showed local tenderness on palpation in the region of the navicular bone. X-ray or CT showed there was an accessory navicular bone. The present history ranged from 6 months to 12 years. There were 14 males and 9 females. The mean age was 14.6 years, ranging from 8 to 35 years. About 2 cm long incision was made at the tip of the medial prominence of the navicular bone. After partial dissection of the posterior tibial tendon, the accesssory navicular bone was exposed and excisied. The prominence of the tuberosity of the navicular bone was cut and shaved. The posterior tibial tenden was repaired before closing the wound. The foot was immobilized with cast or brace in inversion position and no weight-bearing for 2 weeks. Strenuous jumping or dancing must be avoided in 3 months after surgery. The patients with residual symptoms and signs received physical therapy and an arch support for shoes without flatfoot deformity. The average clinical follow-up during was 12 month (ranged, 3 to 18 months). The excellent results in 21 feet and good in 4 feet (3 feet with mild flat deformity and 1 foot with old sprain injury). The average hospital stay was 5 days and no wound infection occurred. All patients resumed the normal life and study after operation. Surgical treatment of the accessory navicular syndrome with simple excision has the advantages of less invasive to the posterior tibial tenden and the medial longitudinal arch of the foot, shorter time of immobilization of the foot and stay in hospital, small incision and good clinical results. This procedure is one of the best selective treatments for the accessory navicular syndrome, especially for the patients without flatfoot deformity and old sprain injury.


Structure and absolute configuration of an unsaturated anteiso fatty acid from Bacillus megaterium.
Gas chromatography in combination with electron ionization mass spectrometry (GC/EI-MS) was used to determine the fatty acids of a membrane lipid from Bacillus megaterium. Special attention was put on the structure and absolute configuration of a monoenoic fatty acid previously described in this sample. GC/EI-MS operated in the selected ion monitoring mode was used to determine twelve fatty acids in the bacterium. Methyl esters were prepared to verify the presence of a 14-methylhexadecenoic acid (a17:1) isomer. The position of the double bond of the a17:1 isomer and four further monoenoic fatty acids was elucidated by means of their picolinyl esters produced by the transesterification of the phospholipid. For the a17:1 isomer, the double bond was located between C-5 and C-6. Silver ion liquid chromatography was used to verify that the double bond was in cis-configuration. The bacterial 14-methylhexadec-5-enoic acid (a17:1Delta5) is chiral due to the stereogenic C-14 carbon. Initial enantioselective measurements were carried out with isomers of a17:1Delta5 which were available in form of racemic and (S)-enantiopure cis- and trans-isomers of a17:1Delta12 previously synthesized. The cis-a17:1Delta12 enantiomers were partly resolved on a chiral stationary phase coated with 50% heptakis(6-O-tert.-butyldimethylsilyl-2,3-di-O-methyl)-beta-cyclodextrin in OV-1701 (beta-TBDM). However, resolution of the enantiomers of the trans-isomer of a17:1Delta12 failed. Only one peak was also observed for the a17:1Delta5 isomer from B. megaterium. Thus, it remained unclear whether the compound a17:1Delta5 was racemic or enantiopure in the sample. To clarify this point, we separated the cis-monoenoic fraction from the saturated fatty acids. Then, the monoenoic fraction was hydrogenated in order to transform a17:1Delta5 into 14-methylhexadecanoic acid (a17:0). This chiral fatty acid was known to be sufficiently enantioseparated on the beta-TBDM column and was found to be (S)-enantiopure in the sample. Hence, these measurements verified that the B. megaterium sample contained enantiopure (S)-a17:1Delta5.


Comparison of patient- and physician-based descriptions of symptoms of endometriosis: a qualitative study.
How do fully-comprehensive patient-centred descriptions of the symptoms of endometriosis compare with the physicians' description of the symptoms? The description of the painful symptoms due to endometriosis is based on numerous distinct parameters. The way these are used to describe symptoms and the way they are interpreted varies significantly between patients and clinicians. The descriptions of severe pelvic pain and dysmenorrhoea and dyspareunia by the clinicians were incomplete compared with those of the patients. Painful symptoms due to endometriosis were found to be of little use to predict the location and severity of the disease. Currently there are few data on the patients' description of symptoms and no questionnaire is available to derive data from patients. Descriptions of painful symptoms by patients and by physicians were obtained by qualitative, interview-based study and analysed using Colaizzi's method. The patients planned to be operated on for painful endometriosis were volunteers for preoperative interview. They were recruited by purposeful sampling to represent different types of endometriosis [i.e. superficial endometriosis, ovarian endometriosis or deeply infiltrating endometriosis (DIE)], the women were selected so that at least five sites of endometriosis were included in the study. The clinicians were experts in endometriosis management. Forty-one patients were recruited, in four reference centres. Among them, 33 had DIE in various locations, including intestinal endometriosis (n = 12) or bladder endometriosis (n = 5), 14 had ovarian endometriosis (including three without associated DIE) and 5 had only superficial endometriosis. The nine experts were French-speaking gynaecological surgeons practicing in university teaching hospitals (seven), a general hospital (one) or a private centre (one). In total, 47 themes were identified of which 30 were perceived by both patients and clinicians, 12 by patients only and 5 by clinicians only. Themes fall into five general categories: (i) severe pelvic pain and dysmenorrhoea, (ii) dyspareunia, (iii) gastro-intestinal symptoms, (iv) bladder symptoms, (v) other symptoms. Patients' and clinicians' descriptions of symptoms were in agreement for general categories, but the clinicians' comprehensive description was incomplete, in particular concerning the severe pelvic pain and dysmenorrhoea's themes and the dyspareunia theme. Patients did not report any clear-cut distinction between pelvic pain and dysmenorrhoea and expressed a dimension of suffering and impaired quality of life inherent to painful symptoms. Most of the patients in the study had already had treatment for endometriosis, including ongoing hormonal treatment. Furthermore, all but a few patients had documented endometriotic lesions and no specific investigations to eliminate additional causes of functional pelvic pain were done. Finally due to the qualitative design of the study the result must be regarded as inferences. The present study provides a first person viewpoint of the painful experience of endometriosis by the patients in a subjective, phenomenological perspective, and points out the differences of perceptions between the physicians and the patients. The considerable variability in patients' descriptions suggests several distinct mechanisms are involved in explaining the pain related to endometriosis. The discordance between clinicians and patients might also reflect this kind of problem with the wording of the items. In future, if the goal is to properly understand the pain experienced by women with endometriosis, assessment tools using the words and phrases used in narratives of pain would potentially be very useful. Funded by IPSEN, Boulogne-Billancourt, France. None of the authors has any conflict of interest to declare. Not applicable.


The risk of action by the Drug Enforcement Administration against physicians prescribing opioids for pain.
Fear of government actions against physicians for prescribing opioids for their chronic pain patients is a cause for undertreatment of pain. This study was conducted to assess the risk of action by the federal Drug Enforcement Administration (DEA). The DEA responded to a written request with a list of all DEA arrests in fiscal 2003. The Federal Register was reviewed for all revocations of DEA registrations for 2003 and 2004. There were 47 arrests in 2003 from among 963,385 doctors registered with the DEA and 56 revocations of registration seen in the 2003 and 2004 period. The reasons for these actions included loss of medical license, fraud, substance abuse by prescriber, sex in exchange for prescriptions, and prescribing without seeing patient. For the majority of cases, there was information to believe that a documented doctor-patient relationship with a chronic pain patient did not exist. When adequate documentation exists in the medical record, the risk of civil, criminal, or administrative action being taken by the DEA against a physician for prescribing opioids for a chronic pain patient is small.


Decrease of neurotrophin-3 mRNA in adult rat hippocampus after pilocarpine seizures.
Neurotrophins such as NT-3 are subject to complex regulation during epileptic seizures. Pilocarpine at a dose of 250 mg/kg induced either limbic seizures (LS) or limbic motor status epilepticus (LMSE) in adult rats. In situ hybridization signals for NT-3 mRNA declined moderately after LS and were nearly lost in LMSE at 3-4 h. Loss of NT-3 mRNA expression does not correlate with cell death and may reflect a functional down-regulation in certain hippocampal neurons.


Epigenetic regulation of gelsolin expression in human breast cancer cells.
Gelsolin is a multifunctional, actin-binding protein that is greatly decreased in many transformed cell lines and tumor tissues, including breast cancers. Downregulation of gelsolin RNA occurs in most breast cancers of rats, mice, and humans, but gross mutations of the gelsolin gene have not been found. Here we demonstrate by PCR and RT-PCR analysis that there are no point mutations in putative regulatory regions or the entire coding region of the cytoplasmic isoform of the gelsolin gene in human breast cancer cells (BCC). To determine if epigenetic modification is involved in downregulating gelsolin expression in MDA-MB-231 (MDA231), MCF7, and T47D BCC, we have used Southern blot analysis, 5-azacytidine (5aza) treatment, and trichostatin A (TSA) treatment. Southern blot analysis performed on genomic DNA demonstrated altered CpG methylation within intron 1 in DNA from all BCC compared to normal, mortal human mammary epithelial cells (HMEC). Treatment of the BCC with 5aza converted the DNA restriction pattern to that seen in untreated HMEC genomic DNA and caused modest increases in gelsolin RNA and protein. Incubation with TSA, an inhibitor of histone deacetylase, induced a dramatic upregulation of gelsolin RNA and protein levels which preceded apoptotic death of all BCC within 48-60 h. Our data support a role for epigenetic changes in chromatin structure leading to downregulation of gelsolin expression in human breast cancer. To our knowledge, this is the first example of a tumor suppressor gene downregulated in human breast cancer by changes in histone acetylation.


Failure of steroid replacement to consistently normalize pituitary function in congenital adrenal hyperplasia: hormonal and MRI data.
Exogenous glucocorticoid replacement in patients with congenital adrenal hyperplasia (CAH), who due to an adrenal 21-hydroxylase enzyme deficiency are unable to produce endogenous glucocorticoids, is aimed at normalizing hypothalamic-pituitary-adrenal function. Excess androgen production by the adrenals is thus decreased. Despite standard glucocorticoid replacement doses (12.5-40 mg, 10.5-27 mg/m2/day hydrocortisone equivalents) 4 of 7 patients ranging in age from 14 to 33 years had abnormalities of the pituitary on MRI. Three appeared to have microadenomas and 1 had an empty sella. Five (3 salt wasters, 2 simple virilizers) of these 7 patients had 60-min p.m. ovine corticotropin-releasing hormone (oCRH) stimulation studies. The mean (logarithm) area under the ACTH curve for 0-60 min after oCRH stimulation was significantly greater in patients than controls (p < 0.0001). Mean ACTH at each time point before and after oCRH stimulation was similarly greater in patients than controls (p < 0.05). Two of these patients had pituitary microadenomas, 1 had an empty sella; all 3 were salt wasters. Despite standard glucocorticoid replacement, adolescent and young adult patients with CAH tend to have high basal ACTH and ACTH hyperresponsiveness to oCRH, as well as structural abnormalities of the pituitary. The inevitable periods of under- and overexposure to glucocorticoids in CAH patients may over time cause abnormalities of the hypothalamic-pituitary-adrenal axis.


Successful Treatment of Focal Segmental Glomerulosclerosis after Kidney Transplantation with Plasma Exchange and Abatacept in a Patient with Juvenile Rheumatoid Arthritis.
Recurrent focal segmental glomerulosclerosis (FSGS) after renal transplantation is difficult to treat. Recently a series of four patients unresponsive to plasma exchange (PE) and rituximab, who were successfully treated with abatacept, has been reported. We present a 26-year-old Caucasian patient who suffered from juvenile rheumatoid arthritis and developed severe proteinuria eleven days after transplantation. An allograft biopsy was suggestive of recurrent focal segmental glomerulosclerosis. He did not respond to PE therapy. A first dose of abatacept produced partial remission. Four weeks later proteinuria again increased and a second biopsy showed progression of disease. After another ineffective course of PE he was given a second dose of abatacept, which was followed by rapid, complete, and sustained resolution of proteinuria. This treatment caused a significant increase in BK and JC viremia. Whether abatacept ameliorated proteinuria via an effect on podocytes or on the patient's primary disease remains speculative.


Characterization of VWF gene conversions causing von Willebrand disease.
We previously reported that von Willebrand Factor gene (VWF) conversions are a relatively frequent cause of von Willebrand disease (VWD), however, their molecular pathomechanisms resulting in variant phenotypes is largely unknown. Here, we characterized VWF conversions harbouring missense and synonymous mutations, through generating a series of mutant constructs followed by transient expression in 293 cells, and qualitative and quantitative analysis of recombinant VWF (rVWF). The characterization of mutant rVWF showed the critical roles of synonymous variants in the pathogenicity of VWF conversions. The gene conversion variants p.Val1229Gly, p.Asn1231Thr, p.Asn1231Ser and p.Ala1464Pro in the absence of synonymous p.Ser1263= and p.Gln1449= showed minimal effect on rVWF synthesis and activity. Interestingly, a construct including the synonymous variants displayed significantly low rVWF expression and activity. The variant p.Pro1266Leu showed gain of rVWF function toward glycoprotein Ibα; surprisingly, this function was significantly abolished in the presence of gene conversion variants p.Val1229Gly-p.Asn1231Thr. Taken together, our expression studies suggest that synonymous variants in the combination of other gene conversion variants suppress the protein expression, possibly due to defective primary mRNA structure or processing. The variants p.Val1229Gly-p.Asn1231Thr affected the VWF gain of function caused by variant p.Pro1266Leu, probably due to conformational changes in VWF.


Blockchain Technology in Healthcare: A Systematic Review.
Since blockchain was introduced through Bitcoin, research has been ongoing to extend its applications to non-financial use cases. Healthcare is one industry in which blockchain is expected to have significant impacts. Research in this area is relatively new but growing rapidly; so, health informatics researchers and practitioners are always struggling to keep pace with research progress in this area. This paper reports on a systematic review of the ongoing research in the application of blockchain technology in healthcare. The research methodology is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and a systematic mapping study process, in which a well-designed search protocol is used to search four scientific databases, to identify, extract and analyze all relevant publications. The review shows that a number of studies have proposed different use cases for the application of blockchain in healthcare; however, there is a lack of adequate prototype implementations and studies to characterize the effectiveness of these proposed use cases. The review further highlights the state-of-the-art in the development of blockchain applications for healthcare, their limitations and the areas for future research. To this end, therefore, there is still the need for more research to better understand, characterize and evaluate the utility of blockchain in healthcare.


Quantum frequency doubling in the topological insulator Bi2Se3.
The nonlinear Hall effect due to Berry curvature dipole (BCD) induces frequency doubling, which was recently observed in time-reversal-invariant materials. Here we report novel electric frequency doubling in the absence of BCD on a surface of the topological insulator Bi2Se3 under zero magnetic field. We observe that the frequency-doubling voltage transverse to the applied ac current shows a threefold rotational symmetry, whereas it forbids BCD. One of the mechanisms compatible with the symmetry is skew scattering, arising from the inherent chirality of the topological surface state. We introduce the Berry curvature triple, a high-order moment of the Berry curvature, to explain skew scattering under the threefold rotational symmetry. Our work paves the way to obtain a giant second-order nonlinear electric effect in high mobility quantum materials, as the skew scattering surpasses other mechanisms in the clean limit.


Influence of the incorporation of a lead foil to intraoral digital receptors on the image quality and root fracture diagnosis.
To evaluate the quality of images obtained with the addition of a lead foil to intraoral digital receptors. Radiographic images of 34 single-rooted human teeth - 19 with vertical root fracture (VRF) and 15 of the control group - were obtained with and without the addition of a lead foil, using the VistaScan, Express, Digora Optime and Digora Toto systems. Images were evaluated by five observers regarding the diagnosis of VRF, using a 5-point scale. In a second moment, an observer preference analysis related to the presence of the lead foil was performed. Images of an acrylic phantom were also obtained with and without the addition of a lead foil, and the quantities of uniformity, grey value and standard deviation of grey values were obtained. There were no significant differences in the VRF diagnostic values, considering the presence of the lead foil. Regarding the image quality preference, the observers preferred images acquired with the lead foil for all systems tested, but with greater values for Digora Optime (61.33%) and Express (61.33%). The presence of the lead foil did influence the image uniformity in all systems tested ( p < 0.05). Moreover, the lead foil increased the mean of grey values for Digora Optime and Express images ( p < 0.05), however it did not influence the SD in any of the digital systems ( p > 0.05). The addition of a lead foil to intraoral digital receptors produces a positive effect in the image quality objectively detected by means of uniformity and subjective visual preference.


Improving the digital health of the workforce in the COVID-19 context: an opportunity to future-proof medical training.
As well as its profound effects on healthcare and wider society, the COVID-19 pandemic will have far-reaching implications for the future training and professional development of healthcare workers and, in particular, doctors. While initial educational priorities focused on creating a more agile workforce with better cross-specialty skill-mix, attention must now shift to how our system can prepare a proportionate response that not only addresses the needs of the pandemic but also the underlying challenges of healthcare: multimorbidity, bridging the evidence-practice gap and delivering integrated, personalised medicine for all. It is our contention that meeting such challenges will require a rapid upskilling of the digital capabilities of the healthcare workforce. In short, optimising the health of the nation will depend, in part, on improving the digital health of the workforce. In this review, we examine how digital technology played its part in the COVID-19 response, and how fundamental changes to medical training are urgently needed in the context of a 'healthcare reset'. Familiarity with health informatics, data science and digital technology have to move to centre stage in order to future-proof our profession in the years to come. The people that deliver care are our systems' greatest asset, and at a time when change is accelerating, we cannot knowingly allow current and future colleagues to be ill-equipped to survive and thrive in the practice of medicine.


Could an isolated human body lower limb model predict leg biomechanical response of Chinese pedestrians in vehicle collisions?
The purpose of the current study was to investigate whether an isolated human body lower limb FE model could predict leg kinematics and biomechanical response of a full body Chinese pedestrian model in vehicle collisions. A human body lower limb FE model representing midsize Chinese adult male anthropometry was employed with different upper body weight attachments being evaluated by comparing the predictions to those of a full body pedestrian model in vehicle-to-pedestrian collisions considering different front-end shapes. The results indicate that upper body mass has a significant influence on pedestrian lower limb injury risk, the effect varies from vehicle front-end shape and is more remarkable to the femur and knee ligaments than to the tibia. In particular, the upper body mass can generally increase femur and knee ligaments injury risk, but has no obvious effect on the injury risk of tibia. The results also show that a higher attached buttock mass is needed for isolated pedestrian lower limb model for impacts with vehicles of higher bonnet leading edge. The findings of this study may suggest that it is necessary to consider vehicle shape variation in assessment of vehicle pedestrian protection performance and leg-form impactors with adaptive upper body mass should be used for vehicles with different front-end shapes, and the use of regional leg-form impactor modeling the local anthropometry to evaluate the actual lower limb injury of pedestrians in different countries and regions.


Fine-tuning MAPK signaling in the brain: The role of MKP-1.
Mitogen-activated protein kinase (MAPK) signaling influences a variety of neuronal properties, including structural characteristics such as spine density, and physiological features like long-term potentiation. Spatiotemporal control of MAPK signaling is crucial to generate specific changes in neuronal physiology. However, while many studies have concentrated on the activation of MAPK signaling by trophic factors such as BDNF and neuronal activity, the mechanisms that lead to its termination have not been well described. Two recent reports begin to address this question by focusing on the role of the MAPK phosphatase, MKP-1, in neuronal function. The first study provides a cellular mechanism underlying MKP-1 action in the brain.1 The second study describes potential roles of MKP-1 during stress and major depression.2.


Aden kidney transplantation.
During the first Yemeni Congress of Uro-Nephrology in Aden, an international team performed the first kidney tranplantations in the region. We report the difficulties encountered and discuss the pros and cons for transplantations in developing countries.


Dynamic compression augments interstitial transport of a glucose-like solute in articular cartilage.
Solute transport through the extracellular matrix is essential for cellular activities in articular cartilage. Increased solute transport via fluid convection may be a mechanism by which dynamic compression stimulates chondrocyte metabolism. However, loading conditions that optimally augment transport likely vary for different solutes. To investigate effects of dynamic loading on transport of a bioactive solute, triangular mechanical loading waveforms were applied to cartilage explants disks while interstitial transport of a fluorescent glucose analog was monitored. Peak-to-peak compression amplitudes varied from 5-50% and frequencies varied from 0.0006-0.1 Hz to alter the spatial distribution and magnitude of oscillatory fluid flow. Solute transport was quantified by monitoring accumulation of fluorescence in a saline bath circulated around the explant. Individual explants were subjected to a series of compression protocols, so that effects of loading on solute desorption could be observed directly. Maximum increases in solute transport were obtained with 10-20% compression amplitudes at 0.1 Hz; similar loading protocols were previously found to stimulate chondrocyte metabolism in vitro. Results therefore support hypotheses relating to increased solute transport as a mediator of the cartilage biological response to dynamic compression, and may have application in mechanical conditioning of cartilage constructs for tissue engineering.


Serum concentrations of tumour necrosis factor-alpha (TNF-alpha) and soluble TNF-alpha receptor p55 in patients with hypothyroidism and hyperthyroidism before and after normalization of thyroid function.
Tumour necrosis factor-alpha (TNF-alpha) is a cytokine with numerous immunological and metabolic activities. Receptors for TNF-alpha have been demonstrated in thyroid follicular cells and TNF-alpha and its receptors have been implicated in the cytotoxic mechanisms that characterize the thyroid destruction in autoimmune thyroid disease. In patients with Graves' disease, serum levels of TNF-alpha have been reported to be elevated and administration of TNF-alpha to humans has been shown to induce hormonal alterations resembling those seen in the nonthyroidal illness syndrome. To evaluate serum concentrations of TNF-alpha and the soluble receptor for TNF-alpha (sTNFR-I) in a group of patients with thyroid dysfunction before and after normalization of thyroid function with appropriate therapy. We studied 20 patients with hypothyroidism (18 women and 2 men, mean age +/- SD, 48.8 +/- 16.1 years) and 20 patients with hyperthyroidism (14 women and 6 men, age 44.6 +/- 15.9 years). Patients were assessed at the time of diagnosis and again after normalization of thyroid function tests with appropriate therapy. A group of 20 healthy subjects (15 women and 5 men, age 44.9 +/- 15.1 years) were also studied as a control group. All subjects were ambulatory and were studied as outpatients during visits to the endocrinology clinic. Serum concentrations of free T4 (FT4), total T3, TSH, TNF-alpha and sTNFR-I were measured in all subjects. TNF-alpha and sTNFR-I were measured using a quantitative enzyme immunoassay. In patients with hypothyroidism serum concentrations of TNF-alpha (3.17 +/- 1.18 pg/ml) and sTNFR-I (1273 +/- 364 pg/ml) were significantly higher than those found in controls (2.42 +/- 0.76 pg/ml, P < 0.05, and 971 +/- 235 pg/ml, P < 0.01, respectively). Normalization of thyroid function with l-thyroxine therapy did not significantly modify TNF-alpha or sTNFR-I levels. There were no differences in pre- and post-therapy values of TNF-alpha and sTNFR-I in patients with autoimmune (n = 14) or nonautoimmune (n = 6) hypothyroidism. Before therapy, patients with hyperthyroidism showed elevated serum concentrations of TNF-alpha (3.36 +/- 1.21 pg/ml; P < 0.01) and sTNFR-I (2274 +/- 579 pg/ml; P < 0.001) in relation to the control group. Treatment of hyperthyroidism was accompanied by a normalization of TNF-alpha levels (2.46 +/- 0.89 pg/ml; P < 0.001) and by a significant decrease in sTNFR-I concentrations (1369 +/- 475 pg/ml; P < 0.001). Post-therapy levels of TNF-alpha and sTNFR-I showed a significant correlation with loss of weight (r = 0.674, P < 0.01, and r = 0.629, P < 0.01, respectively) in hypothyroid patients. No correlation between these parameters was found in the group of patients with hyperthyroidism. In summary, these results confirm the relevance of activation of the TNF-alpha system in patients with thyroid dysfunction, as high plasma concentrations of TNF-alpha and sTNFR-I have been demonstrated in patients with hypothyroidism or hyperthyroidism. Treatment of hyperthyroidism is accompanied by a significant reduction in the previously elevated concentrations of both TNF-alpha and sTNFR-I. However, these changes are not seen when normalizing thyroid function in patients with hypothyroidism.


Platelet and red blood cell utilization and transfusion independence in umbilical cord blood and allogeneic peripheral blood hematopoietic cell transplants.
Allogeneic hematopoietic cell transplantation (HCT) recipients have substantial transfusion requirements. Factors associated with increased transfusions and the extent of blood product use in umbilical cord blood (UCB) recipients are uncertain. We reviewed blood product use in 229 consecutive adult recipients of allogeneic HCT at the University of Minnesota: 147 with leukemia, 82 lymphoma or myeloma; 58% received unrelated UCB and 43% sibling donor peripheral blood stem cell (PBSC) grafts. Although neutrophil recovery was prompt (UCB median 17, range: 2-45 days, and PBSC 14, range: 3-34 days), only 135 of 229 (59% cumulative incidence) achieved red blood cell (RBC) independence and 157 (69%) achieved platelet independence by 6 months. Time to platelet independence was prolonged in UCB recipients (median UCB 41 versus PBSC 14 days) and in patients who had received a prior transplant (median 48 versus 32 days). Patients who received UCB grafts required more RBC through day 60 post-HCT (mean UCB 7.8 (95% confidence interval [CI] 6.7-8.9) versus PBSC 5.2 (3.7-6.7) transfusions, P = .04), and more platelet transfusions (mean 25.2 (95% CI 22.1-28.2) versus 12.9 (9.4-16.4), P < .01) compared to PBSC recipients. Patients receiving myeloablative (MA) conditioning required more RBC and platelet transfusions during the first 2 months post-HCT compared to reduced-intensity conditioning (RIC) (7.4 versus 6.2, P = .30 for RBC; 23.2 versus 17.5, P = .07 for platelets). Despite prompt neutrophil engraftment, UCB recipients had delayed platelet recovery as well as more prolonged and costly blood product requirements. Enhanced approaches to accelerate multilineage engraftment could limit the transfusion-associated morbidity and costs accompanying UCB allotransplantation.


Machine learning-based prediction of cerebral hemorrhage in patients with hemodialysis: A multicenter, retrospective study.
Intracerebral hemorrhage (ICH) is one of the most serious complications in patients with chronic kidney disease undergoing long-term hemodialysis. It has high mortality and disability rates and imposes a serious economic burden on the patient's family and society. An early prediction of ICH is essential for timely intervention and improving prognosis. This study aims to build an interpretable machine learning-based model to predict the risk of ICH in patients undergoing hemodialysis. The clinical data of 393 patients with end-stage kidney disease undergoing hemodialysis at three different centers between August 2014 and August 2022 were retrospectively analyzed. A total of 70% of the samples were randomly selected as the training set, and the remaining 30% were used as the validation set. Five machine learning (ML) algorithms, namely, support vector machine (SVM), extreme gradient boosting (XGB), complement Naïve Bayes (CNB), K-nearest neighbor (KNN), and logistic regression (LR), were used to develop a model to predict the risk of ICH in patients with uremia undergoing long-term hemodialysis. In addition, the area under the curve (AUC) values were evaluated to compare the performance of each algorithmic model. Global and individual interpretive analyses of the model were performed using importance ranking and Shapley additive explanations (SHAP) in the training set. A total of 73 patients undergoing hemodialysis developed spontaneous ICH among the 393 patients included in the study. The AUC of SVM, CNB, KNN, LR, and XGB models in the validation dataset were 0.725 (95% CI: 0.610 ~ 0.841), 0.797 (95% CI: 0.690 ~ 0.905), 0.675 (95% CI: 0.560 ~ 0.789), 0.922 (95% CI: 0.862 ~ 0.981), and 0.979 (95% CI: 0.953 ~ 1.000), respectively. Therefore, the XGBoost model had the best performance among the five algorithms. SHAP analysis revealed that the levels of LDL, HDL, CRP, and HGB and pre-hemodialysis blood pressure were the most important factors. The XGB model developed in this study can efficiently predict the risk of a cerebral hemorrhage in patients with uremia undergoing long-term hemodialysis and can help clinicians to make more individualized and rational clinical decisions. ICH events in patients undergoing maintenance hemodialysis (MHD) are associated with serum LDL, HDL, CRP, HGB, and pre-hemodialysis SBP levels.


Performance evaluation of an on-site volume reduction system with synthetic urine using a water transport model.
The parameters of a model of the transport of water from a wet cloth sheet to the air, developed for deionized water, to establish design procedures of an on-site volume reduction system, were identified for high salt concentrations present in synthetic urine. The results showed that the water penetration was affected neither by the salts, urea or creatinine present in the synthetic urine nor by the salts accumulated on the surface of the vertical gauze sheet. However, the saturated vapour pressure decreased, leading to reduction in the evaporation rate, which occurred as a result of the salts accumulating on the surface of the vertical gauze sheet. Furthermore, a steady-state evaporation condition was established, illustrating salts falling back to the tank from the vertical gauze sheet. Accordingly, the existing design procedure was amended by incorporating the calculation procedure for the saturated vapour pressure using Raoult's law. Subsequently, the effective evaporation area of the vertical gauze sheet was estimated using the amended deign procedures to assess feasibility. This estimation showed that the arid, tropical, temperate and cold climates are suitable for the operation of this system, which require requires a small place at household level for 80% volume reduction of 10 L of urine per day for 12 hours' operation in the daytime.


Weight-bearing ankle dorsiflexion range of motion-can side-to-side symmetry be assumed?
In clinical practice, the range of motion (ROM) of the non involved side often serves as the reference for comparison with the injured side. Previous investigations of non-weight-bearing (NWB) ankle dorsiflexion (DF) ROM measurements have indicated bilateral symmetry for the most part. Less is known about ankle DF measured under weight-bearing (WB) conditions. Because WB and NWB ankle DF are not strongly correlated, there is a need to determine whether WB ankle DF is also symmetrical in a healthy population. To determine whether WB ankle DF is bilaterally symmetrical. A secondary goal was to further explore the correlation between WB and NWB ankle DF ROM. Cross-sectional study. Training facility of the Israeli Defense Forces. A total of 64 healthy males (age = 19.6 ± 1.0 years, height = 175.0 ± 6.4 cm, and body mass = 71.4 ± 7.7 kg). Dorsiflexion ROM in WB was measured with an inclinometer and DF ROM in NWB was measured with a universal goniometer. All measurements were taken bilaterally by a single examiner. Weight-bearing ankle DF was greater on the nondominant side compared with the dominant side (P < .001). Non-weight-bearing ankle DF was not different between sides (P = .64). The correlation between WB and NWB DF was moderate, with the NWB DF measurement accounting for 30% to 37% of the variance of the WB measurement. Weight-bearing ankle DF ROM should not be assumed to be bilaterally symmetrical. These findings suggest that side-to-side differences in WB DF may need to be interpreted while considering which side is dominant. The difference in bilateral symmetry between the WB and NWB measurements, as well as the only moderate level of correlation between them, suggests that both measurements should be performed routinely.


[Regression of myocardial hypertrophy in hypertensives on chronic beta-receptor block].
25 patients (24 males, 1 female; mean age 43.7 years), with previously untreated essential hypertension and echocardiographically proven left-ventricular hypertrophy, received metoprolol 200 mg daily over a period of 12.7 months, five of them additionally hydrochlorothiazide 25 mg. After four weeks, resting recumbent blood pressure had decreased from 157 +/- 18 systolic and 106 +/- 9 diastolic to 128 +/- 11 and 85 +/- 9, respectively; after 12.7 months to 123 +/- 12 and 83 +/- 8 mm Hg (P less than 0.001). On 100 W exercise the blood pressure fell from initially 206 +/- 13 and 117 +/- 9 168 +/- 12 and 97 +/- 9, after 12.7 months to 170 +/- 14 and 98 +/- 9 mm Hg. Left-ventricular mass fell from 147.0 +/- 26 g/m2 by 14% after 6.1 months, by 22.5% after 12.7 months (P less than 0.001). While the left-ventricular diameter in enddiastole and endsystole remained unchanged, septal thickness decreased from 15.5 +/- 2.1 to 14.2 +/- 2.2 mm after 6.1 months and 13.1 +/- 1.9 mm after 12.7 months (reduction of 15.5%). The corresponding values for the left-ventricular posterior wall were 11.9 +/- 1.6 before and 10.8 +/- 1.8 after 6.1 months and 10.1 +/- 1.4 mm after 12.7 months (reduction of 16%). Thus long-term administration of metoprolol resulted in a significant reduction in myocardial hypertrophy without impairment of ventricular function.


Expression, purification, crystallization and preliminary X-ray analysis of an NADP-dependent glyceraldehyde-3-phosphate dehydrogenase from Helicobacter pylori.
The classical glycolytic pathway contains an NAD-dependent glyceraldehyde-3-phosphate dehydrogenase, with NADP-dependent forms reserved for photosynthetic organisms and archaea. Here, the cloning, expression, purification, crystallization and preliminary X-ray analysis of an NADP-dependent glyceraldehyde-3-phosphate dehydrogenase from Helicobacter pylori is reported; crystals of the protein were grown both in the presence and the absence of NADP.


A prehospital glasgow coma scale score < or = 14 accurately predicts the need for full trauma team activation and patient hospitalization after motor vehicle collisions.
Trauma team activation protocols should ideally minimize the undertriage of seriously injured patients and eliminate unnecessary activations for those patients that do not require hospitalization. This study examined which physiologic parameter(s) most reliably predicted the need for hospitalization after motor vehicle collisions (MVCs). A prehospital triage tool using standard physiologic parameters was developed and prospectively analyzed for reliability in predicting subsequent patient admission at a Level II trauma center after MVCs. Data were collected on 4,014 consecutive patients, 2,880 (72%) of whom had all of the physiologic parameters reported and recorded. Patients who arrived in extremis, who were dead on arrival, or who died shortly after arrival despite appropriate trauma team activation were ineligible for the study. Multivariate stepwise logistic regression analysis was used to determine which parameters were associated with hospital admission. The Glasgow Coma Scale (GCS) score was the only prehospital physiologic parameter providing a clinically identifiable difference between those patients admitted (13 +/- 4) and those discharged to home (15 +/- 0.5) (mean + SD) (relative risk for hospitalization, 2.24; 95% confidence interval, 1.86-2.70 for GCS score < 14). The prehospital GCS score is a reliable physiologic parameter for predicting hospital admission after MVC. When obvious indicators (hypoxemia, multiple long bone fractures, focal neurologic deficits) for trauma team activation are lacking, the prehospital GCS score may be used to reduce overtriage and undertriage rates.


[Gastritis].
Eradication of Helicobacter pylori (H. pylori) has suggested not only the decrease in the incidence of peptic ulcer diseases and gastric cancer, and but also the improvement of dyspeptic symptoms. Dyspepsia is a common condition in the world, and dyspepsia-related medical cost is high due to consultations, investigations, and drug consumption. Although the role of H. pylori in functional dyspepsia is still unknown, recent studies including meta-analysis have indicated that H. pylori eradication improves dyspeptic symptoms. In addition, the reduction of medical cost by H. pylori eradication has been discussed in the more recent studies.


Characterization and structure determination of ammonium bismuth oxalate hydrate, Bi(NH(4))(C(2)O(4))(2).xH(2)O.
From on-line coupled TGA-MS and TGA-FTIR measurements, in combination with a quantitative chemical analysis, it was deduced that the chemical formula for an unknown bismuth oxalate compound had to be Bi(NH(4))(C(2)O(4))(2).3.71(6)H(2)O. Solution of the crystallographic structure on the basis of X-ray powder data proved this formula to be correct. The diffraction pattern was indexed by a tetragonal unit cell [a and c respectively 11.6896(2) and 9.2357(3) A; M(20) = 195 and F(30) = 302; Z(calc) = 4], from which the space group I4(1)/amd (No. 141) was derived. Direct methods were applied to solve the structure. The initial structural model was subsequently refined by means of the Rietveld method (R(B) = 8.0%, R(wP) = 14.0%). Bi is 8-fold coordinated by oxygen from the oxalate anions. Since these BiO(8) polyhedrons do not share any edges or vertexes, an open framework is formed with water and ammonium molecules between. As a result, water can easily be removed, which is clearly indicated by the instant weight loss in the TGA upon heating. Moreover, as shown by HT-XRD, this process of water exchange is reversible as long as the heating temperature does not exceed 100 degrees C.


Pharmaceutical care services for asthma patients: a controlled intervention study.
As asthma is associated with an enormous social, psychological, and economic burden, various patient education programs have been developed to improve outcomes, including quality of life. The authors evaluated the effectiveness of community pharmacy-based interventions on lung function, health-related quality of life, and self-management in asthma patients in a 12-month controlled intervention study in 26 intervention and 22 control pharmacies. Pharmacies opted whether to take part as intervention or control pharmacies. According to this, patients (ages 18-65) with mild to severe asthma attending the pharmacies were allocated to the intervention (n = 161) or control group (n = 81), respectively. Intervention patients were educated on their disease, pharmacotherapy, and self-management; inhalation technique was assessed and, if necessary, corrected. Pharmaceutical care led to significantly improved inhalation technique. Asthma-specific quality of life and the mental health summary score of the SF-36 improved significantly in the intervention group. At 12 months, the intervention group showed significant improvements with regard to evening peak flow, self-efficacy, and knowledge.


Alpha-Synuclein in Alcohol Use Disorder, Connections with Parkinson's Disease and Potential Therapeutic Role of 5' Untranslated Region-Directed Small Molecules.
Alpha-synuclein (α-Syn) is a 140-amino acid (aa) protein encoded by the Synuclein alpha SNCA gene. It is the synaptic protein associated with Parkinson's disease (PD) and is the most highly expressed protein in the Lewy bodies associated with PD and other alpha synucleopathies, including Lewy body dementia (LBD) and multiple system atrophy (MSA). Iron deposits are present in the core of Lewy bodies, and there are reports suggesting that divalent metal ions including Cu2+ and Fe2+ enhance the aggregation of α-Syn. Differential expression of α-Syn is associated with alcohol use disorder (AUD), and specific genetic variants contribute to the risk for alcoholism, including alcohol craving. Spliced variants of α-Syn, leading to the expression of several shorter forms which are more prone to aggregation, are associated with both PD and AUD, and common transcript variants may be able to predict at-risk populations for some movement disorders or subtypes of PD, including secondary Parkinsonism. Both PD and AUD are associated with liver and brain iron dyshomeostasis. Research over the past decade has shown that α-Syn has iron import functions with an ability to oxidize the Fe3+ form of iron to Fe2+ to facilitate its entry into cells. Our prior research has identified an iron-responsive element (IRE) in the 5' untranslated region (5'UTR) of α-Syn mRNA, and we have used the α-Syn 5'UTR to screen for small molecules that modulate its expression in the H4 neuronal cell line. These screens have led us to identify several interesting small molecules capable of both decreasing and increasing α-Syn expression and that may have the potential, together with the recently described mesenchymal stem cell therapies, to normalize α-Syn expression in different regions of the alcoholic and PD brain.


Classical Trajectory of Molecules in Electromagnetic Field: A Handy Method to Simulate Molecular Vibrational Spectra.
Within harmonic approximations, molecular vibrational spectra are simulated in a standard way through force field diagonalization and following transformation of Cartesian to normal-mode tensor derivatives. This may become tedious for large systems of many thousands of atoms and also not necessary because of a limited resolution required to interpret an experiment. We developed an algorithm based on the real-time real-field molecular dynamics, effectively at zero temperature, invoked in a molecule by the electromagnetic field of light. The algorithm is simple to implement and suitable for parallel computing, and it can be potentially extended to more complicated molecular-light interaction modes. It circumvents the diagonalization and is suitable to model vibrational optical activity (vibrational circular dichroism and, to a lesser extent, Raman optical activity). For large molecules, it becomes faster than diagonalization, but it also enables the assignment of vibrational spectral bands to local molecular motions.


The reciprocal roles of PARK2 and mitofusins in mitophagy and mitochondrial spheroid formation.
Mitochondrial homeostasis is critical to cellular homeostasis, and mitophagy is an important mechanism to eliminate mitochondria that are superfluous or damaged. Multiple events can be involved in the recognition of mitochondria by the phagophore, and the key one is the priming of the mitochondria with specific molecular signatures. PARK2/Parkin is an E3 ligase that can be recruited to depolarized mitochondria and is required for mitophagy caused by respiration uncoupling. PARK2 induces ubiquitination of mitochondrial outer membrane proteins, which are subsequently degraded by the proteasome. Why these PARK2-mediated priming events are necessary for mitophagy to occur is not clear. We propose that they are needed to prevent a default pathway that would be inhibitory to mitophagy. In the default pathway depolarized and fragmented mitochondria undergo a dramatic three-dimensional conformational change to become mitochondrial spheroids. This transformation requires mitofusins; however, PARK2 inhibits this process by causing mitofusin ubiquitination and degradation. The spherical transformation may prevent recognition of the damaged mitochondria by the autophagosome, and PARK2 ensures that no such transformation occurs in order to promote mitophagy. Whether the formed mitochondrial spheroids functionally represent an alternative mitigation to mitophagy or an adverse consequence in the absence of PARK2 has yet to be determined.


Inherited connexin mutations associated with hearing loss.
One of the most dramatic discoveries in the field of hereditary hearing loss is the association of this sensory defect with connexin mutations. Most significant is the large proportion, 30-50%, of inherited hearing loss that is due to mutations in connexin 26. The proteins these genes encode are expressed in the cochlear duct, in regions containing gap junctions. Together, these findings suggest a crucial role for gap junction proteins in the mammalian inner ear. Mouse models with specific connexin mutations leading to deafness will help resolve the many questions regarding the role of these gap junction proteins in the inner ear.


Investigation of the Electronic Structure and Optical, EPR, and ODMR Spectroscopic Properties for 171Yb3+-Doped Y2SiO5 Crystal: A Combined Theoretical Approach.
Various spectroscopic properties of Yb3+-doped Y2SiO5 crystal have been extensively investigated due to its promising application in quantum information processing. However, the local structure, electronic structure of Yb3+:Y2SiO5 crystal, and its optical and magnetic properties have not been comprehensively studied from a theoretical viewpoint. In this work, the geometric and electronic structures of Yb3+ that replaces two crystallographic Y3+ sites in the Y2SiO5 crystal are first obtained by the method of density functional theory (DFT). Then, the optical, electron paramagnetic resonance (EPR), and optically detected magnetic resonance (ODMR) spectra for 171Yb3+ (nuclear spin I = 1/2) at such two sites are simultaneously calculated in the framework of the complete diagonalization (of energy) matrix (CDM) based on the optimized local structure around 171Yb3+ ion by DFT. The various calculated spectroscopic properties by such combined theoretical approach are consistent with the experimental ones, which demonstrates that CDM is effective and particularly suitable for calculating hyperfine A-tensors under zero, low, and intermediate magnetic field. More importantly, based on the obtained accurate hyperfine structure of 171Yb3+ in Y2SiO5 crystal, the possible "clock transitions", which can enhance the optical coherence time, can be assigned or predicted by the present approach. This study successfully explains the spectroscopic properties of 171Yb3+-doped Y2SiO5 and provides a feasible method to design and search for practical rare-earth-doped quantum information materials for the community.


Parenteral Lipid Tolerance and Adverse Effects: Fat Chance for Trouble?
Lipid emulsions (LEs) are indispensable sources of fuel calories and (essential) fatty acids (FAs) in modern parenteral nutrition formulations. The use of LE, however, also remains associated with the development of adverse effects. Intolerance for LE mostly becomes apparent upon the development of patient complaints or disturbed blood function tests, mainly of the liver. These issues may be associated with the composition, stability, or the infusion rate of the emulsion. Also, altered balances of (anti)oxidants or the presence or absence of protective or toxic bioactive agents such as phytosterols and tocopherol in LE may lead to complications, especially in already vulnerable patients with an inflammatory condition. While the oldest available LEs are based on pure soybean oil (SO-LE), rich in the proinflammatory ω-6 polyunsaturated fatty acid linoleic acid, more recent next-generation LEs where alternative FA sources such as olive and fish oil (partially) replace soybean oil to lower the content of linoleic acid seem safe and effective. Especially LEs containing fish oil (FO-LE) have less proinflammatory characteristics that promise to convey beneficial effects on immune system and organ functions, although much of the available evidence awaits more robust clinical validation.


Microfluidic Point-of-Care Testing: Commercial Landscape and Future Directions.
Point-of-care testing (POCT) allows physicians to detect and diagnose diseases at or near the patient site, faster than conventional lab-based testing. The importance of POCT is considerably amplified in the trying times of the COVID-19 pandemic. Numerous point-of-care tests and diagnostic devices are available in the market including, but not limited to, glucose monitoring, pregnancy and infertility testing, infectious disease testing, cholesterol testing and cardiac markers. Integrating microfluidics in POCT allows fluid manipulation and detection in a singular device with minimal sample requirements. This review presents an overview of two technologies - (a.) Lateral Flow Assay (LFA) and (b.) Nucleic Acid Amplification - upon which a large chunk of microfluidic POCT diagnostics is based, some of their applications, and commercially available products. Apart from this, we also delve into other microfluidic-based diagnostics that currently dominate the in-vitro diagnostic (IVD) market, current testing landscape for COVID-19 and prospects of microfluidics in next generation diagnostics.


The Human Tissue-Engineered Cornea (hTEC): Recent Progress.
Each day, about 2000 U.S. workers have a job-related eye injury requiring medical treatment. Corneal diseases are the fifth cause of blindness worldwide. Most of these diseases can be cured using one form or another of corneal transplantation, which is the most successful transplantation in humans. In 2012, it was estimated that 12.7 million people were waiting for a corneal transplantation worldwide. Unfortunately, only 1 in 70 patients received a corneal graft that same year. In order to provide alternatives to the shortage of graftable corneas, considerable progress has been achieved in the development of living corneal substitutes produced by tissue engineering and designed to mimic their in vivo counterpart in terms of cell phenotype and tissue architecture. Most of these substitutes use synthetic biomaterials combined with immortalized cells, which makes them dissimilar from the native cornea. However, studies have emerged that describe the production of tridimensional (3D) tissue-engineered corneas using untransformed human corneal epithelial cells grown on a totally natural stroma synthesized by living corneal fibroblasts, that also show appropriate histology and expression of both extracellular matrix (ECM) components and integrins. This review highlights contributions from laboratories working on the production of human tissue-engineered corneas (hTECs) as future substitutes for grafting purposes. It overviews alternative models to the grafting of cadaveric corneas where cell organization is provided by the substrate, and then focuses on their 3D counterparts that are closer to the native human corneal architecture because of their tissue development and cell arrangement properties. These completely biological hTECs are therefore very promising as models that may help understand many aspects of the molecular and cellular mechanistic response of the cornea toward different types of diseases or wounds, as well as assist in the development of novel drugs that might be promising for therapeutic purposes.


Phosphenes in low earth orbit: survey responses from 59 astronauts.
It has long been known that many people in space experience sudden phosphenes, or light flashes. Although it is clear that they are related to high-energy particles in the space radiation environment, many details about them are still unknown. In an effort to gain more knowledge about the light flashes, a study was initiated to collect information from people who have recently flown in space. A survey conducted by anonymous questionnaire was performed among astronauts regarding their experience of sudden light flashes in space. In all, 98 surveys were distributed to current NASA and ESA astronauts. Among the 59 respondents, 47 noticed them sometime during spaceflight. Most often they were noted before sleep, and several people even thought the light flashes disturbed their sleep. The light flashes predominantly appear white, have elongated shapes, and most interestingly, often come with a sense of motion. The motion is described as sideways, diagonal, or in-out, but never in the vertical direction. Comparisons with earlier studies of light flashes in space and several ground-based studies during the 1970s are made. One interesting observation from this is that it seems that a small fraction of the light flashes is caused by Cherenkov radiation, while the majority is probably caused by some kind of direct interaction with elements in the retina.


A single protein research integrated advanced biochemistry laboratory course; spectroscopic determination of tyrosyl side chain pKa.
The unique bio-analytical properties of the amino acid tyrosine (Tyr) are the focus of this experiment from the research oriented biochemistry laboratory course at our university. In the present study pK(a(1)), pK(a(2)), and pK(a(3)) values for free Tyr were estimated to be 2.30, 9.40, and 9.97, respectively, when free Tyr was titrated with 1mM NaOH and 1mM HCl using a pH meter. Spectrophotometric analysis of the phenolic side chain pK(a(3)) revealed a value of 10.14, which was consistent with the pK(a)s estimated from the pH meter. The results from this experiment will allow students to compare the free Tyr properties with those present in a protein.


Adjuvant radiotherapy in early stage endometrial cancer.
To compare the rates of overall survival (OS), disease-free survival (DFS) and toxicity in different techniques of postoperative radiotherapy for stage IA endometrioid adenocarcionoma of endometrium, histological grades 1and 2. A historical comparison between treatment regimens was performed, and 133 women with a minimum follow-up of 5 years were included. Teletherapy (TELE group), with 22 patients treated from 1988 to 1996, with a 10 MV linear accelerator, average dose 46.2 Gy. Low dose rate brachytherapy (LDRB group) was performed between 1992 and 1995, in 19 women, with an insertion of Cesium 137, at a 60 Gy dose. Fourteen women operated between 1990 and 1996 did not receive radiotherapy (NO RT group). High dose rate brachytherapy was performed in 78 patients (HDRB group), from 1996 to 2004, in five weekly 7 Gy insertions, prescribed at 0.5 cm from the vaginal cylinder. The 5-year disease-free survival was 94.6% for the HDRB group, 94.1% for the LDRB group, 100% for the TELE group and NO RT groups (p = 0.681). The 5-year overall survival was 86.6% for the HDRB group, 89.5% for the LDRB group and 90% for the TELE group and NO RT groups (p = 0.962). Grades 3-5 late toxicity was 5.3% in LDRB group and 27.3% for the TELE group (p < 0.001). Patients submitted to adjuvant teletherapy showed very high toxicity, which contraindicates that treatment for those patients. There may be a role for adjuvant HDRB, but randomized controlled trials are still needed to evaluate its benefit.