Dynamics of nucleotide incorporation: snapshots revealed by 2-aminopurine fluorescence studies.
Formation of a noncanonical base pair between dFTP, a dTTP analogue that cannot form H bonds, and the fluorescent base analogue 2-aminopurine (2AP) was studied in order to discover how the bacteriophage T4 DNA polymerase selects nucleotides with high accuracy. Changes in 2AP fluorescence intensity provided a spectroscopic reporter of the nucleotide binding reactions, which were combined with rapid-quench, pre-steady-state reactions to measure product formation. These studies supported and extended previous findings that the T4 DNA polymerase binds nucleotides in multiple steps with increasing selectivity. With 2AP in the template position, initial dTTP binding was rapid but selective: K(d(dTTP)) (first step) = 31 microM; K(d(dCTP)) (first step) approximately 3 mM. In studies with dFTP, this step was revealed to have two components: formation of an initial preinsertion complex in which H bonds between bases in the newly forming base pair were not essential, which was followed by formation of a final preinsertion complex in which H bonds assisted. The second nucleotide binding step was characterized by increased discrimination against dTTP binding opposite template 2AP, K(d) (second step) = 367 microM, and additional conformational changes were detected in ternary enzyme-DNA-dTTP complexes, as expected for forming closed complexes. We demonstrate here that the second binding step occurs before formation of the phosphodiester bond. Thus, the high fidelity of nucleotide insertion by T4 DNA polymerase is accomplished by the sequential application of selectivity in first forming accurate preinsertion complexes, and then additional conformational changes are applied that further increase discrimination against incorrect nucleotides.


Existence of two D-alanine:D-alanine ligases in Escherichia coli: cloning and sequencing of the ddlA gene and purification and characterization of the DdlA and DdlB enzymes.
Two distinct genes encoding D-alanine:D-alanine (D-Ala-D-Ala) ligase (ADP forming) activity in Escherichia coli have been cloned by complementation of E. coli strain ST640(lambda 112) deficient in D-Ala-D-Ala ligase activity with a lambda library of E. coli DNA. One of the two genes, designated as ddlB, is identical with the ddl gene already sequenced [Robinson, A.C., Kenan, D.L., Sweeney, J., & Donachie, W.D. (1986) J. Bacteriol. 167, 809-817]. We describe the subcloning and DNA sequencing of the other gene, designated as ddlA on the basis of similarities with the Salmonella typhimurium ddlA gene [Daub, E., Zawadzke, L.E., Botstein, D., & Walsh, C.T. (1988) Biochemistry 27, 3701-3708]. The predicted amino acid sequence of the E. coli DdlA enzyme shows 90% homology with the S. typhimurium DdlA sequence. The ddlB gene was subcloned by use of the polymerase chain reaction into an expression vector containing an optimized ribosome binding site, which expressed the DdlB enzyme to greater than 50% soluble cell protein. Both DdlA and DdlB enzymes were purified to greater than 90% homogeneity and characterized kinetically.


A series of studies on the training of high-intensity muscle power in rugby league football players.
Maximal power (Pmax) levels and the effects of the manipulation of training variables on power output in rugby league football players were investigated in 5 studies. In study 1, players of 3 different ability levels were assessed for Pmax during explosive bench press throws. Pmax levels were a significant descriptor of playing ability within the sport. In study 2, the effect of contrast loading was investigated during jump squats. The result was a significant (p < 0.05) increase in power output in the investigated load. In study 3, the effect of an ascending vs. descending order of loads during explosive bench press throws was investigated. An ascending order resulted in a significantly higher power output for the heaviest load, whereas the descending order resulted in a significantly higher power output for the lightest load. In study 4, the relationship between measures of upper-body strength, power, and speed was investigated in athletes from 3 different levels of playing ability. Strength, power, and speed were significantly correlated overall; however, the relationships were greater in the more experienced training group. In study 5, it was found that stronger athletes utilized a lower percentage of 1 repetition maximum (1RM; 46-51%) to attain Pmax than less strong athletes (58-69%).


M4 @Si28 (M=Al,Ga): metal-encapsulated tetrahedral silicon fullerene.
It is known that silicon fullerenes cannot maintain perfect cage structures like carbon fullerenes. Previous density-functional theory calculations have shown that even with encapsulated species, nearly all endohedral silicon fullerenes exhibit highly puckered cage structures in comparison with their carbon counterparts. In this work, we present theoretical evidences that the tetrahedral fullerene cage Si(28) can be fully stabilized by encapsulating a tetrahedral metallic cluster (Al(4) or Ga(4)). To our knowledge, this is the first predicted endohedral silicon fullerene that can retain perfectly the same cage structure (without puckering) as the carbon fullerene counterpart (T(d)-C(28) fullerene). Density-functional theory calculations also suggest that the two endohedral metallosilicon fullerenes T(d)-M(4)@Si(28) (M=Al and Ga) can be chemically stable because both clusters have a large highest occupied molecular orbital-lowest unoccupied molecular orbital energy gap ( approximately 0.9 eV), strong spherical aromaticity (nucleus-independent chemical shift value of -36 and -44), and large binding and embedding energies.


The moral problem of health disparities.
Health disparities exist along lines of race/ethnicity and socioeconomic class in US society. I argue that we should work to eliminate these health disparities because their existence is a moral wrong that needs to be addressed. Health disparities are morally wrong because they exemplify historical injustices. Contractarian ethics, Kantian ethics, and utilitarian ethics all provide theoretical justification for viewing health disparities as a moral wrong, as do several ethical principles of primary importance in bioethics. The moral consequences of health disparities are also troubling and further support the claim that these disparities are a moral wrong. The Universal Declaration of Human Rights provides additional support that health disparities are a moral wrong, as does an analogy with the generally accepted duty to provide equal access to education. In this article, I also consider and respond to 3 objections to my thesis.


A comparison of the I-gel supraglottic airway as a conduit for tracheal intubation with the intubating laryngeal mask airway: a manikin study.
Insertion of a supraglottic airway and tracheal intubation through it may be indicated in resuscitation scenarios where conventional laryngoscopy fails. Various supraglottic devices have been used as conduits for tracheal intubation, including the intubating laryngeal mask airway (ILMA), the Ctrach laryngeal mask and the I-gel supraglottic airway. A prospective study with 25 participants evaluated the success rate of blind intubation (using a gum-elastic bougie, an Aintree intubating catheter (AIC) and designated tracheal tube) and fibrescope-guided tracheal intubation (through the intubating laryngeal mask airway and the I-gel supraglottic airway) on three different airway manikins. Twenty-five anaesthetists performed three intubations with each method on each of three manikins. The success rate of the fibrescope-guided technique was significantly higher than blind attempts (P<0.0001) with both devices. For fibreoptic techniques, there was no difference found between the ILMA and I-gel (P>0.05). All blind techniques were significantly more successful in the ILMA group compared to the I-gel (P<0.0001 for bougie, Aintree catheter and tracheal tube, respectively). The results of this study show that, in manikins, fibreoptic intubation through both ILMA and I-gel is a highly successful technique. Blind intubation through the I-gel showed a low success rate and should not be attempted.


Hot Deformation Behavior and Processing Maps of ZnSnO3/Cu Composites.
In this work, we designed ternary ZnSnO3 particle-reinforced Cu matrix composites and evaluated the hot deformation behavior of ZnSnO3/Cu composites. The hot deformation characteristics of typical dynamic recrystallization were probed by the resulting true stress-strain curves of ZnSnO3/Cu composites. The influences of deformation conditions, including temperatures (650-850 °C) and strain rates (0.01-5 s-1), on the flow stress of the designed composites were investigated. This revealed that the peak stress increased with the increasing of strain rate and decreasing of temperature. Additionally, the activation energy was calculated to be 237.05 kJ/mol and followed by yielding a constitutive equation for low-stress ZnSnO3/Cu composites. The processing maps established by dynamic materials model theory indicated that the designed composites possessed excellent hot workability, and then the processing parameters (790-850 °C and 0.01-0.04 s-1) of the ZnSnO3/Cu composites were determined for practical industrial production. Our work discloses the deformation behavior of ZnSnO3/Cu matrix composites and extends the rational process design for ternary ceramic/metal materials with excellent hot workability.


Sterile abscess mimicking an abdominal tumor 8 years after laparoscopic cholecystectomy.
Spillage of gallstones (6-40%) are common during laparoscopic cholecystectomy. Development of intraperitoneal and perihepatic abscesses are relatively rare (<0.1%). However, it may pose a diagnostic dilemma mimicking intra-abdominal tumor due to their similar radiologic appearance. We present a 57-year-old woman with history of cholecystectomy 8 years prior who presented with a suspected diagnosis of incarcerated port site hernia with associated radiological evidence of an intra-abdominal tumor. The histological examination of the resected tumor revealed a chronic abscess. It reminds us the importance of careful removal of the stones especially in the setting of acute cholecystitis and should prompt the treating physician about this late possible complication.


Wilson's disease: 'face of giant panda' and 'trident' signs together.
Wilson's disease is an inborn error of metabolism characterized by inability to excrete copper into the bile, with excessive deposition of copper into the eyes, liver and brain. Lentiform nuclei are involved most commonly, but involvement of thalamus, midbrain and pons results in certain characteristic radiological signs on neuroimaging. Atrophy of cerebral and cerebellar cortex is also common yet under-recognized. Identification of these signs helps in the diagnosis in appropriate clinical setting.


Falls from height: spine, spine, spine!
Falls from a height are a major cause of morbidity and hospital cost. Spinal injury is frequently associated with falls from height, but reliable predictive factors have not been identified. Diagnostic evaluation of the spine is complex and debated. Our objective was to characterize spinal injury after falls from height and identify predictive factors of spinal injuries. Medical records of patients with falls from height>10 feet admitted in a Level I trauma center during a period of 66 months were reviewed. Univariate and multivariate analyses were performed to identify independent risk factors of spinal injuries. Of 414 patients, 127 (31%) suffered 277 spinal injuries. Multiple spinal injuries at different levels were found in 62 (49%) patients; in 19 (15%) spinal injuries were at noncontinuous levels. The only independent predictor of spinal injury was alcohol intoxication (odds ratio=3.305; 95% CI, 1.75-6.242; p<0.001) but the number of intoxicated patients was low and the predictive ability weak. Level of falls from height did not correlate with likelihood of spinal injury. Twenty-four of 107 (22%) patients with spinal injuries and a reliable clinical examination had no symptoms related to the spine; all but 2 had distracting injuries. Spinal injury is frequent among survivors of falls from height>10 feet. Because of the absence of reliable predictors of spinal injury, the possibility of multiple noncontinuous fractures, and the presence of distracting injuries clouding the clinical presentation, aggressive evaluation of the entire spine is warranted.


Long-term physical health outcomes of obsessive-compulsive personality disorder traits.
Obsessive-compulsive personality disorder (OCPD) is characterized by pervasive and persistent traits including preoccupation with orderliness, perfectionism, and control. Relatively little is known about the potential relationship between OCPD traits and physical health. We investigated the association between OCPD traits and several self-reported medical conditions in 249 individuals followed prospectively from 1981 until 2004/2005 as part of the Epidemiological Catchment Area. The OCPD trait score was inversely related to hypertension in males, in models unadjusted (OR = 0.66; 95% CI, 0.45-0.90) and adjusted (OR = 0.70; 95% CI, 0.47-0.95) for sociodemographic variables. Perfectionism was inversely related to hypertension in the unadjusted models for men (OR = 0.34; 95% CI, 0.12-0.89). Indecisiveness was positively associated with heart conditions in adjusted models for women (OR = 3.46; 95% CI, 1.11-10.52). OCPD traits are associated with cardiovascular health in both sexes. Further studies are needed to understand the specificity of these relationships, as well as to determine the underlying mechanism.


Staphylococcal enterotoxins.
Staphylococcus aureus (S. aureus) is a Gram positive bacterium that is carried by about one third of the general population and is responsible for common and serious diseases. These diseases include food poisoning and toxic shock syndrome, which are caused by exotoxins produced by S. aureus. Of the more than 20 Staphylococcal enterotoxins, SEA and SEB are the best characterized and are also regarded as superantigens because of their ability to bind to class II MHC molecules on antigen presenting cells and stimulate large populations of T cells that share variable regions on the β chain of the T cell receptor. The result of this massive T cell activation is a cytokine bolus leading to an acute toxic shock. These proteins are highly resistant to denaturation, which allows them to remain intact in contaminated food and trigger disease outbreaks. A recognized problem is the emergence of multi-drug resistant strains of S. aureus and these are a concern in the clinical setting as they are a common cause of antibiotic-associated diarrhea in hospitalized patients. In this review, we provide an overview of the current understanding of these proteins.


Effects on Career Development From Sharing One's Story: Young Professionals' Experiences With Family Planning Voices.
Supporting the development of young family planning professionals is key to fostering communities of practitioners that can help countries achieve family planning goals. The Family Planning Voices (FP Voices) storytelling initiative, created by The Knowledge for Health Project and Family Planning 2020, documents stories from people around the world who are passionate about family planning. This qualitative evaluation used in-depth interviews (n = 11) with young professionals (ages 18-30) to uncover the effects of sharing their story with FP Voices. Participants came from 10 countries in one of three regions, Latin America (n = 2), South Asia (n = 2), and Africa (n = 7). Findings highlight that sharing one's story with FP Voices served as a professional development opportunity and instilled confidence and pride among young professionals. Additionally, participants linked access to a professional headshot and the experience of participating in an interview to their professional development. Participants often discussed the recognition they gained from sharing their story and the resulting increase in professional connections and opportunities. Participants hoped that their stories would inspire and encourage others and support recognition of the value of young professionals to the larger family planning field. In sum, storytelling initiatives like FP Voices can motivate and create community and opportunity among young professionals.


Vestibular schwannomas in children.
This article highlights the clinical presentation and management issues of unilateral vestibular schwannomas in children. We demonstrate how the presentation differs from neurofibromatosis type 2 (NF2) and from adult unilateral vestibular schwannomas. This article is composed of a series of three cases and a literature review. The study was performed at a university hospital (tertiary referral center). Three children, aged 9, 11, and 13 years, with histologically confirmed vestibular schwannomas were studied. All children under 16 years of age in the world literature with unilateral vestibular schwannomas were reviewed. Analysis of presentation and surgical management of these three children and those children reported in the literature. Pattern of presentation relative to children with NF2 and people with adult unilateral vestibular schwannomas. Two patients had multiple cranial nerve weakness and recurrence, and one patient had successful removal of the tumor with preservation of all functions of the cranial nerves, including the facial nerve. Vestibular schwannomas in children are very uncommon. It is likely that it is the first manifestation of NF2, but it may also be a variant of sporadic vestibular schwannomas. A presentation of three cases and a review of 36 other cases in the literature demonstrates how the presentation is different from adult sporadic vestibular schwannomas and NF2 because it lacks primary audiological symptoms. The study also provides evidence of non-NF2 vestibular schwannomas presenting in children and suggests that it is likely that these are a variant of unilateral sporadic vestibular schwannomas. The search for the features of NF2 in these cases remains mandatory.


Mifepristone (RU486) restores humoral and T cell-mediated immune response in endotoxin immunosuppressed mice.
Sepsis and septic shock can be caused by Gram-positive and -negative bacteria and other microorganisms. In the case of Gram-negative bacteria, endotoxin, a normal constituent of the bacterial wall, also known as lipopolysaccharide (LPS), has been considered as one of the principal agents causing the undesirable effects in this critical illness. The response to LPS involves a rapid secretion of proinflammatory cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, interferon (IFN)-γ and the concomitant induction of anti-inflammatory mediators such as IL-10, transforming growth factor (TGF)-β or glucocorticoids, which render the host temporarily refractory to subsequent lethal doses of LPS challenge in a process known as LPS or endotoxin tolerance. Although protective from the development of sepsis or systemic inflammation, endotoxin tolerance has also been pointed out as the main cause of the non-specific humoral and cellular immunosuppression described in these patients. In this report we demonstrate, using a mouse model, that mifepristone (RU486), a known glucocorticoid receptor antagonist, could play an important role in the restoration of both adaptive humoral and cellular immune response in LPS immunosuppressed mice, suggesting the involvement of endogenous glucocorticoids in this phenomenon. On the other hand, using cyclophosphamide and gemcitabine, we demonstrated that regulatory/suppressor CD4(+) CD25(+) forkhead boxP3(+) and GR-1(+) CD11b(+) cells do not play a major role in the establishment or the maintenance of endotoxin tolerance, a central mechanism for inducing an immunosuppression state.


Coupled-cluster with active space selected higher amplitudes: performance of seminatural orbitals for ground and excited state calculations.
The active space approach for coupled-cluster models is generalized using the general active space concept and implemented in a string-based general coupled-cluster code. Particular attention is devoted to the choice of orbitals on which the subspace division is based. Seminatural orbitals are proposed for that purpose. These orbitals are obtained by diagonalizing only the hole-hole and particle-particle block of the one-electron density of a lower-order method. The seminatural orbitals are shown to be a good replacement for complete active space self-consistent field orbitals and avoid the ambiguities with respect to the reference determinant introduced by the latter orbitals. The seminatural orbitals also perform well in excited state calculations, including excited states with strong double excitation contributions, which usually are difficult to describe with standard coupled-cluster methods. A set of vertical excitation energies is obtained and benchmarked against full configuration interaction calculations, and alternative hierarchies of active space coupled-cluster models are proposed. As a simple application the spectroscopic constants of the C(2) B (1)Delta(g) and B(') (1)Sigma(g) (+) states are calculated using active space coupled-cluster methods and basis sets up to quadruple-zeta quality in connection with extrapolation and additivity schemes.


State of the Art in Gold Nanoparticle Synthesisation via Pulsed Laser Ablation in Liquid and Its Characterisation for Molecular Imaging: A Review.
With recent advances in nanotechnology, various nanomaterials have been used as drug carriers in molecular imaging for the treatment of cancer. The unique physiochemical properties and biocompatibility of gold nanoparticles have developed a breakthrough in molecular imaging, which allows exploration of gold nanoparticles in drug delivery for diagnostic purpose. The conventional gold nanoparticles synthetisation methods have limitations with chemical contaminations during the synthesisation process and the use of higher energy. Thus, various innovative approaches in gold nanoparticles synthetisation are under development. Recently, studies have been focused on the development of eco-friendly, non-toxic, cost-effective and simple gold nanoparticle synthesisation. The pulsed laser ablation in liquid (PLAL) technique is a versatile synthetic and convincing technique due to its high efficiency, eco-friendly and facile method to produce gold nanoparticle. Therefore, this study aimed to review the eco-friendly gold nanoparticle synthesisation method via the PLAL method and to characterise the gold nanoparticles properties for molecular imaging. This review paper provides new insight to understand the PLAL technique in producing gold nanoparticles and the PLAL parameters that affect gold nanoparticle properties to meet the desired needs in molecular imaging.


Inhibition of Growth of Lactobacillus bulgaricus by Purine Deoxyribonucleotides.
Morris, George K. (University of Georgia, Athens), and William L. Williams. Inhibition of growth of Lactobacillus bulgaricus by purine deoxyribonucleotides. J. Bacteriol. 90:715-719. 1965.-An inhibition of growth of Lactobacillus bulgaricus GS was observed with deoxyadenylic acid and deoxyguanylic acid. Deoxynucleotides of cytosine, thymine, and uracil, and the deoxynucleosides of adenine, guanine, cytosine, and thymine were inactive as inhibitors. The inhibition was reversed by liver extract (a crude source of two unidentified growth factors for this organism). With suboptimal concentrations of liver extract, the inhibition was reversed by nucleotides of adenine, guanine, uracil, cytosine, and thymine. When the medium contained partially purified sources of the two growth factors rather than crude liver extract, fewer compounds reversed the inhibition. Adenylic acid and guanylic acid reversed the action of either inhibitor. Inosinic acid reversed inhibition caused by deoxyguanylic acid, but not that caused by deoxyadenylic acid. Thymidylic acid reversed inhibition caused by deoxyadenylic acid better than that caused by deoxyguanylic acid. Uridylic acid and cytidylic acid were no longer effective in reversing the inhibitions. This organism preferentially responded to monophosphorylated compounds as inhibitors and as reversers of inhibitions. Studies on the acid-soluble nucleotide pool revealed an accumulation of adenosine triphosphate, guanosine triphosphate, and an unidentified compound which resembled a nucleotide in its physical properties. These data cannot be explained by known metabolic pathways of nucleic acid biosynthesis. This organism responds differently from other related organisms to nucleic acid derivatives; therefore, it may be a new useful tool for studying nucleic acid metabolism and biosynthesis.


Perspectives on research in patient teaching.
Selection of outcome measures needs to go beyond assessment of knowledge gains to include indicators of adherence to the self-care regimen and health outcomes. Because standard didactic approaches are relatively ineffective in fostering participation in self-care, program content should be individualized and may need considerable reinforcement. In studies of program effectiveness, both the experimental and the comparison conditions should be monitored. Although a wide variety of patient, educator, and situational characteristics may mediate program efficacy, a lack of theoretically based studies and insufficient replication precludes generalizable conclusions about these or other aspects of patient teaching.


[Clinical application of 113mIn-chloride for indirect lower radionuclide lymphography in cancer patients].
Carrier-free applications of 113mIn-chloride for indirect lower radionuclide lymphography were studied in 90 cancer patients. The period of radiolabel semiexcretion from site of injection (initial interdigital spaces of foot) ranged 25-74 min. 131mIn-chloride application provided a distinct visualization of retroperitoneal lymph nodes. The results of a radionuclide lymphographic study of 43 patients with uterine carcinoma were confirmed by postoperative histological examination of resected lymph nodes in 88%. The informative value of the pictures of retroperitoneal lymph nodes obtained by gamma chambers and scanners using 131mIn-chloride was essentially identical.


Rare case of Marchiafava-Bignami disease due to thiamine deficiency and malnutrition.
Marchiafava-Bignami disease (MBD) is a rare, toxic demyelinating disorder of the central nervous system associated with chronic alcoholism and malnutrition. The clinical presentation is varied and non-specific, including symptoms of acute dementia, impaired consciousness, dysarthria, hemiparesis, pyramidal tract signs, seizure activity, ataxia and signs of interhemispheric disconnection. The differential diagnosis of MBD may include Wernicke's encephalopathy, multiple sclerosis, encephalitis, infectious or paraneoplastic leucoencephalopathy, infarction, Alzheimer's disease, multi-infarct dementia and frontotemporal lobar degeneration (Pick) disease. The diagnosis of MBD is dependent on MRI findings of hyperintensity of the corpus callosum on T2 and fluid-attenuated inversion recovery T2 sequences, with or without extracallosal lesions. The use of MRI in diagnosis has allowed for early initiation of treatment with parenteral thiamine, and improved the prognosis of MBD from frequently fatal to a mortality of less than 8%. Administration of thiamine within 14 days of symptom onset has demonstrated statistically better outcomes over delayed treatment. We present a case report of MBD diagnosed in a 72-year-old woman who presented with ataxia and slurred speech, in an effort to highlight the importance of obtaining MRI in patients presenting with behavioural disturbance and neurological findings, as well as discuss the relationship between thiamine supplementation and demyelinating diseases in the central nervous system.


Quantitative Biology Undergraduate Major at the University of Southern California.
In 2017, the University of Southern California started a new undergraduate major in quantitative biology. This major combines training in the biological sciences, mathematics, and computer science to prepare students for 21st century biology and medicine. In this article I will discuss the curriculum, the first two cohorts of graduates, the current students, and future plans for the major.


Aspergillus endophthalmitis in orthotopic liver transplantation.
In this report, we describe a patient with drug-induced liver failure who developed endogenous endophthalmitis after liver transplantation. Our patient's clinical course was so fulminant that the eye was lost in less than 1 month, without any response to therapy. Recognition of this infection is important because many patients die of disseminated Aspergillus infection, which may be detected early with bedside funduscopic examination by an ophthalmologist. Probably if the patient had referred to us earlier, it may have been possible to save the eye.


Reaching and grasping with the tongue: Shared motor planning between hand actions and articulatory gestures.
Research has shown connections between articulatory mouth actions and manual actions. This study investigates whether forward-backward hand movements could be associated with vowel production processes that programme tongue fronting/backing, lip rounding/spreading (Experiment 1), and/or consonant production processes that programme tongue tip and tongue dorsum actions (Experiment 2). The participants had to perform either forward or backward hand movement and simultaneously pronounce different vowels or consonants. The results revealed a response benefit, measured in vocal and manual reaction times, when the responses consisted of front vowels and forward hand movements. Conversely, back vowels were associated with backward hand movements. Articulation of rounded versus unrounded vowels or coronal versus dorsal consonants did not produce the effect. In contrast, when the manual responses of forward-backward hand movements were replaced by precision and power grip responses, the coronal consonants [t] and [r] were associated with the precision grip, whereas the dorsal consonant [k] was associated with the power grip. We propose that the movements of the tongue body, operating mainly for vowel production, share the directional action planning processes with the hand movements. Conversely, the tongue articulators related to tongue tip and dorsum movements, operating mainly for consonant production, share the action planning processes with the precision and power grip, respectively.


Smoking prevention campaign for youth in Israel.
Smoking rates among teenagers have increased in many countries including Israel. Youth smoking prevention programs have developed considerably in recent years and the present study examines results of mass media anti-smoking campaign in Israel. Two telephone interviews were conducted one moth and 9 months after exposure to TV advertisements. The two surveys consisted of random samples of Israeli adolescents aged 12-18 years. After one month, 77% of the survey participants remembered the slogan of the TV ads, and 30% used it. After 9 months, 32% remembered it and 6% used it. 28% said they were affected by the TV ads. After 9 months, 25% increased their awareness about anti-smoking behaviors, 2% claimed to have stopped smoking, and 1% claimed to have decreased smoking). Significant changes in anti-smoking awareness were found in survey participants who were exposed to TV ads and also participated in a school program.


Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Experienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial.
Background. First- and second-generation smallpox vaccines are contraindicated in individuals infected with human immunodeficiency virus (HIV). A new smallpox vaccine is needed to protect this population in the context of biodefense preparedness. The focus of this study was to compare the safety and immunogenicity of a replication-deficient, highly attenuated smallpox vaccine modified vaccinia Ankara (MVA) in HIV-infected and healthy subjects. Methods. An open-label, controlled Phase II trial was conducted at 36 centers in the United States and Puerto Rico for HIV-infected and healthy subjects. Subjects received 2 doses of MVA administered 4 weeks apart. Safety was evaluated by assessment of adverse events, focused physical exams, electrocardiogram recordings, and safety laboratories. Immune responses were assessed using enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT). Results. Five hundred seventy-nine subjects were vaccinated at least once and had data available for analysis. Rates of ELISA seropositivity were comparably high in vaccinia-naive healthy and HIV-infected subjects, whereas PRNT seropositivity rates were higher in healthy compared with HIV-infected subjects. Modified vaccinia Ankara was safe and well tolerated with no adverse impact on viral load or CD4 counts. There were no cases of myo-/pericarditis reported. Conclusions. Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations.


Transcriptomic Analysis of Flower Bud Differentiation in Magnolia sinostellata.
Magnolias are widely cultivated for their beautiful flowers, but despite their popularity, the molecular mechanisms regulating flower bud differentiation have not been elucidated. Here, we used paraffin sections and RNA-seq to study the process of flower bud differentiation in Magnolia sinostellata. Flower bud development occurred between 28 April and 30 May 2017 and was divided into five stages: undifferentiated, early flower bud differentiation, petal primordium differentiation, stamen primordium differentiation, and pistil primordium differentiation. A total of 52,441 expressed genes were identified, of which 11,592 were significantly differentially expressed in the five bud development stages. Of these, 82 genes were involved in the flowering. In addition, MADS-box and AP2 family genes play critical roles in the formation of flower organs and 20 differentially expressed genes associated with flower bud differentiation were identified in M. sinostellata. A qRT-PCR analysis verified that the MADS-box and AP2 family genes were expressed at high levels during flower bud differentiation. Consequently, this study provides a theoretical basis for the genetic regulation of flowering in M. sinostellata, which lays a foundation for further research into flowering genes and may facilitate the development of new cultivars.


Precise determination of major and trace elements in micrometer-scale ilmenite lamellae in titanomagnetite using LA-ICP-MS technique: application of regression analysis to time-resolved signals.
Laser ablation ICP-MS (LA-ICP-MS) is a powerful microbeam technique capable of rapid and precise determination for a large spectrum of trace elements at ppm or sub-ppm levels. Micrometer-scale minerals and inclusions are very common in geological materials, for which direct measurement is restricted by the spot size using LA-ICP-MS (generally 20-50 μm). In this study, ilmenite lamellae intergrown with magnetite were selected as an example to describe a practical algorithm that applies regression analysis to extract the chemical compositions of binary phases from mixed LA-ICP-MS signals. The method accuracy is confirmed by the agreement between the regressed value for various trace elements in ilmenite exsolutions and their reference values (direct analyses using EPMA and LA-ICP-MS). Results were obtained for most detectable components (Mg, Mn, V, Nb, Ta, Sc, Zr, Hf, Sn, et c.) and their relative deviations are within ±10%, even for those <10 ppm (such as Hf and W). Relative standard errors on the regressed value were calculated to evaluate the precision of the method, which is mostly within 10%, and the worst up to 25%. Therefore, the algorithm described in this contribution provides a solution for precise determination of trace element compositions for micrometer-scale ilmenite lamellae in titanomagnetite using LA-ICP-MS, and is potentially practical for other geological materials.


Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform NaV1.7.
Voltage-gated sodium ion channel subtype 1.7 (NaV1.7) is a high interest target for the discovery of non-opioid analgesics. Compelling evidence from human genetic data, particularly the finding that persons lacking functional NaV1.7 are insensitive to pain, has spurred considerable effort to develop selective inhibitors of this Na+ ion channel target as analgesic medicines. Recent clinical setbacks and disappointing performance of preclinical compounds in animal pain models, however, have led to skepticism around the potential of selective NaV1.7 inhibitors as human therapeutics. In this Perspective, we discuss the attributes and limitations of recently disclosed investigational drugs targeting NaV1.7 and review evidence that, by better understanding the requirements for selectivity and target engagement, the opportunity to deliver effective analgesic medicines targeting NaV1.7 endures.


Is the coverage of mass-drug-administration adequate for elimination of Bancroftian filariasis? An experience from West Bengal, India.
Bancroftian filariasis is the second most common mosquito-borne disease in India. Government of India adopted mass-drug-administration (MDA) since 2004 for its elimination by 2015 AD. The aim was to assess the coverage, compliance, factors-related to noncompliance to MDA. A cross-sectional survey of 1 week was conducted within 2 weeks after completion of MDA for 2012 in three villages and two municipal wards of North 24 Parganas district of West Bengal, India selected as clusters by multistage random sampling. Information was collected via interview of inhabitants of the clusters selected by systematic random sampling and drug administrators of the selected clusters along with verifying left over medicines, if any. Both appropriate medicine distribution (83.4%) and 61.28% of people who received drug reported consumption and effective consumption rate (48.01%) fell short of the target. The lowest consumption (38.15%) was noted in one of the rural cluster (villages), followed by municipal wards (43.14%). Consumption was significantly higher among rural residents and Hindu community. Fear of the adverse reaction was the commonest (63.02%) cause of noncompliance. Contrary to the requirement, almost all consumptions were unsupervised by drug administrators. Only 10.71% of the respondents reportedly were paid house to house campaign of forthcoming MDA. About 64% participants had heard about filariasis out of which 71% & 47% mentioned swelling of legs as symptoms and mosquito bite as mode of spread, respectively. About one-third opined mosquito control and MDA each as means of prevention. Approximately, 60% participants had heard about MDA. Information education and communication related to MDA program was conspicuously inadequate in the last round. Mass mobilization as in intensive pulse polio immunization with effective monitoring and supervision is the need of the hour for universal coverage of MDA with supervised on the spot consumption of tablets.


Association between CD4(+)CD25(high) T cells and atopy in children.
There is evidence that CD4(+)CD25(high) T-regulatory cells are important for establishing tolerance to allergens, but information in children is limited. To test the hypothesis that greater numbers and function of CD4(+)CD25(high) T cells are associated with a reduced risk of childhood allergies and wheezing. A cohort of 151 six-year-old children from atopic families was analyzed for peripheral blood CD4(+)CD25(high) and CD4(+)CD25(int) T cells by flow cytometry and for clinical and immunologic correlates of atopy. The associations between these variables were assessed by regression analysis. Factors positively associated with % CD4(+)CD25(high)/CD4 T cells were male sex, number of positive allergen-specific IgE tests, total IgE, season, and 1-month average total pollen count preceding blood draw. The percentage of CD4(+)CD25(high)/total CD4 T cells did not correlate with induced cytokine production, and correlated negatively with suppressive capacity of CD4(+)CD25(+) T cells (r = -0.45; P = .034). The percentage of CD4(+)CD25(int)/CD4 T cells was 54% higher in pollen-sensitized children compared with nonsensitized children in spring (P = .023 for interaction), and correlated positively with IL-5, IL-10, and IL-13 (P < or = .001 for all). Our findings suggest that blood CD4(+)CD25(high) cells are a mixture of activated and regulatory T cells, and that these cells could be seasonally regulated by environmental factors such as pollen exposure. Seasonal increases in CD4CD25(high) expression in children with allergy may represent systemic immune activation caused by pollen exposures.


High-throughput polymer monolith in-tip SPME fiber preparation and application in drug analysis.
A simple, low-cost and reproducible automated procedure has been developed to prepare in-tip solid-phase microextraction (SPME) fibers coated with polymer monoliths using a photopolymerization technique. Up to 96 fibers were prepared at one time using a polymerization mixture consisting of ethylene glycol dimethacrylate, dimethoxy-α-phenylacetophenone and 1-decanol. The optimization procedures that affected polymer morphology, such as compositions of the crosslinkers and porogens, polymerization time and fiber thickness as well as extraction efficiency of the immobilized Oasis hydrophilic-lipophilic-balanced extraction sorbent were investigated. Also, the reproducibility of automated in-tip SPME fiber preparation, as well as sample process parameters, such as sample extraction and desorption volumes, are discussed. The performance of the polymer monoliths in-tip SPME assessed with a model drug compound from clinical studies and a head-to-head comparison using in-tip SPME and conventional SPE clearly demonstrated that the SPME is a feasible approach for routine drug analysis in the pharmaceutical industry.


99Tcm-DISIDA hepatobiliary imaging in evaluating gallbladder function in patients with spinal cord injury.
Spinal cord injury (SCI) is associated with increased prevalence of gallstones and acute acalculous cholecystitis. A possible explanation for the increased prevalence of gallstones in SCI patients is decreased gallbladder motility causing gallbladder stasis. In this study, we investigated gallbladder function in patients with SCI. Eighteen normal controls, 16 trauma controls and 46 SCI patients were included in this study. Gallbladder function was measured by technium 99m-labeled imino-diacetic acid analogue ((99)Tc(m)-DISIDA) hepatobiliary imaging and represented by filling fraction (FF) and ejection fraction (EF). The data from SCI patients were analyzed according to old versus young, female versus male, heavy versus light body weight, ASIA A & B versus ASIA C & D classification, high- versus low-level injury, and long versus short injury duration. Fifty-two percent of SCI patients had abnormal FF and 59% had abnormal EF. Significantly decreased FF and EF values were found in SCI patients, especially in female patients with severe and high-level injuries. Quantitative (99)Tc(m)-DISIDA cholescintigraphy showed that SCI can significantly impair gallbladder function.


Genetically modified bone marrow continuously supplies anti-inflammatory cells and suppresses renal injury in mouse Goodpasture syndrome.
In chronic inflammation, macrophages and neutrophils, which are derived from bone marrow, play a pivotal role. Therefore, reconstitution of bone marrow with anti-inflammatory stem cells may modify inflammation. In this study, transplantation-based gene therapy was applied to glomerular inflammation for a long-lasting suppression of the glomerular damage seen in chronic nephritis. Bone marrow cells were harvested from male donor mice, which had received 5-fluorouracil 3 days previously, and transduced with an interleukin 1 (IL-1) receptor antagonist (IL-1Ra) or a mock gene using a retrovirus vector. After confirmation that transduced cells possessed the transgene at approximately 0.7 copies per cell and secreted recombinant IL-1Ra, these cells were infused into sublethally irradiated (6 Gy) female recipients once daily for 4 consecutive days. These female recipient mice had the male Y antigen in bone marrow, liver, and spleen, and 10% to 20% of their spleen cells possessed the transgene even 8 weeks after transplantation. Glomerulonephritis was then induced in these mice. Renal function and histology were retarded in the mice whose bone marrow was reconstituted with IL-1Ra-producing cells compared with mock transduced cells. In situ hybridization using a Y painting probe revealed that transplanted donor cells were recruited into the glomerulus upon induction of nephritis, suggesting therapeutic effects were channeled through the secretion of IL-1Ra from these cells. Furthermore, the survival rate after a second challenge with nephrotoxic antibody was significantly improved in the IL-1Ra chimera. These results suggest that reconstitution of bone marrow for continuous supply of anti-inflammatory cells may be a useful strategy for the treatment of chronic inflammation.


Sodium chloride stimulated respiration of Anacystis nidulans.
With certain salts a stimulation of respiration of the blue-green alga Anacystis nidulans was found in the dark. The stimulation was observed only at high concentrations (10(-2)M--10(-1)M). NaCl or LiCl are the most effective salts and on addition the increase of the respiration is about 2.5fold. Li is assumed to function as a substitute for Na. Potassium salts, except KCl, are ineffective. The order for the effectiveness is: NaCl greater than NaNO3, Na2SO4 greater than KCl greater than KNO3, K2SO4 (=zero). Accordingly, the cation Na+, and to a less degree the anion Cl- are responsible for the stimulatory effect. K, which is ineffective, is passively accumulated by Anacystis according to the membrane potential. Na is actively extruded. At 0.1 M external NaCl, the passive influx of Na is high, but even then it is balanced by an active efflux. This increases the energy consumption of the cells and leads to a stimulated respiration. With DCCD (N,N'-dicyclohexylcarbodiimide) or NEM (N-ethylmaleimide), the Na efflux is inhibited, simultaneously the stimulation of respiration is abolished and the passive influx of Na becomes detectable. At 0.1 M NaCl, the passive influx of Na measured in presence of DCCD is 5 x 10(-6) moles Na/min and ml packed cells. In absence of DCCD on addition of 0.1 M NaCl the extra oxygen consumption is 2 x 10(-6) moles O2/min and ml cells. This may prove that the stimulation of respiration is mainly caused by the active Na extrusion.


Fatal cytokine-release syndrome in a patient receiving toripalimab: a case report.
Immune checkpoint inhibitors, a type of immunotherapy, have demonstrated optimal treatment efficacy in inducing durable antitumor responses in various cancers. Cytokine-release syndrome is a rare immune-related adverse event induced by immune checkpoint inhibitors. In our case, a patient with hypopharyngeal squamous cell carcinoma received toripalimab combined with chemotherapy. On the fourth day post treatment, the patient developed fever and hypotension. Laboratory examination indicated myelosuppression, acute kidney injury and disseminated intravascular coagulation. Meanwhile, serum cytokine levels of IL-6, IL-8, IL-10, IL-1β, IFN-γ and the level of hypersensitive C-reactive protein were markedly elevated. The patient was diagnosed with cytokine release syndrome, which progressed rapidly and led to the patient's demise on the fifth day post treatment.


Cervical carotid artery dissection: current review of diagnosis and treatment.
Carotid artery dissection is a cause of stroke, especially in young and middle-aged patients. A dissection occurs when there is an intimal tear or rupture of the vasa vasorum, leading to an intramural hematoma, which is thought to result from trauma or can occur spontaneously, and is likely multifactorial, involving environmental and intrinsic factors. The clinical diagnosis of carotid artery dissection can be challenging, with common presentations including pain, partial Horner syndrome, cranial nerve palsies, or cerebral ischemia. With the use of noninvasive imaging, including magnetic resonance and computed tomography angiography, the diagnosis of carotid dissection has increased in frequency. Treatment options include thrombolysis, antiplatelet or anticoagulation therapy, endovascular or surgical interventions. The choice of appropriate therapy remains controversial as most carotid dissections heal on their own and there are no randomized trials to compare treatment options.


Clonal expansion in evolution of chronic hepatitis to hepatocellular carcinoma as seen at an X-chromosome locus.
Clonal analysis has shown that hepatocellular carcinoma arises from a single cell. However, the clonality of precancerous lesions and adjacent nonneoplastic tissues is not clear. We analyzed a human androgen receptor locus to elucidate the clonal state of liver tissues including post-hepatitic lesions associated with hepatocarcinogenesis. The analysis was based on a restriction fragment length polymorphism involving an androgen receptor locus on the X chromosome, taking advantage of physiologic random inactivation by methylation of 1 of 2 X chromosomes in females during embryogenesis. Clonality was assessed in 79 randomly located tissue samples microdissected from noncirrhotic liver, including a total of 40 morphologically normal sites in 4 normal livers and 39 sites from a single HCV-infected liver. In addition, 51 regenerative nodules, 4 areas of adenomatous hyperplasia, and 18 hepatocellular carcinomas were sampled. All samples were obtained from livers involved by various neoplasms. Eight of forty samples (20.0%) from the four normal livers and 20 of the 39 samples (51.3%) from the single HCV-infected liver showed a monoclonal pattern. Moreover, 30 of 51 regenerative nodules (58.9%) showed a monoclonal pattern. No histologic differences were evident between mono- and polyclonal nodules. On the other hand, the 18 carcinomas and 4 areas of adenomatous hyperplasia all were monoclonal. Mean calculated monoclonal areas of normal liver and liver with chronic hepatitis were 1.1 and 3.3 mm(2). Our results suggest that areas representing a single clone of hepatocytes are present in normal liver, and these progressively expand as changes advance from chronic hepatitis to hepatocellular carcinoma.


PRIMARY ADRENAL LYMPHOMA: A SINGLE-CENTER EXPERIENCE.
To describe the clinical presentation, biochemistry, imaging features, and treatment outcome of patients with primary adrenal lymphoma (PAL) presenting to a single tertiary care center. We performed a retrospective analysis of case records of 7 patients diagnosed with PAL between January 2011 and May 2014 at our institution in Mumbai, India. Median age of presentation in our series was 48 years (range, 41 to 60 years), with a male to female ratio of 6:1. Bilateral adrenal involvement was seen in 4 of 7 patients (58%). Adrenal insufficiency (AI) was seen in 3 of the 4 patients with bilateral involvement (75%). Computed tomography showed slight to moderate contrast enhancement of adrenal masses in 4 of 5 patients (80%). Diffuse, large, B-cell lymphoma (DLBCL) was the most common immunophenotype (85%). One patient died due to rapid disease progression even before starting chemotherapy. Six patients were treated with chemotherapy and/or external beam radiotherapy. After 1 year, 2 more patients had died, whereas 4 patients were in remission. PAL should always be considered in differential diagnosis of bilateral adrenal mass with AI. DLBCL is the most common histologic subtype of PAL. Despite treatment, long-term prognosis of PAL remains poor.


Measuring the acoustoelectric interaction constant using ultrasound current source density imaging.
Ultrasound current source density imaging (UCSDI) exploits the acoustoelectric (AE) effect, an interaction between ultrasound pressure and electrical resistivity, to map electrical conduction in the heart. The conversion efficiency for UCSDI is determined by the AE interaction constant K, a fundamental property of all materials; K directly affects the magnitude of the detected voltage signal in UCSDI. This paper describes a technique for measuring K in biological tissue, and reports its value for the first time in cadaver hearts. A custom chamber was designed and fabricated to control the geometry for estimating K, which was measured in different ionic salt solutions and seven cadaver rabbit hearts. We found K to be strongly dependent on concentration for the divalent salt CuSO(4), but not for the monovalent salt NaCl, consistent with their different chemical properties. In the rabbit heart, K was determined to be 0.041 ± 0.012%/MPa, similar to the measurement of K in physiological saline (0.034 ± 0.003%/MPa). This study provides a baseline estimate of K for modeling and experimental studies that involve UCSDI to map cardiac conduction and reentry currents associated with arrhythmias.


Neuropathic Pain in Multiple Sclerosis Improved With Oral Famciclovir: A Case Report.
Multiple sclerosis can be a debilitating disease that is often associated with neuropathic pain and discomfort in the trigeminal region. This can pose a therapeutic challenge as the benefits of the treatment options have to be outweighed against significant side effects. The authors present the case of a 67-year-old man, whose control of trigeminal neuralgia with botulinum toxin A injections was lost after an episode of herpes labialis and herpes zoster infection. The pain management of the patient during the episodes of herpes simplex and varicella zoster infections was greatly improved with famciclovir treatment, and subsequently control of trigeminal neuralgia was regained with botulinum toxin A injections. This case serves to highlight the potential association of multiple sclerosis with herpetic infections as well as the treatment challenges, especially management of pain, which they can possess.


Prevention of exercise-induced asthma by drugs inhaled from metered aerosols.
The capacity of salbutamol 0.3 mg (SAL), disodium cromoglycate 3 mg (DSCG), a combination (SAL + DSCG), and ipratropium bromide 80 ug (IB), all given as metered aerosols to prevent exercise-induced (EIA), was compared with that of a placebo, a peroral lactose pill. Seven children participated, having reproducible EIA provoked by running on a treadmill at a heart rate of 170 sustained for 6 min. FEV1 and volume of trapped gas (VTG), defined as the air volume released during rebreathing oxygen with maximum breaths at the end of a multiple breath nitrogen wash out, were used as tests of spasm in large and small airways. SAL and SAL + DSCG offered complete protection in large and small airways. DSCG and IB prevented EIA in large airways (FEV1) to 95%, but only to about 50% in small airways (VTG). SAL or SAL + DSCG gave significantly better protection (FEV1 and VTG) than DSCG and IB (P less than 0.01). Differences between DSCG and IB were not statistically significant. DSCG or propellant caused significant irritation and spasm in small airways (VTG) before exercise. Most subjects seemed to obtain satisfactory protection against EIA by beta 2-agonists.


Different Effects of Three Selected Lactobacillus Strains in Dextran Sulfate Sodium-Induced Colitis in BALB/c Mice.
To analyze the changes of different Lactobacillus species in ulcerative colitis patients and to further assess the therapeutic effects of selected Lactobacillus strains on dextran sulfate sodium (DSS)-induced experimental colitis in BALB/c mice. Forty-five active ulcerative colitis (UC) patients and 45 population-based healthy controls were enrolled. Polymerase chain reaction (PCR) amplification and real-time PCR were performed for qualitative and quantitative analyses, respectively, of the Lactobacillus species in UC patients. Three Lactobacillus strains from three species were selected to assess the therapeutic effects on experimental colitis. Sixty 8-week-old BALB/c mice were divided into six groups. The five groups that had received DSS were administered normal saline, mesalazine, L. fermentum CCTCC M206110 strain, L. crispatus CCTCC M206119 strain, or L. plantarum NCIMB8826 strain. We assessed the severity of colitis based on disease activity index (DAI), body weight loss, colon length, and histologic damage. The detection rate of four of the 11 Lactobacillus species decreased significantly (P < 0.05), and the detection rate of two of the 11 Lactobacillus species increased significantly (P < 0.05) in UC patients. Relative quantitative analysis revealed that eight Lactobacillus species declined significantly in UC patients (P < 0.05), while three Lactobacillus species increased significantly (P < 0.05). The CCTCC M206110 treatment group had less weight loss and colon length shortening, lower DAI scores, and lower histologic scores (P < 0.05), while the CCTCC M206119 treatment group had greater weight loss and colon length shortening, higher histologic scores, and more severe inflammatory infiltration (P < 0.05). NCIMB8826 improved weight loss and colon length shortening (P < 0.05) with no significant influence on DAI and histologic damage in the colitis model. Administration of an L. crispatus CCTCC M206119 supplement aggravated DSS-induced colitis. L. fermentum CCTCC M206110 proved to be effective at attenuating DSS-induced colitis. The potential probiotic effect of L. plantarum NCIMB8826 on UC has yet to be assessed.


Different neural adjustments improve endpoint accuracy with practice in young and old adults.
The purpose of the study was to determine the practice-induced adjustments in the motor-output variability and the agonist-antagonist activity that accompanied improvements in endpoint accuracy of goal-directed isometric contractions in young and old adults. Young and old adults performed 100 trials that involved accurately matching the peak of a force trajectory (25% maximum) to a target force in 150 ms. Endpoint accuracy was quantified as the absolute difference between the target and the peak force and time-to-peak force. Motor-output variability was expressed as the SDs of the force trajectory, peak force, and time-to-peak force. The force and time errors differed between the two groups initially, but after 35 practice trials the errors were similar for the two groups. Reductions in force endpoint error were predicted by decreases in the variability of the force trajectory for both groups, adaptations in the agonist (first dorsal interosseus) and antagonist (second palmar interosseus) EMG for young adults, and adaptations only for the agonist EMG for old adults. Reductions in time endpoint error were predicted by increases in the SD of time-to-peak force and a longer delay to the peak EMG of the antagonist muscle for young adults, but by decreases in the SDs of time-to-peak force and force trajectory and a shorter delay to the peak EMG of the antagonist muscle for the old adults. The findings indicate that the neural adjustments underlying the improvement in endpoint accuracy with practice differed for young and old adults.


Development of an integrated cardiac rehabilitation program to improve the adaptation level of patients after acute myocardial infarction.
Individual's adaptation following acute myocardial infarction (AMI) and low attendance of whole-course cardiac rehabilitation (CR) are significant issues. For optimal health post AMI, an integrated CR program aiming at individual's adaptive behaviors is imperative for improving the CR efficiency and patients' outcomes. This study aims to develop theory-guided interventions to increase CR attendance and adaptation level of patients post-AMI. This study was conducted in a tertiary hospital from July 2021 to September 2022 in Shanghai China. Guided by the theory of adaptation to chronic illness (ACI theory), the study followed the Intervention mapping (IM) framework to develop the interventions for CR program. Four phases included: (1) needs assessment of patients and facilitators using a cross-sectional study and semi-structured, in-depth interviews, (2) identification of implementation outcomes and performance objectives, (3) selection of theoretical methods to explain the mechanism of patients' adaptive behaviors and to use for behavior change, and (4) development of implementation protocol from the results of the previous phases. A total of 226 AMI patient-caregivers paired samples were eligible for the data analysis, 30 AMI patients participated in the qualitative inquiry, 16 experts in the CR field evaluated the implementation protocol, and 8 AMI patients commented on the practical interventions. Following the IM framework, an integrated cardiac rehabilitation program using mHealth strategies was developed for AMI patients to facilitate CR attendance and completion, to improve their adaptation level and health outcomes. Using the IM framework and ACI theory, an integrated CR program was developed to help guide the behavior change and improve adaptation among AMI patients. The preliminary findings suggest that further intervention in enhancing the combination of three-stage CR is required. A feasibility study will be conducted to assess the acceptability and effectiveness of this generated CR intervention.


Judgments of frequency and recency: how they relate to reports of subjective awareness.
In 2 experiments, the author explored the relations of remember versus familiar ratings to judgments of frequency (JOFs) and to judgments of recency (JORs). In both cases, remembered items were associated with more accurate memory judgments. In general, familiar items were judged to have occurred less frequently and less recently than remembered items. However, JOFs and JORs associated with familiar items were more accurate than chance. Implications for theories of remember versus familiar ratings, JOFs, and JORs are considered. Some basic findings that constrain these theories are that (a) remember versus familiar ratings were less sensitive than JOF to presentation frequency and less sensitive than JOR to recency and (b) although remember versus familiar ratings are strongly related to both JOF and JOR, as measured by gamma, the relations are far from perfect.


The Role of Fever Clinics in the Strategic Triage of Suspected Cases of Imported COVID-19.
Novel coronavirus pneumonia (COVID-19) is an acute respiratory infectious disease, which has the characteristic of human-to-human transmission and is extremely contagious. Correctly standardizing the process of early screening of infection or suspected cases in the fever clinic has become a key part of the fight against the pandemic. A retrospective analysis of patients in the fever clinic of Shenyang Medical College Affiliated Central Hospital from January 23 to March 1, 2020, was conducted in the present study. It was found that 16 suspected cases of COVID-19 in the fever clinic were diagnosed with respiratory infections, accounting for 0.59%. In case of a negative result in the second nucleic acid test, strategic triage and typing might be more conducive for the following nucleic acid tests for suspected cases in order to prevent the spread of the epidemic caused by missed diagnosis.


Chemical Characterization and Antibacterial Properties of Fontitrygon margarita (Günther, 1870) Liver Oil.
The aim of this study was to determine the chemical characteristics and antibacterial activity of Fontitrygon margarita liver oil against the bacteria responsible for food poisoning. Oils were extracted from F. margarita liver using two methods (exudation and cooking-pressing) and analyses by Fourier transform infrared (FTIR) spectroscopy. Quality indexes were determined using standard methods and the fatty acid profile was carried out by gas chromatography with a flame ionization detector (GC-FID). Antibacterial activities of these oils, their emulsion, and their interactions with common antibiotics were evaluated by the broth microdilution method. Extraction yield was higher with cooking-pressing (16.90%) compared to exudation (14.49%). The quality indexes of both oils were conformed to Codex Alimentarius Standard. Thiobarbituric acid index was higher with exudation compared to cooking-pressing (3.20 ± 0.14 and 2.36 ± 0.14 μmol MDA/kg, respectively) while acid, iodine, peroxide, and anisidine values did not significantly vary with the extraction methods (2.15-2.30 mgKOH/g, 102.42-106.65 gI2/100 g, 3.34-3.57 meqO2/kg, and 2.85-3.32 respectively). FTIR analyses clearly show that the two spectra are similar (no differences in the frequency and absorbance of their bands). The fatty acid profile revealed that, regardless of the extraction methods, F. margarita oil is richer in monounsaturated (55.97-55.41%) followed by polyunsaturated (28.17-28.52%) and saturated fatty acids (15.86-16.07%). Moreover, these oils showed antibacterial activity on all the bacteria strains tested with MICs between 16 and 256 mg/ml. Regardless of the extraction methods, emulsions showed higher activity (6.25 ≤ MIC ≤25 mg/ml) compared to crude oils. Additionally, F. margarita liver oil potentiated the antibacterial activity of ciprofloxacin, tetracycline, gentamicin, amoxicillin, and chloramphenicol. These results showed the effectiveness of Fontitrygon margarita liver oil against some bacteria responsible for food poisoning, thus demonstrating their antibacterial properties which could be due to their chemical composition.


From Roosevelt to Reagan: federal spending for mental retardation and developmental disabilities.
Results of an analysis of 50 years of federal government spending for mental retardation and developmental disabilities were summarized. Spending for services and income maintenance grew rapidly from the early 1950s through fiscal year (FY) 1981. Since FY 1981, total federal spending for mental retardation has plateaued. Federal support for research and training has declined steadily since the early 1970s. The lack of support for research and training imperils the achievement of national objectives in prevention of retardation and integration of retarded individuals into community settings.


Amino acid- and amine-induced gastrin release from isolated rat endocrine granules.
Secretory granules from rat antral tissue were isolated by differential centrifugation in sucrose and were confirmed as intact by electron microscopy. Gastrin release from the isolated granules was measured in response to stimulation with amino acids or their decarboxylated amine metabolites. Nine of 13 amino acids tested were ineffective at inducing gastrin release, whereas all 13 of the amine metabolites were potent stimulants of gastrin release. A pH gradient across the granule fraction membranes was estimated by acridine orange fluorescence and indicated an acidic interior. Changes in acridine orange fluorescence as an indicator of pH gradient dissipation showed that all of the amines, but only one of the amino acids, reversed acridine orange fluorescence. Ammonium chloride, similar to amines, both reversed acridine orange fluorescence and induced release of gastrin. It is concluded that amines 1) may directly stimulate gastrin granules to release their contents and 2) tend to alkalinize the gastrin granule interior. Some amino acids, in contrast, appear to directly stimulate gastrin release and do not affect the granule pH gradient.


Caring for people with early and advanced chronic obstructive pulmonary disease: how do family carers cope?
To examine the coping strategies of family carers of people with early and advanced chronic obstructive pulmonary disease and how those relate to their subjective health. Caring for a family member with chronic obstructive pulmonary disease can be a stressful experience. Understanding how carers cope with this is critical for improving outcomes. However, this topic has received little attention in the literature, particularly considering the care-giving experience with early chronic obstructive pulmonary disease. A cross-sectional study with a convenience sample of family carers of people with chronic obstructive pulmonary disease. A structured questionnaire was used to collect data on socio-demographics and care-giving characteristics. Self-rated physical and mental health was measured by two items from the International Classification of Functioning, Disability and Health checklist. Coping strategies were assessed with the Carers' Assessment of Managing Index. Descriptive and inferential analyses were performed. A total of 158 family carers participated: 109 caring for people with early and 49 with advanced chronic obstructive pulmonary disease. The two groups differed significantly on self-rated mental health and on problem-solving, emotional-cognitive and managing stress coping type. Significant correlations between self-rated physical health and problem-solving coping and between self-rated mental health and emotion-cognitive and managing stress coping were found for carers of patients with advanced chronic obstructive pulmonary disease. This study provides a unique insight into family carer coping strategies at different stages of chronic obstructive pulmonary disease. Carers of people with early and advanced chronic obstructive pulmonary disease cope differently with their caring demands. Nevertheless, problem-focused coping strategies were perceived as the most helpful by both groups. The findings are relevant to informing early supportive interventions aiming to prevent burden and promote healthy adjustment to care-giving demands within the specific context of chronic obstructive pulmonary disease.


Implementing a user-friendly format to analyze PRRSV next-generation sequencing results and associating breeding herd production performance with number of PRRSV strains and recombination events.
The open reading frames (ORF)5 represents approximately 4% of the porcine reproductive and respiratory syndrome virus (PRRSV)-2 genome (whole-PRRSV) and is often determined by the Sanger technique, which rarely detects >1 PRRSV strain if present in the sample. Next-generation sequencing (NGS) may provide a more appropriate method of detecting multiple PRRSV strains in one sample. This work assessed the effect of PRRSV genetic variability and recombination events, using NGS, on the time-to-low prevalence (TTLP) and total losses in breeding herds (n 20) that detected a PRRSV outbreak and adopted measures to eliminate PRRSV. Serum, lung or live virus inoculation material collected within 3-weeks of outbreak, and subsequently, processing fluids (PFs) were tested for PRRSV by RT-qPCR and NGS. Recovered whole-PRRSV or partial sequences were used to characterize within and between herd PRRSV genetic variability. Whole-PRRSV was recovered in five out of six (83.3%) lung, 16 out of 22 (72.73%) serum and in five out of 95 (5.26%) PF. Whole-PRRSV recovered from serum or lung were used as farm referent strains in 16 out of 20 (80%) farms. In four farms, only partial genome sequences were recovered and used as farm referent strains. At least two wild-type PRRSV strains (wt-PRRSV) were circulating simultaneously in 18 out of 20 (90%) and at least one vaccine-like strain co-circulating in eight out of 20 (40%) farms. PRRSV recombination events were detected in 12 farms (59%), been 10 out of 12 between wt-PRRSV and two out of 12 between wt-PRRSV and vaccine-like strains. Farms having ≥3 strains had a 12-week increase TTLP versus herds ≤2 strains detected. Farms with ≤2 strains (n 10) had 1837 and farms with no recombination events detected (n 8) had 1827 fewer piglet losses per 1000 sows versus farms with ≥3 PRRSV strains (n 8) or detected recombination (n 10), respectively. NGS outcomes and novel visualization methods provided more thorough insight into PRRSV dynamics, genetic variability, detection of multiple strains co-circulating in breeding herds and helped establish practical guidelines for using PRRSV NGS outputs.


Functional-morphologic MR imaging with ultrasmall superparamagnetic particles of iron oxide in acute and chronic soft-tissue infection: study in rats.
To investigate the use of magnetic resonance (MR) imaging enhanced with ultrasmall superparamagnetic particles of iron oxide (USPIO) to identify acute, early chronic, and late chronic abscess formation in an experimental model of soft-tissue abscess. Experimental soft-tissue infection in 15 rats was imaged with an MR imaging unit on days 1 and 2 (acute), days 5 and 6 (early chronic), and days 8 and 9 (late chronic) after inoculation of the infectious agent. All animals were imaged without contrast enhancement and immediately and 24 hours after USPIO administration. MR and histopathologic findings were compared. The changes in relative signal intensity (SI) and in the extent and pattern of contrast enhancement (macrophage distribution) between the animal groups were analyzed. Statistical testing was performed with Kruskal-Wallis analysis of variance and the chi2 test. At 24 hours after USPIO administration, the relative SI of the abscess wall and the relative macrophage extent were 0.50 (0.33-0.73) and 1.03 (0.90-1.08), respectively, for acute infection; 0.11 (0.10-0.18) and 0.94 (0.93-1.01) for early chronic infection; and 0.53 (0.44-0.58) and 0.80 (0.77-0.83) for late chronic infection. The changes in enhancement pattern (P <.001), relative SI (P <.001), and relative macrophage extent (P <.05) with time were significant. The macrophage distribution pattern increases the specificity of MR findings in chronic infection and allows differentiation between areas with active inflammation and areas of reparative granulation tissue.


Embolization and Resection of Epidural Spinal Arteriovenous Malformations: Case Report.
Spinal vascular malformations (sVMs) are relatively uncommon, accounting for 5% to 10% of all spinal cord lesions. Spetzler and Kim developed a paradigm to classify sVMs based on a variety of characteristics into 1 of 6 types, including a subcategory for exclusively epidural sVMs. There is a paucity of literature focused on this category, specifically sources describing the clinical manifestation and management of these lesions. We report 2 cases of purely epidural spinal arteriovenous fistula, with an emphasis on the radiographic features and combined endovascular and microsurgical treatment. We report 2 patients known to have epidural spinal arteriovenous fistula who underwent both embolization and surgical resection between May 2019 and August 2020 at our institution. Data collected included demographic, clinical, and operative course, including age, sex, medical history, presenting symptoms, and preoperative and postoperative imaging. Both of these patients were managed with a combination of an endovascular approach for embolization of feeding arterial source and surgical exploration/resection. In both cases, no residual vascular malformation was identified, and the patients went on to be symptom free after 6 weeks. This report describes the use of a combination of endovascular and surgical approaches to achieve maximal benefit for 2 patients. These cases reinforce the value of a staged multimodal treatment approach in achieving good functional outcomes for patients with these rare and challenging entities.


Histological response to injected gluteraldehyde cross-linked bovine collagen based implant in a rat model.
The aim of present study is to investigate the short and long term histopathological alterations caused by submucosal injection of gluteraldehyde cross-linked bovine collagen based on an experimental rat model. Sixty Sprague-Dawley rats were assigned into two groups as group I and II each containing 30 rats. 0.1 ml of saline solution and 0.1 ml of gluteraldehyde cross-linked bovine collagen were injected into the submucosa of bladder of first (control) and second groups, respectively. Both group I and II were further subdivided into 3 other groups as Group IA, IB, IC and Group IIA, IIB, IIC according to the sacrification period. Group IA and IIA, IB and IIB, IC and IIC rats (10 rats for each group) were sacrificed 3, 6, and 12 months after surgical procedure, respectively. Two slides prepared from injection site of the bladder were evaluated completely for each rat by being unaware of the groups and at random by two independent senior pathologists to determine the fibroblast invasion, collagen formation, capillary ingrowth and inflammatory reaction. Additionally, randomized brain sections from each rat were also examined to detect migration of the injection material. The measurements were made using an ocular micrometer at x10 magnification. The results were assessed using t-tests for paired and independent samples, with p < 0.05 considered to indicate significant differences; all values were presented as the mean (SD). Migration to the brain was not detected in any group. Significant histopathological changes in the gluteraldehyde cross-linked bovine collagen injected groups were fibroblast invasion in 93.3%, collagen formation in 73.3%, capillary ingrowth in 46.6%, inflamatory reaction in 20%. We emphasize that the usage of gluteraldehyde cross-linked bovine collagen in children appears to be safe for endoscopic treatment of vesicoureteral reflux.


Polynitrogen chemistry. Synthesis, characterization, and crystal structure of surprisingly stable fluoroantimonate salts of N5+.
The new N5+ salt, N5+ SbF(6)(-), was prepared from N(2)F(+)SbF(6)(-) and HN(3) in anhydrous HF solution. The white solid is surprisingly stable, decomposing only at 70 degrees C, and is relatively insensitive to impact. Its vibrational spectrum exhibits all nine fundamentals with frequencies that are in excellent agreement with the theoretical calculations for a five-atomic V-shaped ion of C(2)(v)symmetry. The N5+ Sb(2)F(11)(-) salt was also prepared, and its crystal structure was determined. The geometry previously predicted for free gaseous N5+ from theoretical calculations was confirmed within experimental error. The Sb(2)F(11)(-) anions exhibit an unusual geometry with eclipsed SbF(4) groups due to interionic bridging with the N5+ cations. The N5+ cation is a powerful one-electron oxidizer. It readily oxidizes NO, NO(2), and Br(2) but fails to oxidize Cl(2), Xe, or O(2).


A case of severe acute pancreatitis, in overlap syndrome of systemic sclerosis and systemic lupus erythematosus, successfully treated with plasmapheresis.
Here, we describe a case of severe pancreatitis in overlap syndrome of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) in an adult female patient. Treatment with plasmapheresis and high-dose prednisone successfully saved her life and led to remission of the pancreatitis. This is the first case report of severe acute pancreatitis in the setting of overlap syndrome of SLE and SSc. The advantages and disadvantages of the use of corticosteroids are discussed.


Microarray phosphatome profiling of breast cancer patients unveils a complex phosphatase regulatory role of the MAPK and PI3K pathways in estrogen receptor-negative breast cancers.
Phosphatases are proteins with the ability to dephosphorylate different substrates and are involved in critical cellular processes such as proliferation, tumor suppression, motility and survival. Little is known about their role in the different breast cancer (BC) phenotypes. We carried out microarray phosphatome profiling in 41 estrogen receptor-negative (ER-) BC patients, as determined by immunohistochemistry (IHC), containing both ERBB2+ and ERBB2- in order to characterize the differences between these two groups. We characterized and confirmed the distinct phosphatome of the two main ER- BC subgroups (in two independent microarrays series) and that of ER+ BC (in three large independent series). Our findings point to the importance of the MAPK and PI3K pathways in ER- BCs as some of the most differentially expressed phosphatases (like DUSP4 and DUSP6) sharing ERK as substrate, or regulating the PI3K pathway (INPP4B, PTEN). It was possible to identify a selective group of phosphatases upregulated only in the ER- ERBB2+ subgroup and not in ER+ (like DUSP6, DUSP10 and PPAPDC1A among others), suggesting a role of these phosphatases in specific BC subtypes, unlike other differentially expressed phosphatases (DUSP4 and ENPP1) that seemed to have a role in multiple BC subtypes. Significant correlation was found at the protein level by IHC between the expression of DUSP6 and phospho-ERK (p=0.04) but not of phospho-ERK with DUSP4. To show the potential prognostic relevance of phosphatases as a functional group of genes, we derived and validated in two large independent BC microarray series a multiphosphatase signature enriched in differentially expressed phosphatases, to predict distant metastasis-free survival (DMFS). ER- ERBB2+, ER- ERBB2- and ER+ BC patients have a distinct pattern of phosphatase RNA expression with a potential prognostic relevance. Further studies of the most relevant phosphatases found in this study are warranted.


Freestanding mesoporous quasi-single-crystalline CO3O4 nanowire arrays.
We report a facile template-free method for the large-area growth of freestanding hollow Co3O4 nanowire arrays on a variety of substrates including transparent conducting glass, Si wafer, and copper foil, et al. These nanowires have the interesting combined properties of mesoporosity and quasi-single-crystallinity. With their high surface area and crystallinity, and their direct growth on conductive substrate, these Co3O4 nanowire arrays will have promising applications in lithium-ion batteries, chemical sensing, and field-emission and electrochromic devices. Using the prepared nanowire arrays as electrode, an electrochemical sensor for hydrogen peroxide sensing has been demonstrated.


What about dreams? State of the art and open questions.
Several studies have tried to identify the neurobiological bases of dream experiences, nevertheless some questions are still at the centre of the debate. Here, we summarise the main open issues concerning the neuroscientific study of dreaming. After overcoming the rapid eye movement (REM) - non-REM (NREM) sleep dichotomy, investigations have focussed on the specific functional or structural brain features predicting dream experience. On the one hand, some results underlined that specific trait-like factors are associated with higher dream recall frequency. On the other hand, the electrophysiological milieu preceding dream report upon awakening is a crucial state-like factor influencing the subsequent recall. Furthermore, dreaming is strictly related to waking experiences. Based on the continuity hypothesis, some findings reveal that dreaming could be modulated through visual, olfactory, or somatosensory stimulations. Also, it should be considered that the indirect access to dreaming remains an intrinsic limitation. Recent findings have revealed a greater concordance between parasomnia-like events and dream contents. This means that parasomnia episodes might be an expression of the ongoing mental sleep activity and could represent a viable direct access to dream experience. Finally, we provide a picture on nightmares and emphasise the possible role of oneiric activity in psychotherapy. Overall, further efforts in dream science are needed (a) to develop a uniform protocol to study dream experience, (b) to introduce and integrate advanced techniques to better understand whether dreaming can be manipulated, (c) to clarify the relationship between parasomnia events and dreaming, and (d) to determine the clinical valence of dreams.


Singlet oxygen delivery through the porous cap of a hollow-core fiber optic device.
The development of the first photosensitizer/fiber optic device is reported. An oxygen-flowing, fiber-capped configuration is used for the application of heterogeneous, spatially confined singlet oxygen delivery in aqueous media. This is a unique device, unlike other heterogeneous photosensitizers, in which local concentrations of singlet oxygen can be delivered via introduction and withdrawal of the fiber tip.


Mortality trends among Jewish and non-Jewish women in Israel, 1960-82.
Until 1975 in Israel mortality rates in women aged greater than or equal to 25 years old were higher among Jewish women than non-Jewish women. Since then the relationship has been reversed with higher rates in the non-Jewish group. The three main causes of death in the two groups were heart disease, cancer and cerebrovascular disease (CVA). The proportional mortality and death rates from total heart diseases rose in the non-Jewish population during 1970-82, whereas in Jewish women there were only slight changes. With regard to cancer, the proportional mortality and death rates were higher in the Jewish group. However, from 1970 to 1982 cancer mortality in the Jewish population declined continuously, while in the non-Jewish group it rose. Mortality from CVA rose in both Jewish and non-Jewish women until 1974, but then declined. Since then, the rates remained considerably higher in the non-Jewish population. Death from heart disease, cancer and CVA can partially explain the reversal in total mortality rates in 1975.


[Suppression of frameshift mutation as a result of partial inactivation of translation termination factors in Saccharomyces cerevisiae yeast].
Special search for frameshift mutations, which are suppressed by the cytoplasmic [PSI] factor and by omnipotent nonsense suppressors (recessive mutations in the SUP35 and SUP45 genes), partially inactivating a translation termination complex, was initiated in the LYS2 gene in the yeast Saccharomyces cerevisiae. Mutations were obtained after exposure to UV light and treatment with a mixture consisting of 1.6- and 1.8-dinitropyrene (DNP). This mixture was shown to induce mutations of the frameshift type with a high frequency. The majority of these mutations were insertions of one A or T, which is in good agreement with the data obtained in studies of DNP-induced mutagenesis in other eukaryotes. Frameshift suppression in yeast was first shown on the example of the mutation obtained in this work (lys2-90), which carried the insertion of an extra T in the sequence of five T. This frameshift suppression was shown to occur in the presence of the [PSI] factor (i.e., due to the prion form of the translation release factor eRF3) and as a result of mutations in genes SUP35 or SUP45, which partially inactivate translation termination factors eRF3 and eRF1, respectively. Alternative mechanisms of programmed translational frameshifting in the course of translation and the possibility of enhancing the effectiveness of such frameshifting in the presence of the [PSI] factor are considered.


Diversity of bone cell activity as a histomorphometric feature of idiopathic osteoporosis in men.
Although osteoporosis in men is an increasing health problem, studies on osteoporosis in males are still scarce. The aim of our study was to determine the characteristics of bone tissue and bone turnover in men with idiopathic osteoporosis. Transiliac crest bone samples were histomorphometrically analyzed after double tetracycline labeling in 32 men aged 37-65 years who were diagnosed with idiopathic osteoporosis by densitometry of the lumbar spine and hip. Bone volume, osteoid surface, osteoblast surface, eroded surface, osteoid thickness, trabecular thickness, trabecular number, trabecular separation, and mineral apposition rate (MAR) were determined in all trabecular bone specimens. Bone volume and structural parameters indicated trabecular bone loss in most patients. Cellular parameters and MAR indicated variations in bone cell actions. No age-related decrease in histomorphometric parameters was found. After the patients were grouped according to MAR values, osteoblast and eroded surfaces were found to be lower in the group with decreased MAR values and elevated in the group of patients with increased MAR parameter. Trabecular thickness was greater in patients with lower than normal MAR, due to reduced resorption and probably loss of very thin trabeculae. Our results suggest that idiopathic osteoporosis in man resembles many characteristics of postmenopausal osteoporosis in women resulting in impaired trabecular structure due to unbalanced cellular activity and bone turnover rate.


Identifying optimal PD-1/PD-L1 inhibitors in first-line treatment of patients with advanced squamous non-small cell lung cancer in China: Updated systematic review and network meta-analysis.
Objective: After Gemstone-302 was published in Lancet in January 2022, seven PD-(L)1 inhibitors launched or about to be launched in China, but there are no head-to-head RCTs reporting the comparative efficacy for squamous non-small cell lung cancer (sq-NSCLC). Therefore, we aimed to indirectly compare the efficacy of these treatments to provide evidence for clinical decision and Chinese national reimbursement drug listing. Methods: We collected phase III clinical trials targeted on stage IIIB-IV patients for first-line immunotherapy of sq-NSCLC by systematically searching databases. Relative effects of competing treatments were assessed by Bayesian network meta-analysis and non-parametric restricted mean survival time (RMST) model. Hazard ratio (HR), severe adverse events (SAEs, grade 3-5), progression-free survival (PFS) and overall survival (OS) years were the outcomes. Subgroup analysis was done according to PD-(L)1 expression, smoking, gender, Eastern Cooperative Oncology Group performance status, age and disease stage. Sensitivity analysis using the range of parameters distribution as well as different comparison methods was performed to test the robustness of the results. Results: A total of 7 clinical trials with 2,640 patients were included. For OS, the efficiency (HR, 95%CI) ranks from high to low were sugemalimab (0.48, 0.32-0.73), camrelizumab (0.55, 0.40-0.76), sintilimab (0.56, 0.35-0.90), pembrolizumab (0.71, 0.58-0.87) and atezolizumab (0.88, 0.73-1.05). For PFS, the efficiency ranks from high to low were sugemalimab (0.33, 0.24-0.45), camrelizumab (0.37, 0.30-0.46), tislelizumab (0.53, 0.36-0.79), sintilimab (0.54, 0.42-0.69), toripalimab (0.56, 0.38-0.83), pembrolizumab (0.57, 0.47-0.70) and atezolizumab (0.71, 0.59-0.85). Proportional hazard models and non-proportional hazard models showed consistent efficiency ranks. When extrapolated to long-term survival benefit, under non-proportional hazard ratio, sugemalimab achieved the highest PFS benefit (lifeyears, LYs) in 2 years (1.323), with camrelizumab (1.320), sintilimab (1.243), tislelizumab (1.189), pembrolizumab (0.990) and atezolizumab (0.947) ranking in order; Camrelizumab achieved the highest OS benefit (LYs) in 10 years (2.723), with atezolizumab (2.445) and pembrolizumab (2.397) ranking in order. RMST model showed similar results. In terms of safety, PD-(L)1 inhibitors increased the incidence of SAEs when combined with chemotherapy, sugemalimab and camrelizumab was the safest drugs. Conclusion: Sugemalimab is superior both in HR and long-term survival benefit for Chinese patients with advanced sq-NSCLC.


Solution behavior of amidine complexes: an unexpected cis/trans isomerization and formation of di- and trinuclear platinum(III) and platinum(II) species.
Platinum bis-amidine complexes (both the cis and trans isomers) are stable in acetone and chlorinated solvents but are unstable in protic solvents such as methanol or water. In the latter solvents an initial cis/trans isomerization leads to formation of an equilibrium mixture with a cis/trans ratio of about 1:4; subsequently a dinuclear platinum(III) complex (1) is formed under aerobic conditions while, under anaerobic conditions, a trinuclear platinum(II) compound (2) is obtained. We hypothesize that the process of isomerization and formation of polynuclear compounds (1 and 2) have a common precursor: a dinuclear platinum(II) species supported by two bridging amidinato ligands (3), formed in small yield, which can either dissociate back to monomers of cis/trans configuration or evolve in two different polynuclear species depending upon the aerobic/anaerobic conditions. In aerobic conditions, oxidation of platinum(II) to platinum(III) together with formation of two additional amidinato bridges across the two platinum centers takes place leading to compound 1. In contrast, in anaerobic conditions, oxidation of platinum is prevented and the dinuclear platinum(II) precursor remains in solution until it reacts with an extra molecule of the starting mononuclear complex which loses its two amidine ligands and cross-links the two bridging amidinato ligands of 3 to yield compound 2. This latter features two triply bridging amidinato ligands linking the three platinum units to form a pocket. Complexes 1 and 2 have been characterized by means of IR and NMR spectroscopy, mass spectrometry, elemental analysis, and X-ray crystallography.


Metabolic GWAS-based dissection of genetic bases underlying the diversity of plant metabolism.
Plants have served as sources providing humans with metabolites for food and nutrition, biomaterials for living, and treatment for pain and disease. Plants produce a huge array of metabolites, with an immense diversity at both the population and individual levels. Dissection of the genetic bases for metabolic diversity has attracted increasing research attention. The concept of genome-wide association study (GWAS) was extended to studies on the diversity of plant metabolome that benefitted from the development of mass-spectrometry-based analytical systems and genome sequencing technologies. Metabolic genome-wide association study (mGWAS) is one of the most powerful tools for global identification of genetic determinants for diversity of plant metabolism. Recently, mGWAS has been performed for various species with continuous improvements, providing deeper insights into the genetic bases of metabolic diversity. In this review, we discuss fully the achievements to date and remaining challenges that are associated with both mGWAS and mGWAS-based multi-dimensional analysis. We begin with a summary of GWAS and its development based on statistical methods and populations. As variation in targeted traits is essential for GWAS, we review metabolic diversity and its rise at both the population and individual levels. Subsequently, the application of mGWAS for plants and its corresponding achievements are fully discussed. We address the current knowledge on mGWAS-based multi-dimensional analysis and emerging insights into the diversity of metabolism.


Centering healthcare workers in developing digital health interventions: usability and acceptability of a two-way texting retention intervention in a public HIV clinic in Lilongwe, Malawi.
New initiates on antiretroviral therapy (ART) are at high risk of treatment discontinuation, putting their health at risk. In low-resource settings, like Malawi, appropriate digital health applications must fit into local connectivity and resource constraints. Target users' perspectives are critical for app usability, buy-in and optimization. We describe the formative stages of the design of a two-way text-based (2wT) system of tailored reminders and adherence messages for new ART initiates and share results from key informant interviews with HCWs focused on app usability and acceptability. Using a co-creation approach with clients, clinical, technical and evaluation teams and over app development, we held four informal user feedback sessions, a small pilot with 50 clients, and ten key informant (KIIs) to deepen our understanding of healthcare workers (HCWs) needs, acceptability and usability. Formative research informed the design of interactive client-to-HCW communication, refining of the language and timing of weekly text blast motivational messages and tailored client-specific visit reminders. Informal feedback from HCW stakeholders also informed educational materials to enhance 2wT client understanding of how to report transfers, request visit date changes and ask questions related to their visits. In KII, HCWs noted their appreciation for the co-creation process, believing that the participatory HCD process and responsive design team enabled the development of a highly acceptable and usable 2wT digital tool. HCWs also suggested future improvements to promote inclusion of clients of varying literacy levels and economic backgrounds as well as integrating with other health platforms to improve uptake of 2wT. Inclusion of HCWs increased perceptions of app usability and acceptability among HCWs. HCWs believe that 2wT will improve on-time ART visit attendance and provide valuable early retention in care support. The co-creation approach appears successful in designing an app that will meet HCW needs and, therefore, support client adherence to visits.