2,4,8-trihydroxybicyclo [3.2.1]octan-3-one scavenges free radicals and protects against xenobiotic-induced cytotoxicity.
Currently, there is a great deal of interest in the study of natural compounds with free-radical-scavenging activity because of their potential role in maintaining human health and preventing diseases. In this paper, we report the antioxidant and cytoprotective properties of 2,4,8-trihydroxybicyclo [3.2.1]octan-3-one (TBO) isolated from the aqueous extract of Decalepis hamiltonii roots. Our results show that TBO is a potent scavenger of superoxide (O(2)·-), hydroxyl (·OH), nitric oxide (·NO) and lipid peroxide (LOO·) - physiologically relevant free radicals with IC(50) values in nmolar (42-281) range. TBO also exhibited concentration-dependent secondary antioxidant activities such as reducing power, metal-chelating activity and inhibition of protein carbonylation. Further, TBO at nmolar concentration prevented CuSO(4)-induced human LDL oxidation. Apart from the in vitro free-radical-scavenging activity, TBO demonstrated cytoprotective activity in primary hepatocytes and Ehrlich ascites tumour (EAT) cells against oxidative-stress-inducing xenobiotics. The mechanism of cytoprotective action involved maintaining the intracellular glutathione (GSH), scavenging of reactive oxygen species (ROS) and inhibiting lipid peroxidation (LPO). Based on the results, it is suggested that TBO is a novel bioactive molecule with implications in both prevention and amelioration of diseases involving oxidative stress as well as in the general well-being.


Poly(ADP-ribose) catabolism in mammalian cells exposed to DNA-damaging agents.
DNA damage inflicted by the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine, or by UV254nm, stimulated the catabolism of protein-bound poly(ADP-ribose) in the chromatin of cultured hepatocytes. The stimulation was highest at the largest doses of DNA-damaging treatment. As a consequence, the half-life of ADP-ribosyl polymers may drop to less than 41 s. This rapid turnover contrasts with the slow catabolism of a constitutive fraction of polymers exhibiting a half-life of 7.7 h. Our data suggest that post-incisional stimulation of poly(ADP-ribose) biosynthesis in DNA-excision repair is coupled with an adaptation of poly(ADP-ribose) catabolism in mammalian cells.


Reduced lateral mobility of a fluorescent lipid probe in cholesterol-depleted erythrocyte membrane.
The effect of cholesterol depletion of the human erythrocyte membrane on the lateral diffusion rate of a fluorescent lipid probe is reported. At low temperature (-5 to 5 degrees C), the diffusion of the probe is 50% slower in the cholesterol-depleted membrane than in non-depleted membrane. At high temperatures (30 to 40 degrees C), probe mobility is not affected by cholesterol depletion. These results suggest that cholesterol suppresses aspects of phospholipid phase changes in animal cells in a manner consistent with its behavior in artificial bilayers and multilayers. Whole erythrocytes were depleted of 30--50% of their cholesterol by incubation with a sonicated dispersion of dipalmitoyl phosphatidylcholine. Cells were then labeled with 3,3'-dioctadecylindocarbocyanine (diI), a phospholipid-like fluorescent dye, and hemolyzed into spherical ghosts. The rate of lateral motion of diI was measured by observing the fluorescence recovery after local photobleaching with a focused laser spot. The diffusion rate of the lipid probe in both control and cholesterol-depleted erythrocyte membrane is substantially smaller than in any cell or model membrane previously measured.


Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 Receptor.
Chronic abdominal pain is a common symptom of inflammatory bowel diseases (IBDs). Peripheral and central mechanisms contribute to the transition from acute to chronic pain during active disease and clinical remission. Lower mechanical threshold and hyperexcitability of visceral afferents induce gliosis in central pain circuits, leading to persistent visceral hypersensitivity (VHS). In the spinal cord, microglia, the immune sentinels of the central nervous system, undergo activation in multiple models of VHS. Here, we investigated the mechanisms of microglia activation to identify centrally acting analgesics for chronic IBD pain. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) expressed in transient receptor potential vanilloid member 1-expressing visceral neurons that sense colonic inflammation, we tested whether neuronal activity was indispensable to control microglia activation and VHS. We then investigated the neuron-microglia signaling system involved in visceral pain chronification. We found that chemogenetic inhibition of transient receptor potential vanilloid member 1+ visceral afferents prevents microglial activation in the spinal cord and subsequent VHS in colitis mice. In contrast, chemogenetic activation, in the absence of colitis, enhanced microglial activation associated with VHS. We identified a purinergic signaling mechanism mediated by neuronal adenosine triphosphate (ATP) and microglial P2Y12 receptor, triggering VHS in colitis. Inhibition of P2RY12 prevented microglial reactivity and chronic VHS post-colitis. Overall, these data provide novel insights into the central mechanisms of chronic visceral pain and suggest that targeting microglial P2RY12 signaling could be harnessed to relieve pain in patients with IBD who are in remission.


Microstructural Differences of the Cerebellum-Thalamus-Basal Ganglia-Limbic Cortex in Patients with Somatic Symptom Disorders: a Diffusion Kurtosis Imaging Study.
Somatic symp tom disorders (SSDs) are a group of psychiatric disorders characterized by persistent disproportionate concern and obsessive behaviors regarding physical conditions. Currently, SSDs lack effective treatments and their pathophysiology is unclear. In this paper, we aimed to examine microstructural abnormalities in the brains of patients with SSD using diffusion kurtosis imaging (DKI) and to investigate the correlation between these abnormalities and clinical indicators. Diffusion kurtosis images were acquired from 30 patients with SSD and 30 healthy controls (HCs). Whole-brain maps of multiple diffusion measures, including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), mean kurtosis (MK), radial kurtosis (RK), and axial kurtosis (AK), were calculated. To analyze differences between the two groups, nonparametric permutation testing with 10,000 randomized permutations and threshold-free cluster enhancement was used with family-wise error-corrected p values < 0.05 as the threshold for statistical significance. Then, the correlations between significant changes in these diffusion measures and clinical factors were examined. Compared to HCs, patients with SSD had significantly higher FA, MK, and RK and significantly lower MD and RD in the cerebellum, thalamus, basal ganglia, and limbic cortex. The FA in the left caudate and the pontine crossing tract were negatively correlated with disease duration; the MD and the RD in the genu of the corpus callosum were positively correlated with disease duration. Our findings highlight the role of the cerebellum-thalamus-basal ganglia-limbic cortex pathway, especially the cerebellum, in SSDs and enhance our understanding of the pathogenesis of SSDs.


De novo protein synthesis is essential to human interferon gamma gene expression by the stimulation with polyI:polyC.
Transcription of human interferon (IFN) gamma gene is induced in human peripheral lymphocyte nylon-nonadherent cells (NNA cells) by double strand RNA poly I:poly C [(1985) J. Interferon Res. 5, 77-84]. In this report, the necessity of de novo protein synthesis in an early stage of IFN gamma gene expression is described. For induction of IFN gamma gene expression, only initial 4 h treatment of poly I:poly C to NNA cells is sufficient. Addition of inhibitor of protein synthesis, cycloheximide (CHX), at an early stage of induction periods (0-4 h) inhibits the IFN gamma induction by poly I:poly C. Cell free translation assay using RNAs isolated from NNA cells which are induced by poly I:poly C in the presence of CHX reveals that in these RNAs, IFN gamma mRNA does not exist. These results demonstrate that CHX inhibits de novo synthesis of a certain protein (or proteins) and for lack of the protein(s), IFN gamma mRNA cannot be transcribed. The evidence is also described in this report which suggests that the essential protein(s) might be that (those) involved in protein kinase C (pkC) activation.


Mobile phone applications in management of enuresis: The good, the bad, and the unreliable!
The proliferation of medical-type applications or 'apps' on smartphones is a typical example of the impact technology has had on medical practice. Maintaining a bladder diary is a recommended part of evaluating the effect of interventions for patients suffering from enuresis. Traditional pen-and-paper bladder diaries have poor completion rates, inconsistent patterns in data entry, and are deficient in validation. Electronic bladder diaries have been proposed to overcome these obstacles. With increasing numbers of smartphone apps available to the general public, it is important to distinguish well-designed apps for childhood enuresis. To identify, evaluate, and rank all available mobile-phone apps for the management of childhood enuresis. On August 21, 2014, a search was conducted on iTunes, Android Play Store, and BlackBerry World for smartphone apps using the following search terms: bladder, bedwetting, bladder diary, enuresis, incontinence, and wetting. Apps that did not have a bladder diary function and that were unrelated to the investigation, follow-up, and treatment of childhood enuresis were excluded. Apps were rated by a paediatric urology consultant, fellow, registrar, and resident medical officer using standardised criteria including: design; ease of use; languages; quality of instructions; security; accordance with ICCS definition of enuresis; and ability to store histories; record bowel habits; transfer data to other devices; and print data. Across all three search platforms, a total of 1041 apps were identified. Only 24 were included and reviewed based on exclusion criteria. Average ratings for apps ranged from 10 to 30.75 out of 50 based on standardised criteria. Smartphone apps are playing an increasingly significant role in the management of enuresis in place of pen-and-paper bladder diaries. Apps available to the general public vary in quality and it can be difficult for patients to identify one appropriate for use. We found apps with higher ratings consistently had engaging interfaces, were easy to use, and defined the primary purpose clearly. Lower ratings and performance often was caused by poor quality of experience through "freezing"/"crashing." Bladder diary apps can eliminate disadvantages of pen-and-paper diaries in the management of enuresis. Currently, apps available vary in quality. The three best-rated apps currently available are My Dryness Tracker, Bedwetting Tracker, and HapPee Time. There is room for medical associations to collaborate with developers for further app development.


QSAR modeling of toxicity of acyclic quaternary ammonium compounds on Scenedesmus Quadricauda using 2D and 3D descriptors.
Optimized calculation of typical acyclic quaternary ammonium compounds (QACs) was performed at B3LYP/6-311G** level using density functional theory (DFT) method. A two- dimensional quantitative structure-activity relationship (2D-QSAR) model was established with the obtained structure parameters as theoretical descriptors. And then three-dimensional quantitative structure-activity relationship (3D-QSAR) models were built using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods respectively. The 2D and 3D QSAR models exhibit optimum stability and predictive ability, revealing that steric and electronic effects influence the toxicity of acyclic QACs to Scenedesmus Quadricauda mostly.


Analysis of optic disc tilt angle in intrapapillary hemorrhage adjacent to peripapillary subretinal hemorrhage using swept-source optical coherence tomography.
To report findings on the tilt angle of optic nerve heads (ONHs) that developed intrapapillary hemorrhage with adjacent peripapillary subretinal hemorrhage (IHAPSH) using swept-source optical coherence tomography (SS-OCT). Five consecutive patients who presented with IHAPSH were reviewed retrospectively. We reviewed five consecutive eyes from the five patients, analyzed the optic tilt angle obtained from SS-OCT B-scans, and compared the results and other clinical characteristics. All patients had larger optic disc tilt angles in the eyes with IHAPSH than in the contralateral, unaffected eye. The mean ratio of the tilt angle in the eyes with IHAPSH to that in the contralateral eye was 1.37 (95% confidence interval 1.15-1.58). The ONH of IHAPSH was evaluated quantitatively with SS-OCT for the first time in this study. Larger angle tilted discs in IHAPSH-affected eyes are anatomically and histologically more vulnerable and may explain why IHAPSH develops monocularly.


"Nothing to see here": No structural brain differences as a function of the Big Five personality traits from a systematic review and meta-analysis.
Personality reflects social, affective, and cognitive predispositions that emerge from genetic and environmental influences. Contemporary personality theories conceptualize a Big Five Model of personality based on the traits of neuroticism, extraversion, agreeableness, conscientiousness, and openness to experience. Starting around the turn of the millennium, neuroimaging studies began to investigate functional and structural brain features associated with these traits. Here, we present the first study to systematically evaluate the entire published literature of the association between the Big Five traits and three different measures of brain structure. Qualitative results were highly heterogeneous, and a quantitative meta-analysis did not produce any replicable results. The present study provides a comprehensive evaluation of the literature and its limitations, including sample heterogeneity, Big Five personality instruments, structural image data acquisition, processing, and analytic strategies, and the heterogeneous nature of personality and brain structures. We propose to rethink the biological basis of personality traits and identify ways in which the field of personality neuroscience can be strengthened in its methodological rigor and replicability.


Increased production of oxygen free radicals by polymorphonuclear leukocytes in heart failure due to aortic stenosis.
Oxygen free radicals have been linked to a wide variety of cellular damage in biological systems. Polymorphonuclear (PMN) leukocytes stimulation is one of the known sources for oxygen free radicals. It has been suggested that oxygen free radicals depress the excitation-contraction coupling in cardiac muscle. It is possible that a decrease in the myocardial contractility in heart failure might be due to an increased oxygen-free-radical-producing activity of PMN leukocytes. The authors studied, therefore, the release of oxygen free radicals, as measured by luminol-dependent chemiluminescence activity, from the PMN leukocytes in dogs with heart failure due to aortic stenosis. Hemodynamics and phagocytic activity of PMN leukocytes were studied in 6 control dogs and 6 dogs with aortic stenosis of six to nine months' duration. There was a significant decrease in the index of myocardial contractility and an increase in the left ventricular end-diastolic pressure in dogs with aortic stenosis, suggesting left ventricular failure in these dogs. Although there was a tendency for a decrease in the cardiac index in dogs with aortic stenosis, the decrease was not significant. Phagocytic activity of PMN leukocytes in blood was studied in control dogs and dogs with aortic stenosis. Phagocytosis was initiated by addition of opsonized zymosan and chemiluminescence was monitored by use of a luminometer. The peak chemiluminescence activity of the PMN leukocytes in blood of dogs with heart failure was about threefold greater than that in the blood from control dogs.(ABSTRACT TRUNCATED AT 250 WORDS)


Multiscale characterization and contact performance analysis of machining surfaces.
Accurately characterizing the surface topography of parts is crucial to improve the surface measurement accuracy and analyze the surface contact performance. A method is proposed to separate the morphological characteristics of the actual machined surface based on the layer-by-layer error reconstruction method and the signal-to-noise ratio method during the wavelet transform process, so as to evaluate the contact performance of the different joint surfaces. First, the actual machined surface morphological features are separated by using the wavelet transform method, the layer-by-layer error reconstruction method, and the signal-to-noise ratio method. Second, the reconstructed three-dimensional surface contact model is established by the reverse modeling engineering method. Third, the finite element method is used to analyze the impact of processing methods and surface roughness on contact surface parameters. The result demonstrates that the simplified and efficient three-dimensional reconstructed surface is achieved based on the real machining surface in contrast to other existing approaches. The surface roughness has a more significant influence on contact performance. The contact deformation increases with the increase of surface roughness, while the curves of average contact stress, contact stiffness, and contact area have the opposite trend.


Program organization rather than choice of test determines success of cervical cancer screening: Case studies from Bangladesh and India.
The call for elimination of cervical cancer as a public health problem by the World Health Organization has led to intense focus on the burden of disease, available resources, and the possibility of introducing efficient systems for screening and treatment that allow effective cancer control in limited-resource settings. Presently, the focus is on the introduction of rapid, technologically less-demanding, affordable HPV testing. However, until such tests become widely available, the momentum that has been gained using visual inspection with acetic acid (VIA) should not be lost. Countries with limited resources and a heavy burden of cervical cancer, such as Bangladesh and India, introduced and scaled up VIA-based programs with varying degrees of programmatic organization and performance. Despite its limitations, VIA's simplicity and affordability has allowed these countries to build infrastructure, increase numbers of trained healthcare personnel, and develop a system of multilevel coordination within the health system. Such efforts will have long-term advantages provided that countries have access to an appropriate HPV test and build on their efforts to improve program organization through a strengthened health system, translating lessons learned in program implementation, logistics, and compliance with the new paradigm.


The future of nursing: understanding who nurses are.
The Institute of Medicine report The Future of Nursing: Leading Change, Advancing Health highlights the need for more information about the nursing workforce. Without attention to the problem, OR nursing is likely to continue to experience the nursing shortage more acutely than other practice areas. By changing how they acquire and use nursing data, and by advocating for improved exchange of data between federal and state governments and nursing schools, facilities can be better prepared for future workforce challenges.


Fractional flow reserve versus angiography alone in guiding myocardial revascularisation: a systematic review and meta-analysis of randomised trials.
Randomised trials evaluating the efficacy and safety of fractional flow reserve (FFR)-guided versus angiography-guided revascularisation among patients with obstructive coronary artery disease (CAD) have yielded mixed results. To examine the comparative efficacy and safety of FFR-guided versus angiography-guided revascularisation among patients with obstructive CAD. An electronic search of MEDLINE, SCOPUS and Cochrane databases without language restrictions was performed through November 2021 for randomised controlled trials that evaluated the outcomes of FFR-guided versus angiography-guided revascularisation. The primary outcome was major adverse cardiac events (MACE). Data were pooled using a random-effects model. The final analysis included seven trials with 5094 patients. The weighted mean follow-up duration was 38 months. Compared with angiography guidance, FFR guidance was associated with fewer number of stents during revascularisation (standardised mean difference=-0.80; 95% CI -1.33 to -0.27), but no difference in total hospital cost. There was no difference between FFR-guided and angiography-guided revascularisation in long-term MACE (13.6% vs 13.9%; risk ratio (RR) 0.97, 95% CI 0.85 to 1.11). Meta-regression analyses did not reveal any evidence of effect modification for MACE with acute coronary syndrome (p=0.36), proportion of three-vessel disease (p=0.88) or left main disease (p=0.50). There were no differences between FFR-guided and angiography-guided revascularisation in the outcomes all-cause mortality (RR 1.16, 95% CI 0.80 to 1.68), cardiovascular mortality (RR 1.27, 95% CI 0.50 to 3.26), repeat revascularisation (RR 0.99, 95% CI 0.81 to 1.21), recurrent myocardial infarction (RR 0.92, 95% CI 0.74 to 1.14) or stent thrombosis (RR 0.61, 95% CI 0.31 to 1.21). Among patients with obstructive CAD, FFR-guided revascularisation did not reduce the risk of long-term adverse cardiac events or the individual outcomes. However, FFR-guided revascularisation was associated with fewer number of stents. CRD42021291596.


The catalytic mechanism of decarboxylative hydroxylation of salicylate hydroxylase revealed by crystal structure analysis at 2.5 Å resolution.
The X-ray crystal structure of a salicylate hydroxylase from Pseudomonas putida S-1 complexed with coenzyme FAD has been determined to a resolution of 2.5 Å. Structural conservation with p- or m-hydroxybenzoate hydroxylase is very good throughout the topology, despite a low amino sequence identity of 20-40% between these three hydroxylases. Salicylate hydroxylase is composed of three distinct domains and includes FAD between domains I and II, which is accessible to solvent. In this study, which analyzes the tertiary structure of the enzyme, the unique reaction of salicylate, i.e. decarboxylative hydroxylation, and the structural roles of amino acids surrounding the substrate, are considered.


The epidermal Merkel cell is an epithelial cell.
TROMA 1, a monoclonal antibody against cytokeratin, was found to react with epidermal Merkel cells. This demonstrates the epithelial origin of MC.


Beyond the First Wave: Consequences of COVID-19 on High-Risk Infants and Families.
The novel coronavirus disease 2019 (COVID-19) pandemic is affecting care for high-risk newborns in ways that will likely be sustained beyond the initial pandemic response. These novel challenges present an urgent imperative to understand how COVID-19 impacts parent, family, and infant outcomes. We highlight three areas that warrant targeted attention: (1) inpatient care: visitation policies, developmental care, and communication practices; (2) outpatient care: high-risk infant follow-up and early intervention programs; and (3) parent psychosocial distress: mental health, social support, and financial toxicity. Changes to care delivery in these areas provide an opportunity to identify and implement novel strategies to provide family-centered care during COVID-19 and beyond. KEY POINTS: · The COVID-19 pandemic is influencing care delivery for high-risk newborns and their families.. · Rapid changes to care delivery are likely to be sustained beyond the initial pandemic response.. · We have an urgent imperative to understand how COVID-19 impacts infant, parent, and family outcomes..


Factors associated with vaginal birth after previous cesarean section in Brazilian women.
To identify factors associated with a vaginal second delivery in women who had one previous cesarean section. A nested case-control study was carried out as a secondary data analysis of an original retrospective, population-based cohort study of women who delivered their first child during 1985 in the city of Campinas, São Paulo, Brazil, and who were interviewed 10 years later in 1995. The study population consisted of 1352 women who had their first delivery by cesarean section and who had also had at least one subsequent delivery. The group of cases (150 women, around 11% of the sample) consisted of women who had a vaginal second delivery, and the control group was made up of 1202 women who had a cesarean section at second delivery. For each possible associated factor we calculated the odds ratio and 95% confidence interval. For ordered categorical variables the c2 test for trend was used. Unconditional multivariate regression analysis was used to estimate the adjusted odds ratio for each associated factor. The factors significantly associated with vaginal delivery were monthly family income below 5-fold the Brazilian minimum monthly wage, reliance on the Brazilian national health system for healthcare, low maternal age, and first cesarean section indicated because of fetal breech or transverse presentation, or twin pregnancy. Among those women who also had a cesarean section at their second delivery, only 11% had undergone a trial of labor. The main determining factors for a vaginal second delivery in women with a previous cesarean section were unfavorable social and economic factors.


The effects of chronically increased intra-abdominal pressure on the rabbit diaphragm.
Diaphragmatic muscular remodeling is caused by various conditions and was mainly studied in pulmonary pathologies and chronic alterations of intra-thoracic pressure. We investigate the effect of the chronically increased intra-abdominal pressure (IAP) on the diaphragm by morphological and biochemical analysis. Thirty rabbits were divided into control and study groups. IAP was increased in group B to 12 mmHg for 2 months. The left hemidiaphragm underwent morphological, while the right underwent biochemical analysis. In H&E, all fibers were normal. ATPase analysis demonstrated that type I fibers show no differences between groups. Type ΙΙ(Α) were decreased (p = 0.016) while type ΙΙ(Β/X) fibers were increased (p = 0.025) in group B. Fibers with resistance to fatigue were decreased in group B (p = 0.024). In group B, biochemical activity for glutathione reductase (p = 0.004), glutathione peroxidase (p = 0.021), protein carbonylation (0.029), lipid peroxidation (p = 0.005), and balance of preoxidative-antioxidative factors (p = 0.006) was increased. Chronically increased IAP induces alterations to the rabbit diaphragm. Adaptation, equivalent to strenuous contraction, transforms the diaphragm to be functionally more efficient toward workload but makes it vulnerable against oxidative stress.


Fat consumption and factor VII coagulant activity in middle-aged men. An association between a dietary and thrombogenic coronary risk factor.
Diet was measured by 5-day weighed inventory to search for an association between fat intake in the general population and factor VII coagulant activity (VIIc), a strong predictor of coronary heart disease. Of 275 men aged 40-59 years registered with a medical practice, 203 (74%) participated and 170 (62%) provided a satisfactory record. After allowance for the increase in fat intake with body size, a statistically significant and positive association was found between dietary fat and VIIc (r = 0.18; P less than 0.05). The correlation coefficient was increased to 0.24 when adjusted for the effect of day-to-day variability in individual fat intake, thereby providing an improved estimate of the true strength of association. The mean difference in VIIc of 12% of standard between men in the highest and lowest quarters of the distribution of fat intake was similar to that reported between men experiencing coronary heart disease and those remaining free. The results support previous experimental fat-feeding studies and suggest that a high fat diet has adverse consequences for blood coagulability and coronary thrombosis.


TypeSeg: A type-aware encoder-decoder network for multi-type ultrasound images co-segmentation.
As a portable and radiation-free imaging modality, ultrasound can be easily used to image various types of tissue structures. It is important to develop a method which supports the multi-type ultrasound images co-segmentation. However, state-of-the-art ultrasound segmentation methods commonly only focus on the single type images or ignore the type-aware information. To solve the above problem, this work proposes a novel type-aware encoder-decoder network (TypeSeg) for the multi-type ultrasound images co-segmentation. First, we develop a type-aware metric learning module to find an optimum latent feature space where the ultrasound images of the same types are close and that of the different types are separated by a certain margin. Second, depending on the extracted features, a decision module decides whether the input ultrasound images have the common tissue type or not, and the encoder-decoder network produces a segmentation mask accordingly. We evaluate the performance of the proposed TypeSeg model on the ultrasound dataset that contains four types of tissues. The proposed TypeSeg model achieves the overall best results with the mean IOU score of 87.51% ± 3.93% for the multi-type ultrasound images. The experimental results indicate that the proposed method outperforms all the compared state-of-the-art algorithms for the multi-type ultrasound images co-segmentation task.


Seroepidemiology of Toxoplasma gondii among pregnant women in different parts of Sweden.
Surveys of pregnant women in four areas of Sweden in 1987-88, reveal a significant trend for decrease in Toxoplasma seroprevalence from Gotland island (26%, n = 467) in the south through Orebro county (18%, n = 1413) and Stockholm area (18%, n = 939), to Northern Sweden (12%, n = 837). No within area differences were observed between samples from rural and urban localities. Quantitative antibody data indicate marginally higher levels in the north than in the south, and a significant declining trend by age only in Orebro county. Incidence models are used to describe age-seroprevalence profiles for each area, using different assumptions about age- and time-specific infection rates, and to estimate the risk of maternal infection at the time of the survey. It is shown that the patterns of seroprevalence with age in Orebro county and Northern Sweden, but not Gotland island or Stockholm, strongly implicate time-dependent changes in Toxoplasma incidence, consistent with a declining incidence in the past which has possibly been reversed in recent years. The estimates of Toxoplasma incidence and risk of maternal toxoplasmosis are strongly dependent upon the underlying assumption of temporal change in incidence, with wide ranges in the predicted values. These studies demonstrate the difficulties in interpretation of horizontal cross-sectional data and the need for longitudinal studies of age-prevalence and seroconversion in the determination of the true risk of maternal toxoplasmosis.


The effect of thiopentone on somatosensory evoked responses and EEGs in comatose patients.
EEGs and somatosensory evoked responses from the brachial plexus, neck and scalp were recorded in seven comatose patients on continuous thiopentone infusion. Although pathological in five of the patients, the evoked responses were present in all. Additional amounts of thiopentone producing a full suppression of all spontaneous EEG activity had no effects either on the configuration of the evoked responses or on the central conduction times. This resistance of the somatosensory evoked responses to a deep and sustained thiopentone narcosis makes it a useful test in comatose patients receiving this treatment.


Enantioselective synthesis of a 3'-dephenylcryptophycin synthon.
An enantioselective synthesis of tert-butyl (5S,6R)-(E)-5-tert-butyldimethylsilyloxy-6-methyl-2,7-octadieno ate, a precursor for the synthesis of the antimitotic macrolides cryptophycin A and arenastatin A (cryptophycin-24), is presented. The key step in the reaction sequence features a crotyl boration that sets both stereocenters that become the C16 hydroxyl and Cl' methyl in the cryptophycins. Homologation of the terminal olefin via a Heck reaction is presented.


Dual roles of Munc18-1 rely on distinct binding modes of the central cavity with Stx1A and SNARE complex.
Sec1/Munc18 proteins play a fundamental role in multiple steps of intracellular membrane trafficking. Dual functions have been attributed to Munc18-1: it can act as a chaperone when it interacts with monomeric syntaxin 1A, and it can activate soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) for membrane fusion when it binds to SNARE complexes. Although both modes of binding involve the central cavity of Munc18-1, their precise molecular mechanisms of action are not fully understood. In this paper, we describe a novel Munc18-1 mutant in the central cavity that showed a reduced interaction with syntaxin 1A and impaired chaperone function, but still bound to assembled SNARE complexes and promoted liposome fusion and secretion in neuroendocrine cells. Soluble syntaxin 1A H3 domain partially blocks Munc18-1 activation of liposome fusion by occupying the Munc18-1 central cavity. Our findings lead us to propose a transition model between the two distinct binding modes by which Munc18 can control and assist in SNARE-complex assembly during neurotransmitter release.


Cost and health-related quality of life for children hospitalized with respiratory syncytial virus in Central China.
The economic burden of respiratory syncytial virus (RSV) infection and its impact on health-related quality of life (HRQoL) are not well-understood in China. This study assessed total cost and HRQoL for children hospitalized with RSV in Central China. Based on a prospective case series study in Henan Province in 2020-2021, inpatients aged 0-59 months with RSV-related acute respiratory infections (ARIs) were included into analysis. Total cost included direct medical cost (sum of medical cost before and during hospitalization), direct non-medical cost, and indirect cost. Direct medical cost during hospitalization data were extracted from the hospital information system. Other costs and HRQoL status were obtained from a telephone survey conducted in the caregivers of the enrolled patients. Among 261 RSV-infected inpatients, caregivers of 170 non-severe cases (65.1%, 170/261) were successfully interviewed. Direct medical cost per episode was 1055.3 US dollars (US$) (95% CI: 998.2-1112.5 US$). Direct non-medical cost and indirect cost per episode were 83.6 US$ (95% CI: 77.5-89.7 US$) and 162.4 US$ (95% CI: 127.9-197.0 US$), respectively. Quality adjusted life years (QALY) loss for non-severe RSV hospitalization was 8.9 × 10-3 (95% CI: 7.9 × 10-3 -9.9 × 10-3 ). The majority of inpatients were <1 year of age comprising significantly higher cost and more QALY loss than older children. RSV-associated hospitalization poses high economic and health burden in Central China particularly for children <1 year old. Our findings are crucial for determining the priority of interventions and allocation of health resources.


A case with double-chambered right ventricle and left ventricular-right atrial communication (Gerbode defect): potential pitfall for Eisenmenger syndrome.
The ventricular septal defect (VSD) can rarely be associated with other malformations such as double-chambered right ventricle (DCRV) in which hypertrophied muscle bundles divide the right ventricle into two chambers causing progressive obstruction (Mao et al., Asia Pac J Thorac Cardiovasc Surg 5:14-17, 1996). Most VSDs close spontaneously by apposition of the tricuspid leaflets, but the process is rarely disrupted, resulting in communication between left ventricle and right atrium called Gerbode defect [Cho et al., J Cardiovasc Ultrasound 19(3):148-151, 2011]. Hence, the Gerbode defect involves potential misinterpretation of its high-velocity shunt as pulmonary hypertension. Here we present a case with DCRV and Gerbode defect initially misdiagnosed to have Eisenmenger syndrome.


Characterization of the patients with antibodies against nodal-paranodal junction proteins in chronic inflammatory demyelinating polyneuropathy.
Antibodies against nodal-paranodal junction proteins have been detected in some patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), which is a crucial step to define the most effective treatment strategies. In this paper, we tested the positive rates of these antibodies in CIDP and characterized the clinical and electrophysiological features of the antibodies-positive patients. We prospectively recruited 47 patients with CIDP. We detected IgG antibodies against human neurofascin-155 (NF155), neurofascin-186 (NF186), contactin-1 (CNTN1), contactin-2 (CNTN2) and contactin-associated protein-1 (Caspr1), and identified the IgG isotype with cell-based assay (CBA). We collected the demographic, clinical, laboratory, and electrophysiological information of the patients that were seropositive. Five patients (10.6 %) had IgG against NF155, 3 (6.4 %) against Caspr1, 2 (4.3 %) against NF186 and 1 (2.1 %) against CNTN1. All the 11 antibody-positive patients (8 males and 3 females) presented with typical clinical features. Five of them needed assistance in walking, 5 had cranial nerve impairments and 3 had autonomic disturbances. The age at onset of the patients that were anti-NF155-positive was younger (19.60 ± 9.02 years vs. 55.33 ± 11.93 years, P = 0.003) than those that were anti-Caspr1-positive. No significant difference in the functional status was observed between these two groups. The action potentials of 11/79 (13.9 %) motor nerves and 62/93 (66.7 %) sensory nerves exhibited no response. Moreover, 16/68 (23.5 %) nerves presented conduction block and 13/68 (19.1 %) nerves presented temporal dispersion. Distal motor latency (DML) of ulnar nerve and tibial nerve tended to be longer (p = 0.008 and p = 0.006, respectively) in anti-NF155-positive patients than that in anti-Caspr1-positive patients. Of the 11 patients that were antibody-positive patients, corticosteroids were effective in 3/7 (42.9 %), intravenous immunoglobins (IVIG) were effective in 1/7 (14.3 %), and rituximab was effective in 6/8 (75.0 %). Our findings validate the previous observation on the clinico-serological correlation between CIDP and antibodies against nodal-paranodal proteins. Of note, the damage on nerves is more severe in anti-NF155-positive patients than that in anti-Caspr1-positive patients during electrophysiological diagnosis.


Vaccine-associated paralytic poliomyelitis in the Russian Federation in 1998-2014.
Different polio vaccination schemes have been used in Russia: oral polio vaccine (OPV) was used in 1998-2007 and inactivated polio vaccine (IPV) followed by OPV in 2008-2014. This article presents the characteristics of vaccine-associated paralytic poliomyelitis (VAPP) cases in Russia during this period. VAPP cases were identified through the acute flaccid paralysis surveillance system, classified by the National Expert Classification Committee. Criteria for a 'recipient VAPP' (rVAPP) case were poliomyelitis symptoms 6-30days after OPV administration, isolation of the vaccine virus, and residual paralysis 60days after disease onset. Unvaccinated cases with a similar picture 6-60days after contact with an OPV recipient were classified as 'contact VAPP' (cVAPP) cases. During 1998-2014, 127 VAPP cases were registered: 82 rVAPP and 45 cVAPP. During the period in which only OPV was used, rVAPP cases prevailed (73.8%); cases of rVAPP were reduced during the sequential scheme period (15%). Poliovirus type 3 (39.5%) and type 2 (23.7%) were isolated more often. Vaccine-derived poliovirus types 1, 2, and 3 were isolated from three cases of cVAPP. The incidence of VAPP cases was higher during the period of OPV use (1 case/1.59 million OPV doses) than during the sequential scheme period (1 case/4.18 million doses). The risk of VAPP exists if OPV remains in the vaccination schedule.


Modulating the poly-L-lysine structure through the control of the protonation-deprotonation state of L-lysine.
Designing the architecture of L-lysine-based polymeric structures is a highly challenging task that requires careful control of the amino acid reactive groups. Conventional processes to obtain branched polylysine need several steps and the addition of specific catalysts. In the present work, to gain a better understanding and control of the formation of L-lysine-based polymers, we have investigated the correlation between the protonation state of L-lysine and the corresponding hydrothermally grown structures. The samples have been characterized by combining optical spectroscopies, such as UV-Vis, fluorescence, and synchrotron radiation circular dichroism with structural analysis by Nuclear Magnetic Resonance, Fourier Transform Infrared spectroscopy, and dynamic light scattering. We have observed that aqueous precursor solutions with alkaline pHs promote the formation of branched structures. In contrast, high pHs favour the reactivity of the ε-amino groups leading to linear structures, as shown by circular dichroism analyses. On the other hand, acidic conditions trigger the branching of the amino acid. Interestingly, the polymeric forms of L-lysine emit in the blue because the increasing number of intermolecular hydrogen bonds promote the intermolecular charge transfer responsible for the emission. Understanding the correlation between the L-lysine charged states and the polymeric structures that could form controlling the protonation-deprotonation states of the amino acid opens the route to a refined design of polypeptide systems based on L-lysine.


Structure and function of choline kinase isoforms in mammalian cells.
Choline kinase (CK) catalyzes the first phosphorylation reaction in the CDP-choline pathway for the biosynthesis of phosphatidylcholine (PC), yielding phosphocholine (P-Cho) from choline and ATP in the presence of Mg(2+). This enzyme exists in mammalian cells as at least three isoforms that are encoded by two separate genes termed ck-alpha and ck-beta. Each isoform is not active in its monomeric form. The active enzyme consists of either their homo- or hetero-dimeric (or oligomeric) forms. In recent years, the roles of CK in cell growth and cell stress/defense mechanisms have been intensely investigated. These functions of CK do not seem to be directly related to the net PC biosynthesis but predict another important role of this enzyme in certain cell physiology. This review summarizes briefly the recent progress of mammalian CK study which will include the gene structure of each isoform and its possible transcriptional regulation, the active configuration of the enzyme, induction of the particular isoform in chemically induced cell stress, and the possible role of this enzyme as well as of its reaction product, P-Cho, in cell growth and other cellular physiology.


Multivariate studies on the genetics of dermal ridges.
In order to investigate the inheritance of the series of ten ridgecounts, factor analysis was used to reduce the dimensionability to two. These two factors are inherited more or less independently and the heritability of the first is 0.97.


SARS-CoV-2 surveillance in untreated wastewater: detection of viral RNA in a low-resource community in Buenos Aires, Argentina.
To measure SARS-CoV-2 RNA in sewage in a low-resource community in order to determine if it can be considered as an estimator of changes in the prevalence of COVID-19 in the population. In this descriptive observational study we collected samples of surface waters contaminated with sewage and optimized a method of purification of viral RNA using PEG concentration. We determined the amount of genetic material by quantitative real-time PCR using the CDC method for SARS-CoV-2 detection. We quantified viral RNA in surface waters contaminated with sewage of a low resource community and determined that temporal trends of SARS-CoV-2 in wastewater samples mirrored trends in COVID-19 active cases. Measuring of SARS-CoV-2 RNA in sewage can be applied in low-resource communities without connection to sewers as an estimator of changes in the prevalence of COVID-19.


Calcium regulation by SERC-A before and during Alzheimer disease
There are many factors involved in the incidence of Alzheimer's disease that, in combination, impede or hinder normal neuronal functions. Little is currently known about calcium regulation before and during the disease. Internal instability of calcium levels is associated with increased vascular risk, a prevalent condition in a high number of individuals already compromised by Alzheimer's disease. This review provides a reevaluation of the molecular mechanism of the sarcoendoplasmic reticulum calcium ATPase (SERC-A) in the disease and discusses salient aspects of voltage-gated calcium channel function; in these way new alternatives could be open for its treatment. These regulation mechanisms are clinically relevant since the irregular functions of SERC+A has been implicated in pathologies of brain function.


Glucanases and chitinases of Bacillus circulans WL-12.
Lysis of cell walls of various yeast species by beta-1.3- and beta-1,6-glucanases of Bacillus circulans WL-12 was investigated. Selective enzymolysis of cell walls of Pyricularia oryzae by single and combined actions of beta-1,3-,beta-1,6-glucanases and chitinase was followed. Chemical structure of the cell wall glucan of P. oryzae was determined by chemical and enzymatic methods. Multiple component nature of glucanases of B. circulans WL-12, their induction and lytic actions on cell walls of various yeasts were studied. Genes specifying glucanases and chitinases of B. circulans WL-12 were cloned in E. coli, and their nucleotide sequences were determined. Fibronectin type III modules were found in the chitinases. Functions of the domains of the deduced structures of the glucanases and the chitinases were studied by various methods including molecular genetic techniques.


137Cs budget during the period of 1960s in a small drainage basin on the Loess Plateau of China.
A sediment profile with a thickness of 28.12 m in a failed reservoir in a small catchment of the Yuntaishan Gully in the Loess Plateau of China consisted of 44 flood couplets deposited during the period from 1960 to 1970 with total volume of 2.36 x 10(6)m(3). Specific sediment yields for a flood event varied from 300 t km(-2) to 14,400 t km(-2) and annual sediment yields varied from 2500 t km(-2) in 1966 to 40,000 t km(-2) in 1964 with a mean value of 12,700 t km(-2)a(-1) for the period. Average annual (137)Cs concentrations of the sediments increased from 0.92 Bq kg(-1) in 1960 to 4.82 Bq kg(-1) in 1963, then decreased to 1.53 Bq kg(-1) in 1970. The total (137)Cs activity in the reservoir sediments was 9.22 x 10(9) Bq, which accounted for 31.9% of the total (137)Cs fallout precipitation of 2.89 x 10(10) Bq within the catchment during the period. The proportion of the (137)Cs loss from the catchment to the (137)Cs fallout precipitation within the catchment in a year varied between 8.01% and 66.8%, and it was 20.9% for the peak (137)Cs deposition year of 1963 and 52.0% in 1964. By analysis of the (137)Cs budget in the catchment for the (137)Cs peak precipitation period from 1962 to 1964, the (137)Cs surface enrichment coefficient Gamma should be much less than 0.23. And for calculation of soil losses on the cultivated land in the inter-gully area by using the Mass Balance Model II, the value of Gamma should be 0.05-0.1.


Effect of cholestyramine on bile acid kinetics in patients with portal cirrhosis of the liver. Evidence of a selective defect in the formation of cholic acid.
The kinetics of cholic acid (C) and chenodeoxycholic acid (CD) were studied in six patients with portal liver cirrhosis. The studies were conducted both before and after 5-6 weeks of treatment with cholestyramine (12 g/day). In keeping with previous observations, the pool size and formation of C showed subnormal values during the pretreatment period, while the production of CD was within normal limits. The pool sizes of C and CD did not change upon treatment with cholestyramine, but the mean total bile acid formation increased by a factor of about 2.5. The ratio between the amounts of C and CD synthesized remained essentially unchanged. Considering the therapeutic response previously observed in normal subjects and in patients with hyper-beta-lipoproteinemia, the present results suggest a selective impairment of the biosynthesis of C in patients with portal liver cirrhosis. It is suggested that the primary defect may reside in the 12alpha-hydroxylase enzyme system.


Traumatic injuries: organization and ergonomics of imaging in the emergency environment.
Management of trauma patients relies on a simple but obvious concept: Time is life! This is a challenge to the emergency radiologist in his evaluation of the radiological admission survey of severe trauma patients, since the latter need a quick and thorough survey of craniocerebral, cervical, thoracic, abdominal, and limb lesions. This article reviews the architectural design and the management strategies required to fulfill this purpose. Whereas plain films and ultrasonography have precise but limited indications, multislice spiral CT (MSCT) shows an increasingly preponderant role in the imaging evaluation of trauma patients, as demonstrated through three examples (aortic, spine, and craniocerebral trauma). Multislice CT affords a comprehensive assessment of trauma patients' injuries and allows for their categorization according to the severity of traumatic lesions. With respect to the MSCT data volume, the emergency radiologists have to modify the strategies in their examination reading and result transmission, with a growing role attributed to two- and three-dimensional reconstructions. The emergency radiologist's role is thus of prime importance in the management of trauma patients, and this all the more so since development of interventional radiology affords therapeutic procedures alternative to surgery. Trauma radiology and emergency radiology on the whole will assert themselves as consistent and thorough areas of subspecialization.


Biomechanical Assessment of the NIOSH Lifting Equation in Asymmetric Load-Handling Activities Using a Detailed Musculoskeletal Model.
To assess adequacy of the National Institute for Occupational Safety and Health (NIOSH) Lifting Equation (NLE) in controlling lumbar spine loads below their recommended action limits during asymmetric load-handling activities using a detailed musculoskeletal model, that is, the AnyBody Modeling System. The NIOSH committee employed simplistic biomechanical models for the calculation of the spine compressive loads with no estimates of the shear loads. It is therefore unknown whether the NLE would adequately control lumbar compression and shear loads below their recommended action limits during asymmetric load-handling activities. Twenty-four static stoop lifting tasks at different load asymmetry angles, heights, and horizontal distances were performed by one normal-weight (70 kg) and one obese (93 kg) individual. For each task, the recommended weight limit computed by the NLE and body segment angles measured by a video-camera system (VICON) were prescribed in the participant-specific models developed in the AnyBody Modeling System that estimated spinal loads. For both individuals, the NLE adequately controlled L5-S1 loads below their recommended action limits for all activities performed in upright postures. Both individuals, however, experienced compressive and/or shear L5-S1 loads beyond the recommended action limits when lifting was performed near the floor with large load asymmetry. The NLE failed to control spinal loads below the recommended limits during asymmetric lifting tasks performed near the floor. The NLE should be used with caution for extreme tasks involving load handling near the floor with large load asymmetry.


Erythropoietin increases hemoglobin in cancer patients during radiation therapy.
The hemoglobin (Hgb) level of patients during radiation therapy is associated with both survival and local tumor control in several organ sites. This clinical trial tested whether administering recombinant human erythropoietin (r-HuEPO) to cancer patients would increase their Hgb level during the course of radiation therapy without adverse effects. The 40 participating patients had a Hgb value < 13.5 g/dL and a malignant tumor located above the diaphragm without evidence of distant metastasis for which they were scheduled to undergo a 5-8 week course of daily radiation therapy. All 40 patients were given oral ferrous sulfate throughout their radiation therapy course. Half the patients also received 150-300 mg/kg of r-HuEPO subcutaneously three times per week starting 0-10 days prior to the first dose of radiation. The r-HuEPO and control groups did not differ significantly in patient age, gender, tumor type, initial hemoglobin, erythropoietin, or iron bioavailability. The Hgb level increased more than 6% during radiation therapy in all 20 of the r-HuEPO patients but in only 2/20 of the control patients (p < 0.001). The Hgb rose from a mean +/- standard deviation of 11.9 +/- 1.3 g/dL to > 14 g/dL during radiation therapy in 80% of the r-HuEPO group compared to in 5% of the control group (p < 0.001). The mean +/- s.d. change in Hgb concentration during radiation therapy was 27 +/- 15% (an average rise of 5% per week) in the r-HuEPO group and 0 +/- 6% in the control group (p < 0.001). r-HuEPO had no significant measurable effect on blood pressure, white blood cell, neutrophil or platelet count, or liver or renal function. The only reported adverse effect of r-HuEPO administration was an asymptomatic skin rash in one patient. r-HuEPO with ferrous sulfate significantly increased the Hgb level in cancer patients without interfering with their course of radiation therapy, whereas ferrous sulfate alone did not. r-HuEPO appears to be a safe and effective means of increasing red cell mass during radiation therapy.


Bilateral masseter and internal pterygoid muscle hypertrophy: a diagnostic challenge.
To describe an unusual case of bilateral masseter and pterygoid muscle hypertrophy. A 53-year-old female patient presented with a bilateral, painless swelling at the parotid areas without improvement after using antibiotics/systemic corticosteroids/nonsteroidal anti-inflammatory agents. Her medical history included thyroid nodules, but no dental/occlusal disorders were observed. The initial differential diagnosis included salivary gland/jaw bone/masseter pathology, but the CT/MRI revealed only an increase in the size of the masseter and pterygoid muscles. The patient was informed of the benign nature of the swelling and was advised to discontinue the use of nonsteroidal anti-inflammatory agents. The bilateral hypertrophy of masseter muscles should be considered in differential diagnosis in cases of unilateral or bilateral swelling of the parotid or lateral mandible area.


Skin Cancer Risk (Nonmelanoma Skin Cancers/Melanoma) in Vitiligo Patients.
The relative genetic and immune protection against melanoma and nonmelanoma skin cancers in those with vitiligo is reassuring. The results of recent studies allow us to be cautiously optimistic when discussing the risk of skin cancer caused by therapeutic exposure to narrow-band ultraviolet B light. However, we should continue to recommend sun protection at all other times to avoid burning in vitiliginous skin and to decrease incidental ultraviolet exposure. It is also important to perform full skin checks regularly in light of the prolonged courses of phototherapy required to repigment vitiliginous skin and maintain repigmentation thereafter.


Near-IR Fluorescent Recognition of Arginine: High Chemoselectivity and Enantioselectivity Promoted by La3.
The first near IR fluorescent probe for the chemoselective and enantioselective recognition of arginine in aqueous solution is reported in this work. This probe, made of a 1,1'-binaphthyl-based chiral aldehyde unit and a rhodamine-based near IR chromophore, in combination with La3+ exhibits highly chemoselective as well as enantioselective fluorescent enhancement with arginine at λ=764 nm upon excitation at λ=690 nm. Little or no fluorescent response is observed toward the chirality miss-matched arginine enantiomer or other common amino acids and their enantiomers. This probe also allows visual discrimination of the arginine enantiomers because of its fast and distinct color change upon interaction with the substrate.


Women's experiences following emergency Peripartum hysterectomy at St. Francis hospital Nsambya. A qualitative study.
Emergency peripartum hysterectomy (EPH) is a known remedy for saving women's lives when faced with the challenging situation of severe post partum hemorrhage not responsive to conservative management. However, EPH by its nature is also a traumatic birth event that causes serious physical, emotional and psychological harm. Unfortunately at St. Francis Hospital Nsambya nothing much is known about these experiences since no study has been undertaken and these women are not routinely followed up. The purpose of this study was to explore these emotional experiences. This was a qualitative phenomenological study carried out between August and December 2018. All those women who had undergone EPH between January 2015 and August 2018 were eligible to participate in the study. Purposive sampling was used. 18 women were interviewed before saturation was reached. All interviews were audio-recorded and then transcribed verbatim. Thematic analysis was used to analyze the data. Three major themes were identified as the main experiences of these women in this study and they were; Loss of Womanhood, Joy for being alive and Loss of marital safety. Women experience serious emotional consequences following EPH. We recommend routine follow-up to help appreciate these experiences and advise them on appropriate mitigating measures.


Measuring technical efficiency in health care organizations.
The rising cost of health care has created great interest in developing methods to increase the efficiency of health care organizations. Despite this interest most analyses of prospective payment and other programs designed to control expenditures have examined costs and not efficiency. This article examines a new technique--data envelopment analysis (DEA)--that facilitates the conduct of efficiency studies. The utility of DEA is analyzed by comparing this technique with other methods used to measure efficiency, by discussing the application of DEA in the health care industry and by assessing the validity of results from DEA studies. The article concludes with an assessment of the strengths and weaknesses of DEA and suggestions for refining this technique.


Amniotic fluid phosphatidylinositol and phosphatidylglycerol. I. Normal pregnancies.
Phosphatidylinositol (PI) and phosphatidylglycerol (PG) appear normally in the amniotic fluid during the last weeks of pregnancy. The present study indicated as have previous studies (5, 6, 8, 10) that these phospholipids are linked to the surfactant system in the fetal lung. The concentrations of lecithin (L), PI, PG and sphingomyelin (S) were measured in 207 samples from 165 normal pregnancies. The augmentation in PI was found to parallel that in lecithin, and the PI/S ratios reached maximum values at about 30 weeks of gestation. The augmentation in PG appeared about two weeks later. Eleven premature infants who contracted respiratory distress syndrome (RDS) had significantly lower PG concentrations than 15 premature infants with no RDS (p less than 0.01). No correlation to the PI concentrations could be observed. All but one of the 11 affected infants had low L/S ratios.


Treatment of nonunion of the forearm bones with posterior interosseous bone flap.
Reconstructions of forearm fracture nonunions are frequently complex. A few studies that help guide the treatment of forearm nonunion have been reported. We offer a novel surgical technique to treat nonunion of the forearm using a regional vascularized bone graft. Four females and 5 males ranging from 27 to 74 years of age with 7 ulna and 2 radius nonunions were surgically treated by pedicle grafting with a posterior interosseous bone flap (PIBF) and internal fixation with a plate. There were no cases with extensive soft tissue damage or infection. Pre- and postoperatively (mean 21 months), all patients were assessed by radiographs and for function by the Disabilities of the Arm, Shoulder and Hand (DASH) score. Function of the upper extremity was improved in all patients. DASH scores improved from 61.2 points pre-operatively to 12 points at final follow-up. All nonunions were united uneventfully. Following debridement of the necrotic tissue, the bone defect can be filled with a vascularized graft from posterior interosseous pedicles. Pedicled PIBF is a safe and useful novel technique in cases of atrophic or hypertrophic nonunion of the middle third of the radius or proximal two-thirds of the ulna.


Cell suspensions from rat olfactory neuroepithelium: biochemical and histochemical characterization.
Cell suspensions were generated from rat olfactory epithelium by digestion with collagenase and hyaluronidase followed by gentle mechanical disruption. These cell suspensions excluded nigrosin dye and synthesized RNA, protein and carnosine from radiolabeled precursors. Sustentacular cells, repiratory epithelial cells and olfactory neurons but not basal cells could be identified by phase-contrast microscopy. Sedimentation of these cell suspensions at unit gravity in discontinuous gradients of buffered bovine serum albumin resulted in partial separation of the various cell types as indicated by the distribution of several biochemical markers. Olfactory marker protein and carnosine synthetase activity were found in the upper gradient fractions, while carnosinase activity was present predominantly in the lower gradient fractions. Cellular localization of olfactory neuron marker protein and non-neuronal S-100 protein by immunoperoxidase staining of gradient-fractionated cells indicated that neuronal cells were only partially separated from non-neuronal cells by our fractionation techniques. Evaluation of gradient fractionated cells by histochemical staining for carbohydrates demonstrated that secretory Bowman's gland cells were quite efficiently separated from neurons. This study demonstrates the ease with which cell suspensions may be produced from the olfactory epithelium, and emphasizes the importance of utilizing both biochemical and histochemical approaches in studies of mixed populations of cells, particularly when the purity of the cell fractions is a consideration.


Zero-fluoroscopy cryothermal ablation of atrioventricular nodal re-entry tachycardia guided by endovascular and endocardial catheter visualization using intracardiac echocardiography (Ice&ICE Trial).
Stochastic damage of the ionizing radiation to both patients and medical staff is a drawback of fluoroscopic guidance during catheter ablation of cardiac arrhythmias. Therefore, emerging zero-fluoroscopy catheter-guidance techniques are of great interest. We investigated, in a prospective pilot study, the feasibility and safety of the cryothermal (CA) slow-pathway ablation in patients with symptomatic atrioventricular-nodal-re-entry-tachycardia (AVNRT) using solely intracardiac echocardiography (ICE) for endovascular and endocardial catheter visualization. Twenty-five consecutive patients (mean age 55.6 ± 12.0 years, 17 female) with ECG-documentation or symptoms suggesting AVNRT underwent an electrophysiology study (EPS) in our laboratory utilizing ICE for catheter navigation. Supraventricular tachycardia was inducible in 23 (92%) patients; AVNRT was confirmed by appropriate stimulation maneuvers in 20 (80%) patients. All EPS in the AVNRT subgroup could be accomplished without need for fluoroscopy, relying solely on ICE-guidance. CA guided by anatomical location and slow-pathway potentials was successful in all patients, median cryo-mappings = 6 (IQR:3-10), median cryo-ablations = 2 (IQR:1-3). Fluoroscopy was used to facilitate the trans-septal puncture and localization of the ablation substrate in the remaining 3 patients (one focal atrial tachycardia and two atrioventricular-re-entry-tachycardias). Mean EPS duration in the AVNRT subgroup was 99.8 ± 39.6 minutes, ICE guided catheter placement 11.9 ± 5.8 minutes, time needed for diagnostic evaluation 27.1 ± 10.8 minutes, and cryo-application duration 26.3 ± 30.8 minutes. ICE-guided zero-fluoroscopy CA in AVNRT patients is feasible and safe. Real-time visualization of the true endovascular borders and cardiac structures allow for safe catheter navigation during the ICE-guided EPS and might be an alternative to visualization technologies using geometry reconstructions.


The action of piracetam in ischaemic flaps.
The effects of piracetam on skin flap viability, capillary blood flow and temperature were studied in abdominal cutaneous flaps in rats. The drug significantly increased the viability of the distal (random) portion of the flap and this response was dose-related. Compared with controls, the area of skin necrosis was 12.4% less in the piracetam-treated animals and extended necrosis was not observed. Piracetam appeared to act by increasing the capillary blood flow, mainly in the distal portion of the flap. The improved perfusion was reflected as a smaller drop in the recorded temperature compared with controls. Blood levels of this drug in animals receiving the maximum effective dose corresponded to the active drug concentration in human rheology.


Increased iron-stress resilience of maize through inoculation of siderophore-producing Arthrobacter globiformis from mine.
Iron deficiency is common among graminaceous crops. Ecologically successful wild grasses from iron-limiting habitats are likely to harbour bacteria which secrete efficient high-affinity iron-chelating molecules (siderophores) to solubilize and mobilize iron. Such siderophore-producing rhizobacteria may increase the iron-stress resilience of graminaceous crops. Considering this, 51 rhizobacterial isolates of Dichanthium annulatum from iron-limiting abandoned mine (∼84% biologically unavailable iron) were purified and tested for siderophore production; and efficacy of Arthrobacter globiformis inoculation to increase iron-stress resilience of maize and wheat was also evaluated. 16S rRNA sequence analyses demonstrated that siderophore-producing bacteria were taxonomically diverse (seven genera, nineteen species). Among these, Gram-positive Bacillus (eleven species) was prevalent (76.92%). A. globiformis, a commonly found rhizobacterium of graminaceous crops was investigated in detail. Its siderophore has high iron-chelation capacity (ICC: 13.0 ± 2.4 μM) and effectively dissolutes diverse iron-complexes (FeCl3 : 256.13 ± 26.56 μM/ml; Fe2 O3 red: 84.3 ± 4.74 μM/ml; mine spoil: 123.84 ± 4.38 μM/ml). Siderophore production (ICC) of A. globiformis BGDa404 also varied with supplementation of different iron complexes. In plant bioassay with iron-deficiency sensitive species maize, A. globiformis inoculation triggered stress-associated traits (peroxidase and proline) in roots, enhanced plant biomass, uptake of iron and phosphate, and protein and chlorophyll contents. However, in iron deficiency tolerant species wheat, growth improvement was marginal. The present study illustrates: (i) rhizosphere of D. annulatum colonizing abandoned mine as a "hotspot" of siderophore-producing bacteria; and (ii) potential of A. globiformis BGDa404 inoculation to increase iron-stress resilience in maize. A. globiformis BGDa404 has the potential to develop as bioinoculant to alleviate iron-stress in maize.


Comparison of wire-guided localization (WGL) and radio-guided occult lesion localization (ROLL) in localization of non-palpable breast lesions.
The number of patients with non-palpable breast lesions has increased gradually. This is because of the technological development in imaging techniques and the screening programs that lead to early detection of breast lesions. The number of patients with non-palpable breast lesions has increased gradually. This is because of the technological development in imaging techniques and the screening programs that lead to early detection of breast lesions. The aim of marking the non-palpable breast lesions is to achieve accurate lesion localization, to obtain the better cosmetic result with less tissue loss and to provide negative surgical margin. In the current study, we aimed to compare the wire-guided localization (WGL) technique with the radio-guided occult lesion localization (ROLL) technique to assess their accuracy and efficacy in non-palpable breast lesions localization. This is a retrospective study conducted at Baheya center for Early Detection and Treatment of Breast Cancer from January 2018 and June2022,where 670 patients with non-palpable breast lesions underwent an excision were enrolled randomly in ROLL group (n = 320) and WGL (n = 350). Both the localization time and the time of operation were significantly decreased with the ROLL in comparison to WGL(P < 0.001). Complete lesion excision with clear margins were reported in 119/135(88.2%) of ROLL group and in 130/159 (81.8%) of WGL group and the difference was significant (P < 0.001). Reoperations (re-lumpectomy or mastectomy) were done as a second procedure on 16(11.8%) of the ROLL patients compared with 29(18.2%) in the WGL patients(P < 0.001). This study shows that ROLL is as effective as WGL for non-palpable breast lesions excision. Also, ROLL improve the outcomes by decreasing the duration of surgery, localization time, achieving a higher percentage of clear margin in spite of lower specimen size and scar length.


Long-term outcome after Bascom's cleft-lift procedure under tumescent local analgesia for pilonidal sinus disease: a cohort study.
Bascom's cleft-lift procedure for pilonidal sinus disease under tumescent local analgesia is feasible and well tolerated with favourable short-term outcomes. We aimed to assess the 10-year treatment success rate after cleft-lift under tumescent local analgesia. This was a single-centre cohort study based on prospectively registered perioperative data and survey data with additional data from electronic medical records. The cleft-lift procedure was performed under tumescent local analgesia in a day-surgical setting at a tertiary referral hospital between 1 July 2008 and 31 March 2014. The primary outcome was the 10-year risk treatment success defined as complete wound healing within 180 days of surgery or no recurrence assessed with competing risk analyses. Secondary outcomes were time to complete wound healing, persistent pain and cosmetic satisfaction. Two hundred patients with complex pilonidal sinus disease were included. Indication was incomplete wound healing after pilonidal sinus surgery in 43 (21.5%) patients, recurrence after previous intervention in 78 (39.0%) or moderate to complex sinuses assessed by a consultant surgeon in 79 (39.5%). One hundred and ninety-five patients had complete wound healing within 180 days with a median time of 29 days (interquartile range 16-47). The cumulative risk of 10-year recurrence was 11.3% (95% CI 6.2%-16.4%) with a median follow-up time of 8.5 (1.0-10.7) years. Treatment success was 86.1% (95% CI 80.6%-91.5%). No significant predictors were associated with recurrence, and 90% of patients experienced no persistent pain. Cleft-lift performed under tumescent local analgesia has an acceptable 10-year treatment failure rate, making the method feasible in a day-surgery setting.


Endometriosis Cell Proliferation Induced by Bone Marrow Mesenchymal Stem Cells.
Endometriosis is an estrogen-dependent gynecological disorder that affects 10% of reproductive-aged women and causes pelvic pain and infertility. Bone marrow-derived stem cells (BMDCs) are known to engraft endometriosis in association with lesion growth; however, they do not undergo significant clonal expansion. The indirect effects of BMDCs on endometriosis growth and cell proliferation are not well characterized. Here, we demonstrate that BMDCs' co-culture increased endometrial stromal cell proliferation. In vitro studies using endometrial cells showed that BMDCs increased cell proliferation and activation of CDK1 in both an endometriosis cell line and primary endometrial stromal cells from women with endometriosis, however not in normal endometrial cells. In vivo studies using a mouse model of endometriosis showed increased CDK1+ expression associated with engrafted GFP + BMDCs. These results suggest that endometrial cell proliferation is induced by stem cell-derived trophic factors leading to the growth of endometriotic lesions. Targeting the specific signaling molecules secreted by BMDC may lead to novel therapeutic strategies for controlling cell proliferation in endometriosis.


Value of transurethral biopsy in the diagnosis of carcinoma of the prostate.
Needle biopsy, as a simple and reliable method, has been in use for the microscopic diagnosis of carcinoma of the prostate. On the evidence of published observations and of the present study, transurethral biopsy is regarded as a useful supplementary procedure, 10 per cent of the malignant tumours of the prostate being inaccessible to the other current biopsy techniques. The cases in which it has been found to be of particular diagnostic value include 1. carcinoma of the prostate arising from the anterior lobe or from the periurethral area; 2. occult carcinoma: 3. negativity of successive needle biopsies in spite of clinical suspicion of prostatic carcinoma; 4. malignant growth involving the neck of the bladder when cystoscopy fails to identify its primary site.


Barcode-free next-generation sequencing error validation for ultra-rare variant detection.
The advent of next-generation sequencing (NGS) has accelerated biomedical research by enabling the high-throughput analysis of DNA sequences at a very low cost. However, NGS has limitations in detecting rare-frequency variants (< 1%) because of high sequencing errors (> 0.1~1%). NGS errors could be filtered out using molecular barcodes, by comparing read replicates among those with the same barcodes. Accordingly, these barcoding methods require redundant reads of non-target sequences, resulting in high sequencing cost. Here, we present a cost-effective NGS error validation method in a barcode-free manner. By physically extracting and individually amplifying the DNA clones of erroneous reads, we distinguish true variants of frequency > 0.003% from the systematic NGS error and selectively validate NGS error after NGS. We achieve a PCR-induced error rate of 2.5×10-6 per base per doubling event, using 10 times less sequencing reads compared to those from previous studies.


A first-principles calculation of structural, mechanical, thermodynamic and electronic properties of binary Ni-Y compounds.
The intermetallic compounds between rare earth (RE) elements and transition metal elements have been comprehensively researched due to their appealing magnetic, electronic, optical and thermal properties, in which Ni-Y alloys are one kind of important system. In this work, a systematic investigation concerned with structures, elastic, and thermodynamic properties of Ni17Y2, Ni5Y, Ni7Y2, Ni3Y, Ni2Y, NiY, Ni2Y3 and NiY3 in Ni-Y systems is implemented by means of first-principles calculations. NiY has the lowest formation enthalpy within -0.49 kJ per mol per atom. Ni5Y has the largest bulk modulus, shear modulus and Young's modulus of 181.71 GPa, 79.75 GPa and 208.70 GPa, respectively. Furthermore, the effects of different concentrations of yttrium on the mechanical and thermal properties of Ni-Y compounds are estimated by using the Voigt-Reuss method. The electronic density of states and chemical bonding between Ni and Y are key factors that determine mechanical and thermodynamic properties of these compounds. What's more, results indicate that all compounds are dynamically stable as shown by the calculated phonon dispersions.


Reaching the malaria elimination goal in Brazil: a spatial analysis and time-series study.
Since 2015, the Global Technical Strategy (GTS) for Malaria 2016-2030 has been adopted by the World Health Organization (WHO) as a comprehensive framework to accelerate progress for malaria elimination in endemic countries. This strategy sets the target of reducing global malaria incidence and mortality rates by 90% in 2030. Here it is sought to evaluate Brazil's achievements towards reaching the WHO GTS milestone in 2030. Considering the total number of new malaria cases in 2015, the main research question is: will Brazil reach the malaria elimination goal in 2030? Analytical strategies were undertaken using the SIVEP-malaria official databases of the Brazilian Malaria Control Programme for the Brazilian Amazon region from 2009 to 2020. Spatial and time-series analyses were applied for identifying municipalities that support the highest numbers of malaria cases over the years. Forecast analysis was used for predicting the estimated number of new cases in Brazil in 2025-2050. Brazil has significantly reduced the number of new malaria cases in 2020 in comparison with 2015 in the states of Acre (- 56%), Amapá (- 75%), and Amazonas (- 21%); however, they increased in the states of Pará (156%), Rondônia (74%), and Roraima (362%). Forecast of the predicted number of new malaria cases in 2030 is 74,764 (95% CI: 41,116-141,160) in the Brazilian Amazon. It is likely that Brazil will reduce the number of new malaria cases in the Brazilian Amazon in 2030 in relation to that in 2015. Herein forecast shows a reduction by 46% (74,754 in 2030 forecast/137,982 in 2015), but this reduction is yet far from the proposed reduction under the WHO GTS 2030 milestone (90%). Stable and unbeatable transmission in the Juruá River Valley, Manaus, and Lábrea still support endemic malaria in the Brazilian Amazon. Today's cross-border malaria is impacting the state of Roraima unprecedently. If this situation is maintained, the malaria elimination goal (zero cases) may not be reached before 2050. An enhanced political commitment is vital to ensure optimal public health intervention designs in the post-2030 milestones for malaria elimination.


Metrological capability of the Brazilian laboratories of analyses of radionuclides in environmental samples.
The metrological capability of 24 Brazilian laboratories of radionuclide determinations in environmental samples was analysed for purposes to establish requirements for accreditation of laboratory for each radionuclide. For each type of analysis, the range of activity per unit mass or volume, the range of the reference value and its correspondent uncertainty were described. The accuracy was established using the statistical criteria of USE.P.A. for the laboratory performance classification. The precision of the analyses, expressed by its variation coefficient of the laboratory determinations, was classified in intervals of 5%. The data base was constituted by 3013 results of analyses obtained in 28 intercomparison runs performed from 1991 to 2000, for K, Th, Unat, gross alpha, gross beta, and other 27 radionuclides, in matrices of water, soil, vegetation, air filter and milk. The quality criteria established were the variation coefficient less than 5% and good performance in intercomparison runs. Results included from 5% to 10% are also considered, for special types of matrices and radionuclides.


Demonstration of a circulating autoantibody against a soluble eye-muscle antigen in Graves' ophthalmopathy.
Mouse monoclonal antibodies against antigens in human eye muscle, orbital connective tissue, and lacrimal tissue and guineapig harderian gland have been produced by means of the hybridisation technique. From 14 fusions, over 30 antibodies have been produced, of which 24 have been maintained and characterised for the present studies. All were IgG1. Most were organ-specific, but eye-muscle antibodies tended to cross-react with skeletal muscle, one eye-muscle antibody cross-reacted with thyroidal microsomes, and both lacrimal monoclonal antibodies reacted strongly with mucus-secreting cells in human small intestine. Only one of the antibodies fixed complement. Orbital monoclonal antibodies were used as probes to identify orbital antigens. Most antigens were in the cytosol fraction, but a few were demonstrated in cytoplasmic membranes. Circulating autoantibodies against a human-eye-muscle soluble antigen were detected in 17 of 23 patients with Graves' ophthalmopathy but in only 1 of 14 patients with Hashimoto's thyroiditis, in 2 of 11 patients with subacute thyroiditis, in no patient with Graves' hyperthyroidism without eye disease, and in none with multinodular goitre.


Comparative genomics analysis of WAK/WAKL family in Rosaceae identify candidate WAKs involved in the resistance to Botrytis cinerea.
Wall associated kinase (WAK) and WAK-like (WAKL) are typical pattern recognition receptors act as the first sentry of plant defense. But little of WAK/WAKL family is known in Rosaceae. In this study, 131 WAK/WAKL genes from apple, peach and strawberry were identified using a bioinformatics approach. Together with 68 RcWAK/RcWAKL in rose, we performed a comparative analysis of 199 WAK/WAKL in four Rosaceae crops. The phylogenetic analysis divided all the WAK/WAKL into five clades. Among them, the cis-elements of Clade II and Clade V promoters were enriched in jasmonic acid (JA) signaling and abiotic stress, respectively. And this can also be verified by the rose transcriptome responding to different hormone treatments. WAK/WAKL families have experienced a considerable proportion of purifying selection during evolution, but still 26 amino acid sites evolved under positive selection, which focused on extracellular conserved domains. WAK/WAKL genes presented collinearity relationship within and between crops, throughout four crops we mined four orthologous groups (OGs). The WAK/WAKL genes in OG1 and OG4 were speculated to involve in plant-Botrytis cinerea interaction, which were validated in rose via VIGS as well as strawberry by qRT-PCR. These results not only provide genetic resources and valuable information for the evolutionary relationship of WAK/WAKL gene family, but also offer a reference for future in-depth studies of Rosaceae WAK/WAKL genes.


Increased expression and phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoforms in urinary exosomes in pre-eclampsia.
Glycolysis is altered in various kidney diseases, but little is known about glycolysis in pre-eclampsia, a multi-system disorder with major pathological effects on the kidney. Urinary exosomes provide a non-invasive alternative for studying changes in kidney metabolism. This study aims to characterise the expression and phosphorylation of isozymes of the key glycolytic regulatory protein, 6-phosphofructokinase-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2), in urinary exosomes of subjects with pre-eclampsia (PE), compared to normotensive non-pregnant (NC) and normotensive pregnant (NP) controls. A cross-sectional study of NC (n = 19), NP (n = 23) and PE (n = 29) subjects was performed. Exosomes were isolated from urine samples by differential ultracentrifugation, and then analyzed by Western blot and densitometry for expression of PFK-2/FBPase-2 isozymes (PFKFB2, PFKFB3 and PFKFB4) and phosphorylation of PFKFB2 at residues Ser483 and Ser466 and PFKFB3 at Ser461. PFKFB2 expression was increased 4.7-fold in PE compared to NP (p < 0.001). PFKFB2 phosphorylation at Ser483 was increased 2.6-fold in PE compared to NP (p = 0.002). Expression of phosphorylated PFKFB2/PFKFB3 at Ser466/Ser461 was increased in PE, being present in 77.4% (95% CI 59.9-88.9%) of PE and 8.3% (95% CI 1.2-27.0%) of NP samples (p < 0.001). PFKFB3 was more commonly expressed in PE, detected in 90.3% (95% CI 74.3-97.4%) of PE and 8.3% (95% CI 1.2-27.0%) of NP samples (p < 0.001). PFKFB4 had a 7.2-fold increase in expression in PE compared to NP (p < 0.001). No significant differences between NP and NC groups were observed. Regulatory proteins that increase glycolysis are increased in the urinary exosomes of subjects with pre-eclampsia, suggesting that renal glycolysis may be increased in this condition.


Kidney transplantation of living unrelated and ABO-incompatible donor-recipient combinations.
In Japan, ABO-incompatible (ABO-IC) living kidney transplantation (LKT) has been performed among more than 2000 patients between 1989 and 2010 seeking to compensate for the shortage of donor organs. In addition, many patients lack a genetically living related donor (LRD); therefore, volunteer spouses (unrelated, LURD) have been considered since about 1990. We performed 112 LKT between April 2003 and March 2011, including 44 (39%) spousal and two other LURD. The other 66 cases received LRD kidneys. We divided patients into two groups: 44 patients (group 1) received a kidney from a spouse (LURD) and 66 (group 2) from LRD. During the induction phase, tacrolimus or cyclosporine, mycophenolate mofetil, and methylprednisolone were prescribed for immunosuppression. Basiliximab was administered on postoperative days 0 and 4. For ABO-IC LKT, plasmapheresis was performed to remove anti-AB antibodies prior to LKT. Splenectomy was performed at the time of or before LKT. Since March 2010, rituximab administration was performed before transplantation instead of splenectomy. Death-censored graft survival rates were 97.7% in group 1 and 98.5% in group 2, respectively. The incidences of acute rejection episodes were 31.8% and 24.2% in groups 1 and 2, respectively. There were three cases of antibody-mediated rejection in group 1. No patient experienced a lethal infectious complication. Our results demonstrated that spousal LKT (LURD) was equivalent to LRD. In response to the shortage of deceased donors and genetically LRD, LKT between married couples or from ABO-IC donors will spread in Japan.


Reactogenicity, immunogenicity and breakthrough infections following heterologous or fractional second dose COVID-19 vaccination in adolescents (Com-COV3): A randomised controlled trial.
This was the first study to investigate the reactogenicity and immunogenicity of heterologous or fractional second dose COVID-19 vaccine regimens in adolescents. A phase II, single-blind, multi-centre, randomised-controlled trial recruited across seven UK sites from September to November 2021, with follow-up visits to August 2022. Healthy 12-to-16 years olds were randomised (1:1:1) to either 30 µg BNT162b2 (BNT-30), 10 µg BNT162b2 (BNT-10), or NVX-CoV2373 (NVX), 8 weeks after a first 30 µg dose of BNT162b2. The primary outcome was solicited systemic reactions in the week following vaccination. Secondary outcomes included immunogenicity and safety. 'Breakthrough infection' analyses were exploratory. 148 participants were recruited (median age 14 years old, 62% female, 26% anti-nucleocapsid IgG seropositive pre-second dose); 132 participants received a second dose. Reactions were mostly mild-to-moderate, with lower rates in BNT-10 recipients. No vaccine-related serious adverse events occurred. Compared to BNT-30, at 28 days post-second dose anti-spike antibody responses were similar for NVX (adjusted geometric mean ratio [aGMR]) 1.09 95% confidence interval (CI): 0.84, 1.42] and lower for BNT-10 (aGMR 0.78 [95% CI: 0.61, 0.99]). For Omicron BA.1 and BA.2, the neutralising antibody titres for BNT-30 at day 28 were similar for BNT-10 (aGMR 1.0 [95% CI: 0.65, 1.54] and 1.02 [95% CI: 0.71, 1.48], respectively), but higher for NVX (aGMR 1.7 [95% CI: 1.07, 2.69] and 1.43 [95% CI: 0.96, 2.12], respectively). Compared to BNT-30, cellular immune responses were greatest for NVX (aGMR 1.73 [95% CI: 0.94, 3.18]), and lowest for BNT-10 (aGMR 0.65 [95% CI: 0.37, 1.15]) at 14 days post-second dose. Cellular responses were similar across the study arms by day 236 post-second dose. Amongst SARS-CoV-2 infection naïve participants, NVX participants had an 89% reduction in risk of self-reported 'breakthrough infection' compared to BNT-30 (adjusted hazard ratio [aHR] 0.11 [95% CI: 0.01, 0.86]) up until day 132 after second dose. BNT-10 recipients were more likely to have a 'breakthrough infection' compared to BNT-30 (aHR 2.14 [95% CI: 1.02, 4.51]) up to day 132 and day 236 post-second dose. Antibody responses at 132 and 236 days after second dose were similar for all vaccine schedules. Heterologous and fractional dose COVID-19 vaccine schedules in adolescents are safe, well-tolerated and immunogenic. The enhanced performance of the heterologous schedule using NVX-CoV2373 against the Omicron SARS-CoV-2 variant suggests this mRNA prime and protein-subunit boost schedule may provide a greater breadth of protection than the licensed homologous schedule. National Institute for Health Research and Vaccine Task Force. International Standard Randomised Controlled Trial Number registry: 12348322.


Increased bioactive TNF in human systemic lupus erythematosus: associations with cell death.
In systemic lupus erythematosus (SLE) serum TNF is increased and correlates with its soluble receptors and with disease activity. We therefore investigated (i) whether the TNF in SLE serum is bioactive, (ii) whether SLE cells react to TNF and (iii) whether there are associations with cell death, which is regarded as pathogenic in SLE. Sera from active SLE patients induced an increase in fibroblast CD54, which was abolished by blocking antibodies against TNF, suggesting TNF bioactivity. SLE lymphocytes had a similar surface expression of TNF-RI as healthy lymphocytes, their expression of TNF-RII was slightly increased. Recombinant TNF induced cell death in PBMC of SLE patients, suggesting functional receptors. Serum levels of sTNF-RII (as a surrogate marker for TNF activity) correlated with sTNF-RI and disease activity, as expected, and also correlated with the percentage of dying lymphocytes and with lymphocytic CD95. SLE sera contain increased amounts of biologically active TNF. Peripheral blood lymphocytes of SLE patients express functional TNF receptors. Finally, associations with cell death and CD95 receptors suggest that TNF may be pathogenic in SLE.


GSTT1 and GSTM1 gene deletions are not associated with hepatotoxicity caused by antitubercular drugs.
Susceptibility to antitubercular drug (ATD)-induced hepatotoxicity may be genetically mediated, with variant alleles of genes such as N-acetyltransferase (NAT2) and CYP2E1 reported as risk factors. Two studies of Asian populations have reported that GSTM1*0 ⁄ *0 (null) genotype was a likely predictor of hepatotoxicity, whereas another of a Caucasian population implicated GSTT1*0 ⁄ *0. We undertook a prospective case-control study to investigate whether GSTM*0 ⁄ *0 and GSTT1*0 ⁄ *0 were risk factors for ATD-induced hepatotoxicity. Pulmonary tuberculosis patients on isoniazid, rifampicin and pyrazinamide who developed hepatotoxicity using defined criteria were prospectively identified. These cases were then matched with at least one control subject on the same drugs but without hepatotoxicity. Genotyping for GSTM1 and GSTT1 was performed by multiplex PCR on genomic DNA. The odds ratios for the frequency of specific GSTM1 and GSTT1 homozygotes in the case and control subjects were calculated to test for association between the genotypes and hepatotoxicity. Hundred and fifty-one subjects (51 cases, 100 controls) were enrolled. Odds ratio for GSTM1 null genotype was 1.00 (95% CI 0.51-1.97) and GSTT1 null was 2.02 (95% CI 0.39-10.39), respectively, showing that these genotypes are not associated with hepatotoxicity. GSTM1 *0 ⁄ *0 or GSTT1 *0 ⁄ *0 or both null genotypes, do not appear to be associated with ATD-induced hepatotoxicity in our Indian population.


Sodium Intake Requirements for Preterm Neonates: Review and Recommendations.
It is widely accepted that sodium is an essential nutritional electrolyte and its deficiency is associated with neurological sequelae and poor growth. The provision of an adequate sodium intake to preterm neonates is hampered by the technical difficulty in clinically assessing total body sodium content. As addressed in this review, there is a lack of consensus on the definition of hyponatremia early in life, but there is no evidence that it should deviate from the widely accepted normative data for adult subjects. A low urinary sodium content is accepted by many as reflecting total body sodium deficiency, yet spot urinary sodium measurements are of questionable clinical value. The hormonal regulation of sodium homeostasis is here reviewed and the mechanism accounting for sodium deficiency-induced growth impairment in preterm infants addressed. Lastly, we provide evidence-based gestational and postnatal age-dependent recommendations for the provision of adequate sodium intake to preterm neonates.


Mechanism of androgen-receptor augmentation. Analysis of receptor synthesis and degradation by the density-shift technique.
The ductus deferens smooth muscle tumor cell line (DDT1MF-2) contains receptors for, and is stimulated by, androgens. Cells cultured in the absence of androgens maintain a basal level of androgen receptors. Following incubation with various concentrations of the synthetic androgen methyltrienolone (R1881) for 1-6 h, the concentration of these receptors increased from 6.0 to 12.2 fmol/micrograms of DNA, while the equilibrium dissociation constant (Kd) of 0.5 nM for this steroid remained unchanged. The steroid-induced increase in androgen receptor levels was specific for androgens and dependent upon protein synthesis. The mechanism of receptor augmentation was examined by utilization of isotopically dense amino acids to determine rates of receptor appearance and degradation in the presence or absence of [3H]R1881. In the absence of androgens, the half-life of the androgen receptor was 3.1 h, with a rate constant (kD) of 0.22/h. In the presence of 1 nM [3H]R1881, however, the half-life was 6.6 h, with kD = 0.11/h. The rate constant for receptor synthesis (ks) in the absence or presence of [3H]R1881 was calculated to be 1.35 and 2.23 fmol/micrograms of DNA/h, respectively. Thus, androgen-induced androgen-receptor augmentation is explained by an increase both in receptor half-life and in rates of receptor synthesis.


The influence of estrogen therapies on bone mineral density in premenopausal women with anorexia nervosa and amenorrhea.
Low bone mineral density is one of the primary risks of chronic amenorrhea, and the effects of potentially long-term menstrual disruption on bone mass are serious concerns for individuals with a past or current anorexia nervosa (AN) diagnosis. As such, estrogen therapies are frequently used to address amenorrhea associated with AN. A systematic review of the literature was conducted to examine the effectiveness of estrogen therapies on bone mineral density in women with amenorrhea. Data regarding the effectiveness of oral contraceptives were of low quality and mixed, with the majority of studies finding no benefit of these treatments on bone mineral density. Hormone replacement therapy findings were also mixed, though promising results were found in a study comparing transdermal administration of physiologic estrogen, delivered in developmentally sensitive incremental doses to placebo controls. Though this study suggests a possible role for estrogen therapies in addressing bone density loss in women with AN, in general, more studies are needed. Clinical drawbacks of using these therapies in the treatment of AN, including the loss of menses resumption as a clinical marker for weight and nutritional rehabilitation, must be considered in the decision to use estrogen therapies, particularly given the uncertain effectiveness of most of these treatments.


Stabilization for chronic sternoclavicular joint instability.
We present a surgical reconstruction technique for chronic unstable sternoclavicular (SC) joint utilizing the tendon of sternocleidomastoid (SCM) muscle and additional augmentation utilizing the palmaris longus free tendon graft to secure the medial end of the clavicle to the first rib. This double stabilization procedure may strengthen the SC joint fixation for the chronic SC joint instability.