Increased slow dynamics defines ligandability of BTB domains.
Efficient determination of protein ligandability, or the propensity to bind small-molecules, would greatly facilitate drug development for novel targets. Ligandability is currently assessed using computational methods that typically consider the static structural properties of putative binding sites or by experimental fragment screening. Here, we evaluate ligandability of conserved BTB domains from the cancer-relevant proteins LRF, KAISO, and MIZ1. Using fragment screening, we discover that MIZ1 binds multiple ligands. However, no ligands are uncovered for the structurally related KAISO or LRF. To understand the principles governing ligand-binding by BTB domains, we perform comprehensive NMR-based dynamics studies and find that only the MIZ1 BTB domain exhibits backbone µs-ms time scale motions. Interestingly, residues with elevated dynamics correspond to the binding site of fragment hits and recently defined HUWE1 interaction site. Our data argue that examining protein dynamics using NMR can contribute to identification of cryptic binding sites, and may support prediction of the ligandability of novel challenging targets.


The likely effects of thermal climate change on vertebrate skeletal muscle mechanics with possible consequences for animal movement and behaviour.
Climate change can involve alteration in the local temperature that an animal is exposed to, which in turn may affect skeletal muscle temperature. The underlying effects of temperature on the mechanical performance of skeletal muscle can affect organismal performance in key activities, such as locomotion and fitness-related behaviours, including prey capture and predator avoidance. The contractile performance of skeletal muscle is optimized within a specific thermal range. An increased muscle temperature can initially cause substantial improvements in force production, faster rates of force generation, relaxation, shortening, and production of power output. However, if muscle temperature becomes too high, then maximal force production and power output can decrease. Any deleterious effects of temperature change on muscle mechanics could be exacerbated by other climatic changes, such as drought, altered water, or airflow regimes that affect the environment the animal needs to move through. Many species will change their location on a daily, or even seasonal basis, to modulate the temperature that they are exposed to, thereby improving the mechanical performance of their muscle. Some species undergo seasonal acclimation to optimize muscle mechanics to longer-term changes in temperature or undergo dormancy to avoid extreme climatic conditions. As local climate alters, species either cope with the change, adapt, avoid extreme climate, move, or undergo localized extinction events. Given that such outcomes will be determined by organismal performance within the thermal environment, the effects of climate change on muscle mechanics could have a major impact on the ability of a population to survive in a particular location.


Balancing risks.
Regulatory policies designed to reduce the health risk of environmental and/or synthetic chemicals generally aim for zero or negligible levels. Foods, on the other hand, especially those with a long history in the human diet, have been treated as essentially safe, even though they too contain various chemicals including nutrients. The recent debate on the presence in food of acrylamide, a possible human carcinogen, is likely to shake up the traditional paradigm held by regulatory agencies on chemical health risks. The current stance on the safety of acrylamide in food seems to be an extension of the traditional approach to assessment of environmental and/or synthetic chemicals. However, even foods which have long been a part of the human diet contain components that do not necessarily meet the safety margins applied to environmental and/or synthetic chemicals. In the future, a greater understanding of the effect of these agents on biological systems as well as the development of analytical methods for testing will result in many questions being raised concerning chemicals in foods, such as acrylamide which is under scrutiny today. Regulatory policies currently employ various standards for controlling chemical risk. These standards are dependent upon the labeling of the chemical in question, e.g., whether carcinogenic or non-carcinogenic, synthetic or natural, or whether a food or industrial chemical. Regardless of labeling, all chemicals to which we are exposed should be evaluated on an equal footing. Then, according to the level of the identified health risk, regulations could or could not be applied based on local circumstances, e.g., public acceptance, voluntary risk vs. involuntary risk, etc. In order to create a standardized system for chemical risk assessment, the introduction of uniform measures is essential. Loss of life expectancy (LLE) is one possible measure to assess chemical health risk. When LLE has been used, animal toxicity data have indicated that an ad libitum diet intake has considerably more impact on health risk than the acrylamide concentration of the ingested food. Reassessing the health effects of chemicals with a system of uniform measures could reveal many risks that need to be preferentially addressed above and beyond keeping minor toxicants to zero or negligible levels. Recognition of such risks may result in changes that conflict with existing regulations. In any case, whether consciously or unconsciously, people have always been exposed to a certain degree of chemical risk in their daily life. Based on the premise that the public can accept some degree of chemical risk in balance with other risks in their lives, regulatory bodies should be able to take a flexible and effective approach. In order to efficiently and comprehensively maximize the protection of our health against potential harm from chemicals using limited public resources, it is now time for regulatory agencies to restructure their policy frameworks across categories for controlling chemical health risks.


Superenhancer drives a tumor-specific splicing variant of MARCO to promote triple-negative breast cancer progression.
The transcription variation, leading to various forms of transcripts and protein diversity, remains largely unexplored in triple-negative breast cancers (TNBCs). Here, we presented a comprehensive analysis of RNA splicing in breast cancer to illustrate the biological function and clinical implications of tumor-specific transcripts (TSTs) arising from these splicing junctions. Aberrant RNA splicing or TSTs were frequently harbored in TNBC and were correlated with a poor outcome. We discovered a tumor-specific splicing variant of macrophage receptor with collagenous structure-TST (MARCO-TST), which was distinguished from myeloid cell-specific wild-type MARCO. MARCO-TST expression was associated with poor outcomes in TNBC patients and could promote tumor progression in vitro and in vivo. Mechanically, MARCO-TST interacted with PLOD2 and enhanced the stability of HIF-1α, which resulted in the metabolic dysregulation of TNBC to form a hypoxic tumor microenvironment. MARCO-TST was initiated from a de novo alternative transcription initiation site that was activated by a superenhancer. Tumors with MARCO-TST expression conferred greater sensitivity to bromodomain and extraterminal protein inhibitors. This treatment strategy was further validated in patient-derived organoids. In conclusion, our results revealed the transcription variation landscape of TNBC, highlighting MARCO-TST as a crucial oncogenic transcript and therapeutic target.


Corrective treatment for tear trough deformity in a young population utilizing two-dimensional fat injections.
Tear trough deformity (TTD) is becoming a growing concern for those seeking facial rejuvenation, and various treatment strategies have been reported. Among treatment options is micro-autologous fat injection, which appears to be an effective approach to recontour the tear trough in the young. The study we present here investigated the reliability and effectiveness of two-dimensional fat injections (TDFI) in the treatment of young patients with TTD. This study evaluated patients with TTD who underwent TDFI between December 2018 and December 2020. The proposed procedure involved ligament releasing and fat injection into the tear trough in two different directions. The average age of the 102 enrolled patients was 25.9 ± 3.8 years. Significant improvement and maintenance of TTD were observed during the follow-up period (13.2 months average) with no major complications being observed. Improvement of dark cycles and enhanced aegyo sal were observed. Patient satisfaction based upon self-administered post-procedure questionnaires disclosed that 58.8% were very satisfied, 38.2% were satisfied, and 2.9% neutral with the results. Two-dimensional fat injections is an effective and reliable method with high satisfaction and low risk of complication. Long-term results demonstrated its utility for young-type TTD.


Clinical and functional characterisation of the combined respiratory chain defect in two sisters due to autosomal recessive mutations in MTFMT.
Exome sequencing identified compound heterozygous mutations in the recently discovered mitochondrial methionyl-tRNA formyltransferase (MTFMT) gene in two sisters with mild Leigh syndrome and combined respiratory chain deficiency. The mutations lead to undetectable levels of the MTFMT protein. Blue native polyacrylamide gel electrophoresis showed decreased complexes I and IV, and additional products stained with complex V antibodies, however the overall steady state level of mt-tRNA(Met) was normal. Our data illustrate that exome sequencing is an excellent diagnostic tool, and its value in clinical medicine is enormous, however it can only be optimally exploited if combined with detailed phenotyping and functional studies.


Urological and Gynaecological Considerations for the Use of Gonadotropin-releasing Hormone Analogues in Transgender and Nonbinary Adolescents: A Narrative Review.
Gonadotropin-releasing hormone analogues (GnRHAs) delay the progression of puberty in transgender and nonbinary (TGNB) adolescents and reduce the impact of dysphoria due to ongoing physical development. The intervention remains contentious despite growing evidence to support this practice. To stimulate discussion on this topical issue in the urological and gynaecological community given potential ramifications for future fertility, physical development, and options for gender affirmation surgery (GAS). We conducted searches of the MEDLINE (from 1946) and Embase (from 1974) databases for the benefits and potential challenges of hormone blockade in TGNB adolescents on February 1, 2022. Evidence with a primary focus on clinical issues of interest to urologists and gynaecologists was objectively synthesised and reported. The onset of puberty represents a period of distress for TGNB adolescents as secondary sexual characteristics develop. GnRHAs are prescribed to inhibit sex hormone production, but the decision to treat should be balanced against the known (and unknown) adverse effects. Fertility preservation is more likely to be successful if GnRHA treatment is delayed for as long as possible. Some adolescents may decide to stop GnRHA use to harvest spermatozoa or oocytes before starting gender-affirming hormone treatment. Transfeminine individuals should consider that options for genital GAS may become more limited, as vaginoplasty with penile skin inversion requires an adequate stretched penile length. Transmasculine individuals may no longer require chest reconstruction for breast development. Offers of GnRHA treatment to TGNB adolescents should be balanced by careful preparation and counselling. Urologists and gynaecologists can complement the expertise of specialist psychosocial and adolescent endocrinology teams, and should be involved early in and throughout the treatment pathway to maximise future functional and surgical outcomes. Puberty blockers for transgender and nonbinary adolescents have benefits, but timing is important to preserve fertility and surgical options.


Imaging orofacial tissues by magnetic resonance.
Magnetic resonance imaging was used to study the human orofacial complex. Two imaging methods, a fixed head coil and a surface coil, were used. Images from a database of 31 subjects revealed details of many structures including the masseter, temporal, medial and lateral pterygoid muscles, the teeth, articular condyles, and facial bones. A dentigerous cyst and a maxillary sinus "polyp" were also identified. Our study demonstrates the utility of this imaging modality in the identification and localization of soft tissue lesions. The strengths and weaknesses of the technique and its clinical potential are discussed.


Detecting outlying samples in a parallel factor analysis model.
To explore multi-way data, different methods have been proposed. Here, we study the popular PARAFAC (Parallel factor analysis) model, which expresses multi-way data in a more compact way, without ignoring the underlying complex structure. To estimate the score and loading matrices, an alternating least squares procedure is typically used. It is however well known that least squares techniques suffer from outlying observations, making the models useless when outliers are present in the data. In this paper, we present a robust PARAFAC method. Essentially, it searches for an outlier-free subset of the data, on which we can then perform the classical PARAFAC algorithm. An outlier map is constructed to identify outliers. Simulations and examples show the robustness of our approach.


Chronic diabetes harms islet-cell transplants by inhibiting graft vascularisation.
Pancreatic islet-cell transplantation is very effective in treating insulin-dependent diabetes in animals but has had no success in humans. Most animals have received islet-cell grafts after short periods of diabetes, while patients have been grafted after years of disease. We have shown a detrimental effect of chronic diabetes on islet-cell grafts in animals, which is at least partially ameliorated by peritransplant insulin infusion. We suggest that this detrimental effect may be mediated by poor vascularisation. There is further evidence from wound healing and tumour grafting experiments, and from the recent insulin pump studies in humans to support our hypothesis. To be successful, islet-cell grafts in humans may have to be performed earlier in the course of the disease and be preceded by a period of accurate diabetic control.


Characterising oral lesions in patients who presented with chronic vesiculobullous lesions during a 10-year period.
Vesiculobullous lesions are a subset of lesons with an aetiologic spectrum that ranges from infection to aberrant mmune function. The bulk are chronic immune-mediated or autoimmune diseases in which inappropriate production of antibodies against auto-antigens results in the development of these conditions. All departmenta patient records in the ten-year period were reviewed and those indicating a provisional diagnosis of oral chronic immune-mediated lesions were included in the study. Simple descriptive statistics were used. Chronic immune-mediated conditions included were lichen planus, pemphigus vulgaris, benign mucous membrane pemphigoid, including cicatricial pemphigoid, bullous pemphigoid, erythema multiforme and systemic lupus erythematosus. The files of forty-five patients (12 males, 33 females) who had been provisionally diagnosed with immune-mediated oral lesions during a ten-year period, from 2001 to 2010, were identified. Of these, 22 (49%) recorded final diagnoses of chronic immune-mediated conditions. This paper characterises the oral lesions of chronic immune-mediated conditions diagnosed in patients attending the oral medicine clinic during a ten-year period.


The influence of close relationships on nocturnal blood pressure dipping.
This study examined the influence of relationship-specific dimensions of social support (i.e., support, depth, conflict) on nocturnal blood pressure (BP) dipping and mental health (i.e., satisfaction with life, stress, and depression) among 303 normotensive and un-medicated hypertensive males and females ages 20-68. Results revealed that support was associated with better, and conflict with poorer, mental health; however, neither was associated with BP dipping. In contrast, relationship depth was associated with greater life satisfaction and greater systolic and diastolic BP dipping, and the effect on dipping was independent of sleep quality, age, hypertensive status, marital status, and level of perceived network support. Relationship conflict was moderated by marital status and gender. Low conflict for females, or with one's spouse, is associated with greater nocturnal diastolic BP dipping. Overall, this study found an association between close relationships and BP dipping, thus identifying one virtually unexplored mechanism by which close relationships may have a protective influence on health.


Amoeba-Inspired Heuristic Search Dynamics for Exploring Chemical Reaction Paths.
We propose a nature-inspired model for simulating chemical reactions in a computationally resource-saving manner. The model was developed by extending our previously proposed heuristic search algorithm, called "AmoebaSAT [Aono et al. 2013]," which was inspired by the spatiotemporal dynamics of a single-celled amoeboid organism that exhibits sophisticated computing capabilities in adapting to its environment efficiently [Zhu et al. 2013]. AmoebaSAT is used for solving an NP-complete combinatorial optimization problem [Garey and Johnson 1979], "the satisfiability problem," and finds a constraint-satisfying solution at a speed that is dramatically faster than one of the conventionally known fastest stochastic local search methods [Iwama and Tamaki 2004] for a class of randomly generated problem instances [ http://www.cs.ubc.ca/~hoos/5/benchm.html ]. In cases where the problem has more than one solution, AmoebaSAT exhibits dynamic transition behavior among a variety of the solutions. Inheriting these features of AmoebaSAT, we formulate "AmoebaChem," which explores a variety of metastable molecules in which several constraints determined by input atoms are satisfied and generates dynamic transition processes among the metastable molecules. AmoebaChem and its developed forms will be applied to the study of the origins of life, to discover reaction paths for which expected or unexpected organic compounds may be formed via unknown unstable intermediates and to estimate the likelihood of each of the discovered paths.


Screening of nuclear targeting proteins in Acinetobacter baumannii based on nuclear localization signals.
Nuclear targeting of bacterial proteins is an emerging pathogenic mechanism in bacteria. However, due to the absence of an appropriate screening system for nuclear targeting proteins, systematic approaches to nuclear targeting of bacterial proteins and subsequent host cell pathology are limited. In this study, we developed a screening system for nuclear targeting proteins in Acinetobacter baumannii using a combination of bioinformatic analysis based on nuclear localization signal (NLS) and the Gateway(®) recombinational cloning system. Among 3367 open reading frames of A. baumannii ATCC 17978, 34 functional or hypothetical proteins were predicted to carry the putative NLS sequences. Of the 29 clones generated by the Gateway(®) recombinational cloning system, 14 proteins tagged with green fluorescent protein (GFP) were targeted to nuclei of host cells. Among the 14 nuclear targeting proteins, S21, L20, and L32 ribosomal proteins and transposase carried putative nuclear export signal (NES) sequences, but only transposase harbored the functional NES. After translocation to nuclei of host cells, four A. baumannii proteins induced cytotoxicity. In conclusion, we have developed a screening system for nuclear targeting proteins in A. baumannii. This system may open the way to a new field of bacterial pathogenesis.


Anti-inflammatory effects of crocin and crocetin in rat brain microglial cells.
Microglial cells play critical roles in the immune and inflammatory responses of the central nervous system (CNS). Under pathological conditions, the activation of microglia helps in restoring CNS homeostasis. However, chronic microglial activation endangers neuronal survival through the release of various proinflammatory and neurotoxic factors. Thus, negative regulators of microglial activation have been considered as potential therapeutic candidates to target neurodegeneration, such as that observed in Alzheimer's and Parkinson's diseases. Crocin and crocetin, found in the fruits of gardenia and in the stigmas of saffron, have been considered for the treatment of various disorders in traditional oriental medicine. Crocin and crocetin have been reported to have diverse pharmacological functions, such as anti-hyperlipidemic, anti-atherosclerotic, and anti-cancer effects. Specifically, the neuroprotective potential of crocetin derivatives has previously been demonstrated. The specific aim of this study was to examine whether crocin or crocetin represses microglial activation. Crocin and crocetin were shown to be effective in the inhibition of LPS-induced nitric oxide (NO) release from cultured rat brain microglial cells. These compounds reduced the LPS-stimulated productions of tumor necrosis factor-α, interleukin-1β, and intracellular reactive oxygen species. The compounds also effectively reduced LPS-elicited NF-κB activation. In addition, crocin reduced NO release from microglia stimulated with interferon-γ and amyloid-β. In organotypic hippocampal slice cultures, both crocin and crocetin blocked the effect of LPS on hippocampal cell death. These results suggest that crocin and crocetin provide neuroprotection by reducing the production of various neurotoxic molecules from activated microglia.


Characterization and biocompatibility studies of new degradable poly(urea)urethanes prepared with arginine, glycine or aspartic acid as chain extenders.
Polyurethanes are very often used in the cardiovascular field due to their tunable physicochemical properties and acceptable hemocompatibility although they suffer from poor endothelialization. With this in mind, we proposed the synthesis of a family of degradable segmented poly(urea)urethanes (SPUUs) using amino acids (L-arginine, glycine and L-aspartic acid) as chain extenders. These polymers degraded slowly in PBS (pH 7.4) after 24 weeks via a gradual decrease in molecular weight. In contrast, accelerated degradation showed higher mass loss under acidic, alkaline and oxidative media. MTT tests on polyurethanes with L-arginine as chain extenders showed no adverse effect on the metabolism of human umbilical vein endothelial cells (HUVECs) indicating the leachables did not provoke any toxic responses. In addition, SPUUs containing L-arginine promoted higher levels of HUVECs adhesion, spreading and viability after 7 days compared to the commonly used Tecoflex(®) polyurethane. The biodegradability and HUVEC proliferation on L-arginine-based SPUUs suggests that they can be used in the design of vascular grafts for tissue engineering.


Structural and biological characterization of a novel spermicidal vanadium(IV) complex: bis(pi-cyclopentadienyl)-N,N-diethyl dithiocarbamato vanadium(IV) tetrafluoro borate, [VCp2(DeDtc)](BF4).
In a systematic search for vanadocene complexes with sperm immobilizing activity as a new class of contraceptive agents, we identified V(eta 5-C5H5)2((C2H5)2 NCS2)(BF4) (=[VCp2(DeDtc)](BF4)) as the most potent and stable spermicidal compound. Here we report the detailed biologic and physicochemical characterization of this lead spermicidal compound by computer-assisted sperm analysis, electron paramagnetic resonance spectroscopy, electrochemistry, and X-ray crystallography. [VCp2(DeDtc)](BF4) crystallized in the monoclinic space group P2(1)/c, with unit cell dimensions a = 7.0877(4) A, b = 22.2881(14) A, c = 11.8021(7) A, beta = 94.107(1) degree, V = 1859.6(2) A3. The final structure of [VCp2(DeDtc)](BF4) had an R factor of 0.0581 for 3191 independent reflections. The two sulfur atoms of the dithiocarbamate and centroids of the cyclopentadienyl rings in this vanadocene complex with unique contraceptive potential occupy four tetrahedral--like coordination sites about the central metal atom.


Pulmonary microembolism: a cause of lung injury.
Microthrombi found in the pulmonary capillaries in patients dying with post-traumatic pulmonary insufficiency suggests that pulmonary microembolism (PME) may be etiologically important, but a temporal relationship has not been demonstrated. We used a modified Lim-Blaisdell model of PME to cause a severe ischemic soft tissue injury in dogs. The appearance of microaggregates (MA) in the venous circulation was measured using a laser optical scanning technique. The effect of MA on pulmonary physiologic and histologic parameters was measured and compared to control animals. In the ischemic soft tissue injury group, following restoration of local circulation, the platelet count dropped by 72% (P less than 0.00002), the number of MA increased by 800% (P less than 0.00002), the mean pulmonary artery pressure (PA) increased from 15.6 to 32 mm Hg (P less than 0.00002), and electron micrographs of lung obtained at 4 hr after ischemic insult revealed PM with severe lung injury that was consistent with a capillary membrane leak. The control group never demonstrated a significant change in platelets, MA, PA, or histologic lung injury. These findings imply that MA found in the pulmonary microcirculation are temporally related to the development of physiologic and anatomic lung abnormalities.


Presenting clinical trial information: a comparison of methods.
The study objective was to assess the relative effects of 2 approaches to teaching about a clinical trial, in terms of patients' satisfaction, information understanding, and whether or not they would enter such a trial. One hundred patients receiving radiation therapy for a variety of cancer diagnoses were randomized to receive information about a hypothetical trial, either by audio tape or interactive computer program. A day later, information understanding was assessed. One week later, method satisfaction and whether respondents would enter such a trial were assessed. There were no differences in understanding or satisfaction. Members of the computer program group tended to report a more positive attitude towards trial entry (chi 2 = 4.0; 1 df; P = 0.05). Overall, refusers tended to be women with higher understanding scores. The results suggest that teaching with interactive components might not adversely affect trial accrual. Further work involving an actual trial entry decision is merited; the sex of the respondent should be controlled in designing this future work.


Evolution of a natural dihydropteroate synthase and development of a signal amplified fluorescence method for detection of 44 sulfonamides in milk.
In this study, the recognition mechanisms and affinities of a natural dihydropteroate synthase for 44 sulfonamides were studied respectively. Then the key contact amino acid Ser222 was mutated to Arg222 by using site-directed mutagenesis method to produce a mutant. Results showed that the binding energies and affinities for the 44 drugs were generally improved. Then this mutant was used as recognition reagent to develop a direct competitive fluorescence method on 96-well microplate for determination of the 44 drugs in milk. Due to the used signal amplified fluorescent tracer, the limits of detection for the 44 drugs were in the range of 0.025-0.65 ng/mL, and the sensitivities were improved for about 6-86 folds in comparison with the conventional fluorescent tracer. After comprehensive comparison, the present method showed generally better performances than the previously reported immunoassays for sulfonamides. Therefore, this method could be used as an efficient tool for the routine screening of sulfonamides residues in large number of food samples.


Clinical significance of prostate volume and testosterone reduction on lower urinary tract symptoms in patients with prostate cancer undergoing androgen deprivation therapy.
To investigate the effect of both prostate volume and serum testosterone changes on lower urinary tract symptoms in patients with prostate cancer undergoing androgen deprivation therapy. A total of 167 patients who received androgen deprivation therapy for prostate cancer treatment from January 2010 to August 2020 were enrolled in this retrospective study. Changes in the International Prostate Symptom Score (IPSS) in the patient groups stratified by prostate volume and the amount of testosterone reduction were assessed every 4 weeks until 12 weeks after androgen deprivation therapy initiation. Longitudinal mixed models were used to assess the adjusted effects of prostate volume and testosterone reduction on IPSS change. All mean values of IPSS-total score (IPSS-total), voiding subscore (IPSS-vs), and storage subscore (IPSS-ss) significantly decreased from baseline to week 12 in both patients with small (< 33 mL) and large (≥ 33 mL) prostates. The mean values of IPSS-total, IPSS-vs, and IPSS-ss similarly decreased in patients with large prostate with a baseline IPSS-total of ≥ 13. However, in those with small prostate, IPSS-ss specifically remained unchanged, while IPSS-total and IPSS-vs significantly decreased. In addition, only in patients with small prostate (< 33 mL), patients with lesser testosterone reduction (< Δ400 ng/dL) showed greater improvement in IPSS-ss by 7.5% compared with those with greater testosterone reduction (≥ Δ400 ng/dL). In conclusion, although androgen deprivation therapy generally improves lower urinary tract symptoms, it may worsen specifically storage symptoms in patients with relatively small prostate and greater testosterone reduction. Our finding suggests that testosterone may influence lower urinary tract symptoms in these patients.


Atrial trigeminy induced by a normally functioning DVI pacemaker.
Atrial trigeminy was seen in a patient with a normally functioning DVI pacemaker (Byrel-5992). Atrial competition resulted from coincidence of sinus and atrial escape rates together with late ventricular sensing. This resulted in atrial output stimuli occurring within the QRS complex. Alternate impulses occurred late enough to conduct to the ventricle after recovery of the AV node. Reprogramming the pacemaker to either a faster DVI rate or to VVI abolished the arrhythmia.


How I do it: transnasal retraction during transoral robotic oropharyngeal resection.
Collapse of the resection plane presents a frustrating problem during transoral robotic resection, in a situation already typified by limited vision and access for instruments. We present a quick and cost-effective retraction technique to effectively mitigate this issue and increase the ease and reliability of robotic oropharyngeal resection. This technique utilises a simple transnasal apparatus to create greater exposure of the resection plane. A Y-suction catheter is inserted into the oropharynx via the nasal cavity. A silk suture is then used to attach it to the oropharyngeal resection specimen. When pulled from the nasal cavity, this apparatus adds a non-intrusive, tremor-free fixation point that pulls the resected specimen along a unique cephalo-posterior vector. This significantly improves access and vision of the desired dissection plane. The entire process takes approximately 1-2 min per side to properly execute. It can be adapted for various pathologies and subsites of the oropharynx. This transnasal technique is a simple, minimally invasive, and inexpensive method for improving wound tension during transoral oropharyngeal resection.


Cancer in Systemic Sclerosis: Analysis of Antibodies Against Components of the Th/To Complex.
The aim of this study is to describe 4 of the most common autoantibodies against components of the Th/To complex: human POP1 (hPOP1), RPP25, RPP30, and RPP40. We report their prevalence and clinical characteristics in a systemic sclerosis (SSc) population, and determine whether these specificities are associated with cancer. A case-control study was performed using data from the Johns Hopkins Scleroderma Center Cohort. A total of 804 adult patients with SSc were included; 401 SSc patients with no history of cancer after at least 5 years of disease were compared to 403 SSc patients who ever had a history of cancer. Antibodies against hPOP1, RPP25, RPP30, and RPP40 were assayed by immunoprecipitation of 35 S-methionine-labeled proteins generated by in vitro transcription/translation. Demographic and clinical characteristics were compared between groups. Of 804 patients, 67 (8.3%) had antibodies against any component of the Th/To complex. Patients with antibodies to any component were significantly more likely to have limited cutaneous disease, less likely to have tendon friction rubs, and more likely to have findings consistent with interstitial lung disease or pulmonary hypertension. Patients with antibodies against hPOP1, RPP25, RPP30, and/or RPP40 were significantly less likely to develop cancer within 2 years of SSc onset (0% versus 11% of antibody-negative patients; P = 0.009). SSc patients who produce autoantibodies to components of the Th/To complex have a clinical phenotype characterized by limited cutaneous disease and pulmonary involvement. Our findings show that the presence of any Th/To autoantibody may have a protective effect against contemporaneous cancer.


Students' appraisal of a preparedness model for the provision of oral health care during a pandemic.
The COVID-19 pandemic has impacted the provision of oral health care worldwide, prompting the discussion of preparedness. This study aimed to perform an initial appraisal of the usability, spatial representation, and clarity of a newly developed preparedness model from the perspective of senior undergraduate dental students at the University of British Columbia, Vancouver, Canada, enrolled in the 2020-21 academic year. Answers were analyzed thematically via an inductive coding process between March and June 2021. All the 111 students in years 3 (#55) and 4 (#56) appraised the preparedness model, generating more than 200 pages of text. Four main themes were identified across the essays: streamlined depiction, information-based approach, adaptability to an ever-changing situation, and room for improvement. Although the majority of students appraised the model as being useful in fostering information-seeking behaviour, few students disagreed with the model's portrayal and made further suggestions. Preparedness models can better guide oral health care providers during a health crisis such as a pandemic. The recently developed preparedness model was appraised as useful by senior undergraduate dental students, although alternative portrayals of the model were suggested. A comprehensive assessment of the newly developed model (and of its variations) is warranted to better support oral health care service delivery during a pandemic.


Clinical Practice Experiences Using a Professional Diabetes Management Ecosystem During COVID.
Challenges of patient care in diabetes were exacerbated by COVID, undermining the ability of patients to engage in-person with health care professionals (HCPs). To combat this, there has been accelerated adoption of telemedicine to support patient and provider connectivity. We collated survey information regarding telemedicine from 21 European clinical institutions. Health care professionals joined virtual meetings focusing on the OneTouch Reveal (OTR) ecosystem and its utility for conducting telemedicine. Selected HCPs provided clinical case studies to explain how the OTR ecosystem supported patient care. Remote consultations increased by nearly 50% in 21 European clinics during the pandemic (Belgium [24%], Iberia [65%], Germany [34%], Italy [54%]). In all, 52% of people with diabetes using OTR app to connect remotely with HCPs had type 1 diabetes and 48% had type 2 diabetes. Remote connection methods included telephone (60%), email (19%), video chat (10%), text only (3%), or a mix of these methods (8%). Health care professionals usually reviewed patient data during consultations (45%) rather than before consultations (25%). Fifty-five percent of HCPs indicated digital ecosystems like OTR ecosystem would become their standard of care for diabetes management. In-depth conversations with HCPs provided a deeper understanding of how a digital ecosystem integrated into clinical practice and population management. In addition, five patient case studies using OTR ecosystem were provided by a selection of our HCPs. Diabetes management solutions, such as OTR ecosystem, supported telemedicine during the pandemic and will continue to play a valuable role in patient care beyond the pandemic.


Chromosomal anomalies in patients with short stature.
The incidence of chromosomal anomalies in patients with short stature (SS) was studied in order to determine the value of routine karyotyping in this population. This study was a retrospective evaluation of 972 patients (719 females and 253 males) with SS. Chromosomal analysis was performed on cultured peripheral lymphocytes. The incidence of chromosome aberrations in males was 2.77% (7/253) and in females 9.8% (71/719). Several groups were made according to clinical features and familial antecedents of SS. We observed different incidence rates of chromosomal anomalies among groups of patients, mainly in females. The incidence in the group without familial antecedents was 18.89%, however, in females with familial antecedents it was 4.45%. In females with isolated SS we detected karyotype anomalies in the 3.98%, while in patients with phenotypic features, amenorrhoea and SS the incidence was 77.78%. In females the most frequent anomaly was Turner syndrome, present in 55 patients (77.46%). Karyotype analysis is recommended for all girls with unexplained SS and associated abnormalities. In females with isolated SS a cost-benefit analysis must be done in each case.


CO2 fixation and its regulation in Anacystis nidulans (Synechococcus).
Anacystis nidulans (Synechococcus) had a minimal doubling time of 5 hrs at 30 degrees C at saturating light intensity and carbon dioxide concentration. Half maximal growth rates in saturating CO2 occured at a light intensity of 0.54 mW per cm2, and there was an apparent threshold intensity of 0.13 mW per cm2 below which no growth occurred. Growth rate in saturating light was dependent on the concentration of CO2+H2CO3 in the medium, rather than on total dissolved CO2; half maximal rates were estimated at 0.1 mM CO2+H2CO3. Under saturating conditions of light and CO2, 14CO2 was fixed primarily into 3-PGA, and subsequently moved into sugar phosphates and amino acids. Incorporation into aspartate was relatively slow. CO2 fixation was strictly light-dependent. The changes in adenylate and pyridine nucleotide pools were followed in light/dark and dark/light transitions. Whereas adenylates relaxed slowly over 15-20 min to the concentrations characteristic of illuminated cells following the abrupt changes induced by darkening, the sharp drop in intracellular NADPH showed little dark recovery although rapid restoration occurred on reillumination. Other pyridine nucleotides showed no changes during these transitions. The nucleotide specificity and Km of partially purfied GAP dehydrogenase suggest a role for this enzyme in the regulation of CO2 fixation.


Arthroscopic glenohumeral folds and microscopic glenohumeral ligaments: the fasciculus obliquus is the missing link.
This study tested the hypotheses that the folds in the inferior glenohumeral capsule appear at the borders and crossings of the underlying capsular ligaments and that embalming may result in misinterpretation of these folds as ligaments. The inferior capsular structures in 80 unembalmed cadaver shoulders were compared with 24 embalmed shoulders. During arthroscopy and dissection, an anteroinferior fold was more prominently seen in internal rotation and was almost obliterated in external rotation. A posteroinferior fold appeared in external rotation and almost disappeared in internal rotation. During dissection, the anteroinferior fold developed at the border of the anterior band of the inferior glenohumeral ligament (ABIGHL) and where this ligament crossed with the fasciculus obliquus (FO). Several patterns of crossing of the ABIGHL and the FO were seen that determined the folding-unfolding mechanism of the anteroinferior fold and the appearance of possible synovial recesses. The axillary part of the IGHL is formed by the FO on the glenoid side and by the ABIGHL on the humeral side. The posteroinferior fold was determined by the posterior band of the IGHL. The folds in the embalmed specimens did not necessarily correspond with the underlying fibrous structure of the capsule. The folds and recesses observed during arthroscopy indicate the underlying capsular ligaments but are not the ligaments themselves. The IGHL complex is formed by its anterior and posterior bands and also by the FO. Both findings are important during shoulder instability procedures because the ligaments need to be restored to their appropriate anatomy and tension. Because the FO may also be involved, Bankart-type surgery may have to reach far inferiorly. Midsubstance capsular shift procedures also need to incorporate this ligament.


Considerations for implementing United States pharmacopeia chapter 797 pharmaceutical compounding-sterile preparations.
To ensure the quality of compounded preparations, an efficient quality-assurance program is necessary. This article clearly defines the elements necessary to establish a quality-assurance program that meets the standards set forth in the United States Pharmacopeia in the area of personnel training. It is essential that compounders have knowledge of the substances used in compounding and the devices used in the compounding facility. Specific and continuous training is essential to provide the compounder with the necessary knowledge to get the job completed. Knowledge of basic science principles is necessary to enable the compounder to understand and interpret scientific data and reports provided by the suppliers. In addition, handling and manipulating the equipment requires specific training to ensure that the results generated by the equipment are correct and accurate.


How many cardiovascular events can be prevented with optimal management of high-risk Canadians?
Strong evidence exists to support the use of statins, acetylsalicylic acid (ASA) and angiotensin-converting enzyme inhibitors (ACEI) in patients at high risk of cardiovascular (CV) events; however, current practice pattern data indicate that a significant care gap exists between evidence and practice. To quantify the reduction in CV events that may be obtained with the optimal use of vascular protection therapy in Canadians at high risk of cardiovascular events. Canadian Community Health Survey data from 2003 were used to estimate the prevalence of heart disease and/or diabetes, which were applied to an age-specific population in Canada to calculate the total number of high-risk patients. The number of events over 10 years was estimated using a state transition model, published risk equations, practice pattern data from Canadian registries and published therapy efficacy from clinical trials. Among 2.2 million high-risk Canadians, current care with statin, ASA and ACEI therapy has reduced the estimated occurrence of CV events over the next 10 years by approximately 400,000 from 1.01 million. Universal use of combination statin, ASA and ACEI therapy for high-risk patients, compared with current care, would prevent as many as 143,000 more CV events over the next 10 years. Great advances in the management of CV disease have been made; however, CV disease remains a substantial burden to patients and to the Canadian health care system. Canadian physicians have the opportunity to further reduce this burden through optimal management of high-risk patients based on clinical guidelines.


Bacteriophages benefit from mobilizing pathogenicity islands encoding immune systems against competitors.
Bacteria encode sophisticated anti-phage systems that are diverse and versatile and display high genetic mobility. How this variability and mobility occurs remains largely unknown. Here, we demonstrate that a widespread family of pathogenicity islands, the phage-inducible chromosomal islands (PICIs), carry an impressive arsenal of defense mechanisms, which can be disseminated intra- and inter-generically by helper phages. These defense systems provide broad immunity, blocking not only phage reproduction, but also plasmid and non-cognate PICI transfer. Our results demonstrate that phages can mobilize PICI-encoded immunity systems to use them against other mobile genetic elements, which compete with the phages for the same bacterial hosts. Therefore, despite the cost, mobilization of PICIs may be beneficial for phages, PICIs, and bacteria in nature. Our results suggest that PICIs are important players controlling horizontal gene transfer and that PICIs and phages establish mutualistic interactions that drive bacterial ecology and evolution.


A shape-memory poly(ε-caprolactone) hybridized TiO2/poly(l-lactide) composite with antibacterial properties.
Organic-inorganic composites as an efficient strategy to upgrade the structural and functional properties of synthetic polymers are attracting extensive attentions. However, there are few studies on the shape memory (SM) behavior of organic-inorganic composites. In the work, poly(ε-caprolactone) hybridized TiO2 nanomaterial (PCL-TiO2) is made as the switching phase and integrated into poly (l-lactide) (PLLA) to construct an SM composite. PCL-TiO2/PLLA shows "sea-island" structure and better interfacial adhesion than PCL/PLLA, which facilitates the transmission of elastic power between the switching phase and the fixing phase. PCL-TiO2 as switching phase exhibits lower enthalpy at 57 °C than PCL, and PCL-TiO2 also acts as "heat dispersion pump station", which builds a dynamically responsive system and initiates shape change. The shape fixing and recovery ratio of PCL-TiO2/PLLA are 93.9 % and 94.4 %, respectively, and go back to the original shape within 15 s at 57 °C. At the same time, PCL-TiO2 endows SMP with good antibacterial properties. Then this work provides a well-placed way for developing SM materials with structure-function integration.


International Epidemiology of Carbapenemase-Producing Escherichia coli.
Carbapenemase-producing (CP) Escherichia coli (CP-Ec) are a global public health threat. We aimed to describe the clinical and molecular epidemiology and outcomes of patients from several countries with CP-Ec isolates obtained from a prospective cohort. Patients with CP-Ec were enrolled from 26 hospitals in 6 countries. Clinical data were collected, and isolates underwent whole-genome sequencing. Clinical and molecular features and outcomes associated with isolates with or without metallo-β-lactamases (MBLs) were compared. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after the index culture. Of the 114 CP-Ec isolates in Consortium on resistance against carbapenems in Klebsiella and other Enterobacterales-2 (CRACKLE-2), 49 harbored an MBL, most commonly blaNDM-5 (38/49, 78%). Strong regional variations were noted with MBL-Ec predominantly found among patients in China (23/49). Clinically, MBL-Ec were more often from urine sources (49% vs 29%), less often met criteria for infection (39% vs 58%, P = .04), and had lower acuity of illness when compared with non-MBL-Ec. Among patients with infection, the probability of a better DOOR outcome for a randomly selected patient with MBL-Ec as compared with non-MBL-Ec was 62% (95% CI: 48.2-74.3%). Among infected patients, non-MBL-Ec had increased 30-day (26% vs 0%; P = .02) and 90-day (39% vs 0%; P = .001) mortality compared with MBL-Ec. Emergence of CP-Ec was observed with important geographic variations. Bacterial characteristics, clinical presentations, and outcomes differed between MBL-Ec and non-MBL-Ec. Mortality was higher among non-MBL isolates, which were more frequently isolated from blood, but these findings may be confounded by regional variations.


[Epistaxis].
Epistaxis is a common clinical condition that can be challenging. Anterior epistaxis is managed by compression, cauterization or diathermy. Merocel and Rapid Rhino nasal packs are often successfully used. Refractory posterior epistaxis should be handled by otorhinolaryngologists. If conservative strategies such as combined anterior and posterior nasal packing fail the patient should be referred to surgical intervention. The evidence for early endoscopic ligation and/or diathermy of the sphenopalatine or etmoidal anterior arteries is significant, and the patients experience less co-morbidity.


Seminal anti-Müllerian hormone level is a marker of spermatogenic response during long-term gonadotropin therapy in male hypogonadotropic hypogonadism.
In adult men, anti-Müllerian hormone (AMH) levels are higher in semen than in serum, but the significance and control of its seminal secretion are still unknown. This study evaluated seminal and serum AMH levels during long-term gonadotropin therapy in men with hypogonadotropic hypogonadism (HH). A total of 20 men with never treated prepubertal-onset HH received i.m. hCG to normalize testosterone (T) and induce puberty. Afterwards, 11 of them, requiring fertility, were treated with HCG plus recombinant FSH (rFSH) (75 IU) twice a week, whereas 9 continued to receive hCG alone for 12 months. Before and during therapy, serum AMH, inhibin B and T levels were assessed. Semen samples were also collected during therapy for sperm count and seminal AMH assay. HCG alone decreased basal high serum AMH and stimulated T and inhibin B levels. rFSH plus hCG increased seminal AMH levels, which were consequently significantly higher than with hCG alone, and positively correlated to sperm densities and testicular volumes at 3 and 12 months (P < 0.001). Our data demonstrate that rFSH, added to hCG, stimulates seminal AMH and spermatogenesis in HH. Thus, seminal AMH levels are under T and FSH control and are closely related to progression of spermatogenesis. Our results also suggest that an early seminal AMH increase may be a marker of good future response to gonadotropin therapy in HH.


Evaluation of serum FoxO1, mTORC1, IGF-1, IGFBP-3 levels, and metabolic syndrome components in patients with acne vulgaris: A prospective case-control study.
Recently, insulin-like growth factor-1 (IGF-1), forkhead box transcription factor (Fox) O1, and mechanistic target of rapamycin complex 1 (mTORC1) signaling have been introduced as key elements in acne pathogenesis. The aim of this study is to investigate the relationship between serum levels of IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), FoxO1 and mTORC1, and the components of metabolic syndrome (MS) and AV. This prospective case-control study was carried out on 89 participants, including 49 AV patients and 40 controls. The serum levels of IGF-1, IGFBP-3, insulin, FoxO1, and mTORC1 were measured along with the components of MS. The blood pressure (BP) measures were significantly higher in the AV patients than in the controls (P = .001). The mean high-density lipoprotein cholesterol (HDL-C) levels were significantly lower in the AV patients than in the controls (P = .040). The numbers of accompanying MS components were significantly higher in the AV patients than in the controls (P = .001). The IGFBP-3 levels were significantly higher in the AV patients than in the controls (P = .02). The IGF-1, mTORC1, and FoxO1 levels were higher in the AV patients than in the controls; neither were statistically significant (P = .093, P = .741, and P = .564, respectively). The higher BP and IGFBP-3 levels, the lower HDL-C levels and the common presence of MS components demand caution in terms of new therapeutic strategies and possible associated comorbidities.


Spectral and thermal studies with anti-fungal aspects of some organotin(IV) complexes with nitrogen and sulphur donor ligands derived from 2-phenylethylamine.
Some complexes of 2-phenylethyl dithiocarbamate, thiohydrazides and thiodiamines with dibenzyltin(IV) chloride, tribenzyltin(IV) chloride and di(para-chlorobenzyl)tin(IV) dichloride have been synthesized and investigated in 1:2 and 1:1 molar ratio. The dithiocarbamate ligand act as monoanionic bidentate and thiohydrazide, thiodiamines act as neutral bidentate ligand. The synthesized complexes have been characterized by elemental analysis and molecular weight determination studies and their bonding pattern suggested on the basis of electronic, infrared, 1H and 13C NMR spectroscopy. Using thermogravimetric (TG) and differential thermal analysis (DTA) various thermodynamic and kinetic parameters viz. reaction order (n), apparent activation energy (Ea), apparent activation entropy (S#) and heat of reaction (DeltaH) have been calculated and correlated with the structural aspects for solid-state decomposition of complexes. The ligands and their tin complexes have also been screened for their fungitoxicity activity against Rhizoctonia solanii and Sclerotium rolfsii and their ED50 values calculated.


Modified high-performance liquid chromatography technique for detection of vancomycin in human vitreous.
To standardize the technique and methodology for estimating the level of vancomycin in human vitreous using a modified high-performance liquid chromatographic method. Sample preparation involved spiking the vitreous with known quantities of the drug followed by a brief treatment with 30% trichloroacetic acid. Samples were analyzed on a C18 reverse-phase column using a mobile phase of 50 mM phosphate buffer (pH 4.0) and 10% acetonitrile. Vancomycin was detected at 198 nm. It showed a retention time of 2.2 min in the vitreous. A linear increase in the area under the peak corresponding to the drug was observed with increase in concentration of vancomycin in the vitreous. The method was applied to detect the vancomycin levels in vitreous of 5 patients with exogenous endophthalmitis, 24-48 h after intravitreal injection of vancomycin 1 mg/0.1 ml. The mean concentration of vancomycin in these samples was 120.022 +/- 59.87 microg/ml (43.859-179.09 microg/ml). The present technique allowed a quantification limit of 1 microg/ml. This technique is suitable to estimate vancomycin levels in human vitreous in a variety of clinical and experimental studies. It has the added advantages of being less expensive, simple and rapid.


Obstruction to left coronary artery blood flow secondary to obliteration of the coronary ostium in supravalvular aortic stenosis.
Supravalvular aortic stenosis is characterized by obstruction of the left ventricular outflow tract distal to the aortic valve, and may result in diminished coronary artery blood flow. This report describes the cases of 2 patients in whom obstruction to left coronary artery flow was caused by obliteration of the coronary ostium itself. This mechanism differs from the more commonly recognized cause--valve leaflet adhesion to the obstructing ridge of aortic tissue. The coronary artery obstruction found in these 2 patients required direct enlargement of the left coronary ostium in both. This mechanism of impaired coronary artery flow deserves emphasis, as traditional methods of extended patch aortoplasty may fail to relieve the coronary ostial narrowing.


Access to, interest in and attitude toward e-learning for continuous education among Malaysian nurses.
Continuous nursing education (CNE) courses delivered through e-learning is believed to be an effective mode of learning for nurses. Implementation of e-learning modules requires pre-assessment of infrastructure and learners' characteristics. Understanding the learners' needs and their perspectives would facilitate effective e-learning delivery by addressing the underlying issues and providing necessary support to learners. The aim of this study was to examine access to computer and Internet facilities, interest in and preferences regarding e-learning, and attitudes toward e-learning among nurses in Peninsular Malaysia. The study utilized a cross-sectional descriptive survey. Government hospitals and community clinics in four main regions of Peninsular Malaysia. A total of 300 registered nurses. Data were collected using questionnaires, which consisted of demographic and background items and questions on access to computer and Internet facilities, interest and preferences in e-learning, and attitudes toward e-learning. Descriptive analysis and a chi-squared test were used to identify associations between variables. Most Malaysian nurses had access to a personal or home computer (85.3%, n=256) and computer access at work (85.3%, n=256). The majority had Internet access at home (84%, n=252) and at work (71.8%, n=215); however, average hours of weekly computer use were low. Most nurses (83%, n=249) did not have an e-learning experience but were interested in e-learning activities. Most nurses displayed positive attitudes toward e-learning. Average weekly computer use and interest in e-learning were positively associated with attitudes toward e-learning. Study findings suggest that organizational support is needed to promote accessibility of information and communications technology (ICT) facilities for Malaysian nurses to motivate their involvement in e-learning.


Thoughts and experiences on leg amputation among patients with diabetic foot ulcers.
Although leg amputation is common among patients with diabetic foot ulcers, only few studies have examined the thoughts regarding leg amputation from the perspective of patients. This study aims to explore the thoughts of patients with diabetic foot ulcers regarding leg amputation. A qualitative design using semi-structured interviews were used and analysed using Interpretative Phenomenological Analysis (IPA). In all five patients participated and the interview questions were focused on thoughts in relation to a possible leg amputation. Four significant themes were revealed: 1) "Considered-not spoken"-reflections on being alone with one's thoughts, 2) "What people think about me"-concerns about consequences on social relations, 3) "The tough ones and the ones who whine"-considerations about expected self-efficacy and 4) "Limitations and opportunities"-thoughts about physical consequences. Even if an amputation is not yet planned, having a diabetic foot ulcer can result in divergent thoughts regarding leg amputation. The findings indicate that amputation is considered a taboo which makes it difficult for the patient to talk about it within either the health care context or with relatives. Health care professionals should therefore be aware of how they communicate regarding leg amputation.


SHP2 is a downstream target of ZAP70 to regulate JAK1/STAT3 and ERK signaling pathways in mouse embryonic stem cells.
Previous research indicated that ZAP70, a Syk family tyrosine kinase, is expressed in mouse embryonic stem cells (mESCs) and regulates the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) signaling through consolidating SHP1 enzymatic activity. In this study, we report that SHP2 is another downstream target of ZAP70 in mESCs. We found that SHP2 phosphorylation and enzymatic activity are affected by Zap70 expression. In addition, we present evidence that ERK pathways activated by ZAP70 and SHP2 reduce the protein level of leukemia inhibitory factor (LIF) receptor. Based on these results, we propose that SHP2 is an essential mediator of the ZAP70 signal to regulate JAK1/STAT3 and ERK pathways in undifferentiated mESCs.


Increase in trauma volume as compared to emergency department volume during the COVID-19 pandemic.
During the months between April through June 2020 when we experienced the largest number of COVID-19 patients in our hospital, the volume of patients in the Emergency Department (ED) was decreased by more than 30%. In contrast to most early reports we did not notice a decrease in trauma volume during this time period. We compared trauma patients presenting to our Level III Trauma Center, between April 2019 through June 2019 to those presenting from April 2020 through June 2020, the initial surge in COVID-19 patients. We compared ground level falls (GLF), motor vehicle crashes (MVC), bicycle and skateboard crashes, assault, and other. There was a 13% increase in trauma patients presenting during the study period in 2020 as compared to 2019, and the total number of trauma patients as a percentage of total ED patients also increased 269/9235 (2.9%) to 308/6216 (5.0%), P < 0.0001. There was no significant difference in demographics or outcome data between the trauma patients presenting during the two time periods. Although traffic decreased by more than 40%, the number of MVC's was similar. The volume of patients presenting to our Trauma Center as compared to the total ED volume increased during the time period from April through June 2020 versus the year just prior to the COVID-19 pandemic. Despite the fact that the total traffic volume decreased more than 40 percent between these two time periods, the actual number of motor vehicle crashes remained similar.


Coordination among the body segments during reach-to-grasp action involving the trunk.
To understand the internal representations used by the nervous system to coordinate multijoint movements, we examined the coordination among the body segments during reach-to-grasp movements which involve grasping by the hand and reaching by the arm and trunk. Subjects were asked to reach and grasp an object using the arm only, the trunk only, and some combinations of both arm and trunk. Results showed that kinematic parameters related to the transport component of the arm and the trunk, such as peak velocity and time to peak velocity, varied across conditions and that the coordination pattern between the arm and trunk was different across conditions. However, parameters related to the grasp component, such as peak aperture, time to peak aperture, and closing distance, were invariant, regardless of whether the hand was delivered to the target by the arm only, the trunk only, or both. We hypothesize that a hierarchy of motor control processes exists, in which the reach and grasp components are governed by independent neuromotor synergies, which in turn are coordinated temporally and spatially by a higher-level synergy.


Ethnic differences in prenatal growth and the association with maternal and fetal characteristics.
The objectives of this study were to determine ethnic differences in prenatal growth and to examine their association with differences in maternal and fetal characteristics such as maternal height, weight, age, parity and fetal gender. A total of 1494 women from Rotterdam, The Netherlands, with a low-risk pregnancy who participated in a population-based cohort study, the Generation R Study, were offered three ultrasound examinations during pregnancy. Multilevel modeling was applied to determine ethnic differences in (estimated) fetal weight (including birth weight) and in the separate biometric variables that were used to calculate the estimated fetal weight (abdominal circumference, head circumference and femur length). Additionally the association of ethnic differences with maternal and fetal characteristics (i.e. maternal weight, height, age, parity and fetal gender) was studied. Turkish, Cape Verdian, Surinamese-Creole and Surinamese-Hindustani women had on average smaller fetuses than the native Dutch women. The differences became more pronounced towards term. In the Turkish group the differences were no longer statistically significant when adjusted for maternal weight, height, age, parity and fetal gender. In the Cape Verdian, Surinamese-Creole and Surinamese-Hindustani groups the differences decreased after adjustment (31%, 16% and 39%, respectively). This study shows that there are ethnic differences in fetal growth, which to a large extent may be attributed to differences in maternal weight, height, age and parity. For some ethnic groups, however, additional factors are involved, as differences remain significant after correction for fetal and maternal characteristics.


Calcitonin therapy in central giant cell granuloma of the jaw: a randomized double-blind placebo-controlled study.
The successful therapeutic use of calcitonin in patients with a central giant cell granuloma has been shown in several case reports. In a prospective, randomized, double-blinded, placebo-controlled clinical trial, 14 patients with a histologically confirmed central giant cell granuloma and normal calcium and parathyroid hormone serum levels were studied over 2 years. Patients were treated with intranasally administered salmon calcitonin (200 IU/day) or a placebo once a day. The placebo-controlled period was 3 months, after which all patients were treated with calcitonin for 1 year. Treatment response was assessed at the end of the placebo-controlled study phase (3 months), at the end of therapy (15 months' timepoint with patients being on calcitonin treatment for either 12 or 15 months) and at 6 months' follow-up. The chi(2)-test was used to compare the proportion of patients with a tumour reduction >/=10% of the pretreatment measurement between the 2 populations at the 3 timepoints: no differences were observed between the placebo group and the calcitonin group. At the 6-month follow-up timepoint, tumour volume had decreased by >/=10% in a total of 7 patients with a 37.9% (95% CI 31.3-44.5%) mean volume reduction in this subgroup. Complete remission was not observed.


[TKI Resistance for T790M Mutation].
Epidermal growth factor receptor (EGFR) the development of orally activesmall molecule inhibitors for non-small cell lung cancer (NSCLC) provides anew treatment plan. EGFR gene mutation in patients with activation EGFR tyrosine kinase inhibitor (EGFR-TKIs) therapy for the treatment of sensitive, so that a large number of clinical benefit. The first generation of reversible ATP-competitive EGFR-TKIs, gefitinib and erlotinib as first-line, second-line or has the effect of maintenance therapy. Although the initial effect of these drugs have, but most patients will produce drug resistance. Within a year, 50%-60% patients had T790M housekeeping gene mutation associated with. Irreversible EGFR-TKIs recent background: afatinib and dac-omitinib covalent binding and inhibition of multiple ErbB family receptors (EGFR, HER2 and HER4). People evaluate these drugs as first-line treatment of significance, and acquired drug resistance situation significance on the first generation EGFR-TKIs. Afatinib is the first ErbB family approved blocking agent, used to treat with EGFR activating mutations in patients with non small cell lung cancer; dacomitinib are in the later stages of clinical development. EGFR inhibitors specifically targeting T790M resistance mutations (AZD9291, CO-1686, HM61713) are in the early stages of development. As discussed in this paper, the scope of the EGFR-TKIs kinase to target different, EGFR receptor binding was reversible and drug interaction potential is also different. For clinicians, these differences of the multi drug treatment of patients with non-small cell lung cancer with meaning, from the innovative anticancer drug combination therapy strategy point of view, these differences are also of great significance.


Analysis of fatty acids in A. szechenyianum Gay. by microwave-assisted extraction and gas chromatography-mass spectrometry.
Aconitum szechenyianum Gay. is a traditional Chinese medicinal herb with the detumescent and styptic effects and antitumor activity. There have been only a few researches on its chemical components, but no detailed report has appeared on its fatty acids. To develop a simple and effective method for the extraction of fatty acids from A. zechenyianum Gay. and then to investigate the fatty acid components. Microwave-assisted extraction (MAE) was optimized with response surface methodology, and the fatty acid compositions of extract were determined by GC-MS with previous derivatisation to fatty acid methyl esters (FAMEs). The results were compared with that obtained by classical Soxhlet extraction (SE). Compared with SE, MAE showed significantly higher fatty acid yields, shorter extraction time, and lower energy and solvent consumption. The major fatty acids in A. szechenyianum Gay. are linoleic acid, palmitic acid, linolenic acid, oleic acid and stearic acid, and the unsaturated fatty acids occupy 66.4% of the total fatty acids.


Exposure to the field of renal transplantation during undergraduate medical education in the UK.
There is a lack of surgeons in the field of renal transplantation, with a predicted shortage of over 20 consultants by the year 2005. Early positive exposure to the field, commencing at undergraduate level, has been identified as being vital to improving rates of recruitment. This study was performed to assess the exposure of undergraduates to the field of renal transplantation during medical education in the UK. In October 2004 a questionnaire was sent to the clinical deans of all UK medical schools regarding undergraduate exposure to renal transplantation. Twenty-five replies were received, giving a response rate of 96%. All but one school had a centre for renal transplantation in their region. Three schools (12%) gave no formal lecture or tutorial on the subject during the entire course. Of the remainder, between one to four formal sessions were provided, ranging from 15 minutes to 3 hours duration. Six medical schools (24%) provided no compulsory clinical exposure to renal transplantation, with a further five (20%) saying that students may receive exposure by chance. The average length of attachment was three weeks. Twenty-one medical schools (84%) provided between 1-10% of students a choice to study renal transplantation, as part of electives and special study modules. This study reveals a variation between, and within, medical schools in the levels of formal teaching. If the trends in recruitment to renal transplantation are to be reversed, we have an obligation to improve upon the medical education that students currently receive.


Expanding the synthetic biology toolbox: engineering orthogonal regulators of gene expression.
Despite substantial progress in synthetic biology, we still lack the ability to engineer anything as complex as Nature has. One of the many reasons is that we lack the requisite tools for independently controlling the expression of multiple genes in parallel. While our toolbox is still spare, the situation is rapidly changing. This opinion discusses some recent approaches and open challenges in designing orthogonal regulators of gene expression in bacteria.


Isolated hepatic perfusion with 200 mg melphalan for advanced noncolorectal liver metastases.
The liver is one of the most common sites for metastatic solid tumors. If the liver is the only site of metastatic disease, regional treatment options can offer the benefit of high local exposure with limited systemic toxicity, especially for patients without (further) systemic treatment options. We report the results of our experience with isolated hepatic perfusion (IHP) in patients with isolated liver metastases from a variety of primary tumors. Nineteen patients with isolated unresectable liver metastases from a variety of tumors (13 uveal melanomas, 2 neuroendocrine carcinomas, 2 gastrointestinal stromal tumors, 1 hepatocellular carcinoma, and 1 high-grade sarcoma) were treated with a 60-min IHP using 200 mg melphalan. Patients were monitored for toxicity, response according to response evaluation criteria in solid tumors (RECIST) criteria, and survival. One melanoma patient was not perfused due to insufficient isolation of the liver. There was no treatment-related mortality. Reversible grade 3 or 4 hepatoxicity occurred in 10 (56%) patients, while veno-occlusive disease occurred in 4 (22%) patients. Of the 12 uveal melanoma patients who were perfused, 4 (33%) patients had a partial hepatic response, 6 (50%) patients had stable hepatic disease, and 2 (17%) patients were immediately progressive. Median disease-free survival was 6.6 months with a median overall survival of 10.0 months. Fifty percent of other primary tumors showed at least partial remission, including one complete remission in a high-grade sarcoma patient. IHP with melphalan shows activity in patients with liver metastases from a variety of primary tumors, but other or additional drugs may improve therapeutic outcome.


A retrospective study of the value of chemotherapy as adjuvant therapy to surgery and radiotherapy in grade 3 and 4 gliomas.
The aim of this retrospective study was to evaluate the effect of adjuvant chemotherapy among patients < 55 years of age with anaplastic gliomas (historical grade 3, n = 85) with four cycles 4 weeks apart of 160 mg carmustine (BCNU) infused into the internal carotid artery, combined with vincristine 2 mg and procarbazine 50 mg x 3 for 1 week (i.a.BCNU-PV) versus no adjuvant chemotherapy. In glioblastomas (histological grade 4, n = 257) the same chemotherapy was evaluated versus two cycles 4 weeks apart of 160 mg lomustine (CCNU) orally instead of BCNU, combined with vincristine and procarbazine (PCV) versus no chemotherapy. All patients in both groups received radiotherapy. Among glioblastoma patients < 55 years of age there was a significant (P = 0.03), but moderately increased survival in the i.a.BCNU-PV group versus the two other arms that did not differ from each other. This difference could be explained by an uneven distribution of prognostic factors, especially age group (< 50 years versus 50-54 years) in favour of the i.a.BCNU-PV group. In anaplastic gliomas, the median survival in the i.a.BCNU-PV group was 80 months versus 25 months for the no chemotherapy arm (P = 0.004). No significant differences in the distribution of prognostic factors were found between the two therapy arms. We suggest that the role of adjuvant chemotherapy in glioblastomas is unclear, while i.a.BCNU-PV as adjuvant chemotherapy among patients < 55 years of age and with anaplastic gliomas increased survival markedly.


A transcriptional regulatory element screening system reveals a novel E2F1/pRb transcription regulation pathway.
We developed a transcriptional regulatory element library which contains 160 independent known transcriptional regulatory elements linked to luciferase reporter vectors. That library proved valuable in the identification of p53 response elements and of E-box sequence preferences of several E-box binding proteins, and we used it to explore E2F1 target regulatory elements. Among those 160 elements, we found 3 E2F1 response elements, an E2F1 consensus sequence, an insulin response element which contained the E2F consensus sequence, and a basal level enhancer (BLE1) which had a nonconsensus E2F binding sequence. BLE1 functioned as multiple copy, with E2F1 in a dose-dependent manner, and had a sequence specificity for E2F1. Electrophoretic mobility shift assay revealed that BLE1 specifically interacts with E2F1 comparable to the E2F element. Interestingly, transactivation via five copies of BLE1 was not repressed but rather was stimulated by E2F1 in combination with the retinoblastoma tumor suppressor protein (pRb). The retinoblastoma control element (RCE) contains a direct repeated BLE1 in the c-fos gene promoter which also functioned like the multiple BLE1. Our data show that E2F1 has potential binding activity to the RCE and a different transcriptional regulation pathway which cooperates with pRb. Our transcriptional regulatory element screening system is useful for identifying novel transcriptional pathways.


Oligomeric structure, enzyme kinetics, and substrate specificity of the phycocyanin alpha subunit phycocyanobilin lyase.
Phycobiliproteins carry linear tetrapyrrole chromophores (bilins) thioether-linked to specific cysteine residues. The process of bilin attachment to apoprotein in vivo has been characterized for only one bilin attachment site on one phycobiliprotein, that on the alpha subunit of phycocyanin (alpha PC). In the cyanobacterium Synechococcus sp. PCC 7002, the addition of phycocyanobilin to apo-alpha PC is catalyzed by the protein products of the cpcE and cpcF genes. We have purified and further characterized the recombinant CpcE and CpcF proteins. CpcE and CpcF form an enzymatically active 1:1 complex (CpcEF), stable to size exclusion chromatography. CpcEF causes a reduction in alpha PC fluorescence and strongly affects its absorption spectrum but has no effect on the beta subunit. The CpcEF bilin addition activity exhibits simple Michaelis-Menten kinetics with respect to the apo-alpha PC and to bilin. CpcEF also catalyzes the addition of phycoerythrobilin to apo-alpha PC; phycoerythrobilin is thought to be on the biosynthetic pathway of phycocyanobilin. CpcEF shows a preference for phycocyanobilin relative to phycoerythrobilin, both in binding affinity and in the rate of catalysis, sufficient to account for selective attachment of phycocyanobilin to apo-alpha PC.


Sex determination from fingerprint ridge density and white line counts in Filipinos.
Fingerprints are distinct physical characteristics that remain unchanged throughout an individual's lifetime. This study derived Filipino-specific probability formulae from fingerprints to be used for sex discrimination in human identification cases. Ridge density from three different areas - distal radial area, distal ulnar area, and proximal area - as well as white line counts from fingerprints of 200 male and 200 female Filipinos were collected and analyzed statistically. Ridge densities of radial and ulnar areas emerged as displaying significant differences between the sexes, with 16ridges/25mm(2) or more in radial area and 15ridges/25mm(2) or more in ulnar area being more likely to be female, whereas 13ridges/25mm(2) or less in radial area and 12ridges/25mm(2) or less in ulnar area were more likely to be male. A white line count of 0 was more likely to be male while a white line count of 2 or more was more likely to be female. The results of this study show sex differences in Filipino fingerprints and support the observation of previous studies that females have finer ridges than males.


Mechanism of vitamin E inhibition of cyclooxygenase activity in macrophages from old mice: role of peroxynitrite.
Vitamin E inhibits cyclooxygenase activity in macrophages from old mice by reducing peroxynitrite production. PGE(2) is a proinflammatory mediator that has been linked to a variety of age-associated diseases such as cancer, arthritis, and cardiovascular disease. Furthermore in the aged, increased cyclooxygenase (COX)-2-mediated PGE(2) production contributes to decline in T-cell-mediated function. Previously we reported that increased macrophage PGE(2) production in the aged is due to higher COX-2 activity and that supplementation with vitamin E significantly reduced the age-associated increase in macrophage PGE(2) production posttranslationally without changing COX-2 expression. Peroxynitrite, a product of nitric oxide (NO) and superoxide (O(-)(2)), increases the activity of COX without affecting its expression. Thus, we investigated if vitamin E inhibits COX activity through decreasing peroxynitrite formation. Macrophages from old mice had higher PGE(2) levels, COX activity, and NO levels than those from young mice, all of which were significantly reduced by vitamin E. When added individually, inhibitors of NO and O(-)(2) did not significantly reduce COX activity; however, when the inhibitors were combined, COX activity was significantly reduced in macrophages from old mice fed 30 ppm vitamin E. Increasing NO levels alone using SNAP or O(-)(2) levels, using X/XO, had no effect; however, increasing peroxynitrite levels using Sin-1 or X/XO + SNAP significantly increased COX activity in macrophages from old mice fed 500, but not those fed 30 ppm vitamin E. These data strongly suggest that peroxynitrite plays an important role in the vitamin E-induced inhibition of COX activity. These findings have important implications for designing interventions to reverse and/or delay age-associated dysregulation of immune and inflammatory responses and diseases associated with them.


Ultrastructural demonstration of L-glutamate decarboxylase and cysteinesulfinic acid decarboxylase in rat retina by immunocytochemistry.
The gamma-aminobutyric acid (GABA) synthesizing enzyme, L-glutamate decarboxylase (GAD), and the taurine synthesizing enzyme, cysteinesulfinic acid decarboxylase (CSAD) have been localized in rat retina at the ultrastructural level by indirect immunoelectron microscopy. GAD immunoreactivity (GAD-IR) was seen only in some amacrine cells and their terminals. CSAD immunoreactivity (CSAD-IR) was found in most retinal neuronal types and their processes including photoreceptor cells (rod and cone cells), bipolar cells, amacrine cells and ganglion cells. The GAD-IR positive amacrine terminals have been found to make synaptic contact with other GAD-IR negative bipolar and amacrine terminals, and ganglion cell dendrites. Most of the GAD-IR positive terminals are presynaptic. Occasionally, GAD-IR positive amacrine terminals are postsynaptic to another amacrine terminal or ganglion cell body. In the inner plexiform layer, CSAD-IR positive amacrine terminals also make synaptic contacts with other nerve terminals, similar to that of GAD-IR positive amacrine terminals. In addition, CSAD-IR positive bipolar terminals make synaptic contact with some CSAD-IR positive as well as negative amacrine terminals. Both CSAD-IR positive amacrine and bipolar terminals are mostly presynaptic to other CSAD-IR negative terminals. In the outer plexiform layer, CSAD-IR was found to be associated with synaptic vesicles and the synaptic membrane in certain cone pedicles and rod spherules. It is concluded that only a fraction of amacrine cells in rat retina may use GABA as a neurotransmitter. The presence of CSAD-IR in some amacrine, bipolar, photoreceptor and ganglion cells in rat retina is compatible with the notion that taurine may play some important roles, such as those of neurotransmitter or neuromodulator in mammalian retina.


Variability of phosphorus concentration in large, shallow and eutrophic Lake Taihu, China.
To understand the variation of total phosphorus and the factors influencing total phosphorus in large, shallow, eutrophic lakes, two years of monthly investigation and one month of daily investigation was carried out in Lake Taihu, China. High temporal variations of total phosphorus in surface water were observed, ranging from 42 microg/L to 250 microg/L during the two years of monitoring at the center of the lake, and 134 microg/L to 737 microg/L during the one month of monitoring in Meiliang Bay during the algal bloom season. High variation in phytoplankton biomass during the bloom season significantly affected total-phosphorus concentration in lake water. The accumulated total phosphorus in algae may be caused by the release from sediment during the blooms. Intensive sediment resuspension caused by wind-induced waves also had significant effects on total phosphorus. Therefore, care should be taken when using total phosphorus or ratios of total nitrogen to total phosphorus for trophic state evaluation in large, shallow and eutrophic lakes.


Kawasaki disease: a decade of experience from North India.
Kawasaki disease (KD) has not been frequently reported from developing countries, especially from India. In this series from a tertiary level center in North India, we report on the clinical features and management of patients with KD seen between January 1994 to November 2004. KD was diagnosed on the basis of standard diagnostic criteria. Investigations included work-up for other causes of fever along with chest X-rays, electrocardiograms, and 2-D echocardiography. Thallium scintigraphy and coronary angiography were performed in 20 and 3 cases, respectively. Sixty-nine children (49 boys and 20 girls) fulfilled the diagnostic criteria. Mean age at diagnosis was 4.9 +/- 3.0 years (range 0.3-14 years) and as many as 23 cases (33.3%) were above 5 years of age. Clustering was seen during the winter months. Extreme irritability, out of proportion to the degree of fever, was a characteristic feature. Redness of the lips and tongue was common but rash was seen only in 43 cases and lymphadenopathy in 47 cases. Thrombocytosis was present in 52.2% of the patients. Sixty-four patients received intravenous immunoglobulin. Cardiac abnormalities included extrasystoles in 1, coronary artery dilatation in 5, valvular regurgitation in 3, and perfusion defects on thallium scintigraphy in 4. There was no mortality. KD appears to occur at an older age in Indian children as compared to reports from Japan. Irritability is a characteristic clinical finding. Cardiac abnormalities are frequent during the acute stage but regress gradually. The disease needs to be considered in the differential diagnosis of all children with persistent unexplained fever.


Photoinduced Single- and Multiple-Electron Dynamics Processes Enhanced by Quantum Confinement in Lead Halide Perovskite Quantum Dots.
Methylammonium lead iodide perovskite (MAPbI3) is a promising material for photovoltaic devices. A modification of MAPbI3 into confined nanostructures is expected to further increase efficiency of solar energy conversion. Photoexcited dynamic processes in a MAPbI3 quantum dot (QD) have been modeled by many-body perturbation theory and nonadiabatic dynamics. A photoexcitation is followed by either exciton cooling (EC), its radiative (RR) or nonradiative recombination (NRR), or multiexciton generation (MEG) processes. Computed times of these processes fall in the order of MEG < EC < RR < NRR, where MEG is on the order of a few femtoseconds, EC is in the picosecond range, while RR and NRR are on the order of nanoseconds. Computed time scales indicate which electronic transition pathways can contribute to increase in charge collection efficiency. Simulated mechanisms of relaxation and their rates show that quantum confinement promotes MEG in MAPbI3 QDs.


Co-stimulatory molecules on peripheral blood mononuclear cells and tissue infiltrating cells of skin wart and in vitro poke weed mitogen stimulation.
Skin wart is a lesion caused by human papilloma viruses (HPVs) that can infect both male and female. Quantify the number of CD28+, CD86+, CD152+ and gammadelta+ in peripheral blood mononuclear cells (PBMCs) of subjects with skin wart. Identify CD86+ and gammagamma+ cells in skin wart cryosections. Sixteen subjects with skin warts on face, hand, finger, knee, foot or plantar, both male and female, aged between 19-59 years-old, were recruited from Ramathibodi Hospital, Mahidol University, Bangkok. CD86 and CD152, on peripheral blood mononuclear cells (PBMCs) of subjects with skin wart are significantly lower compared to controls. Tissue cryosection staining for CD86+ and gammadelta+ cells showed no difference among subjects with skin wart and control. Proliferative response to poke weed mitogen of subjects with skin wart is significantly lower than control subjects. There was no difference in the number of subjects positive for CD28 and CD86 cell between normal and skin wart subject, but an increase in skin wart subjects with gammadelta+ cells.


Temperature-sensitive miR-483 is a conserved regulator of recombinant protein and viral vector production in mammalian cells.
Cell engineering and bioprocess optimizations such as low temperature cultivation represent powerful tools to improve cellular performance and product yields of mammalian production cells. Besides monoclonal antibodies (mABs), novel biotherapeutic formats such as viral vectors will gain increasing importance. Here, we demonstrate that similar to Chinese hamster ovary (CHO) cells, product yields of recombinant adeno-associated virus (rAAV) producing HeLa cells can be markedly increased by low temperature cultivation. MicroRNAs (miRNAs) are small non-coding RNAs that critically regulate cell phenotypes. We thus investigated differential miRNA expression in response to mild hypothermia in CHO and HeLa production cells. We discovered miR-483 to be substantially up-regulated upon temperature down-shift in both cell types. Functional validation experiments revealed that introduction of miR-483 mimics led to a significant increase in both rAAV and mAB production in HeLa and CHO cells, respectively. Furthermore, inhibition of miR-483 up-regulation during mild hypothermia significantly decreased product yields, suggesting that miR-483 is a key regulator of cellular productivity in mammalian cells. In addition, miRNA target gene identification indicated that miR-483 might regulate genes directly involved in cellular survival and protein expression. Our results highlight that miR-483 is a valuable tool for product-independent engineering of mammalian production cells.


Sleep and vigilance states: Embracing spatiotemporal dynamics.
The classic view of sleep and vigilance states is a global stationary perspective driven by the interaction between neuromodulators and thalamocortical systems. However, recent data are challenging this view by demonstrating that vigilance states are highly dynamic and regionally complex. Spatially, sleep- and wake-like states often co-occur across distinct brain regions, as in unihemispheric sleep, local sleep in wakefulness, and during development. Temporally, dynamic switching prevails around state transitions, during extended wakefulness, and in fragmented sleep. This knowledge, together with methods monitoring brain activity across multiple regions simultaneously at millisecond resolution with cell-type specificity, is rapidly shifting how we consider vigilance states. A new perspective incorporating multiple spatial and temporal scales may have important implications for considering the governing neuromodulatory mechanisms, the functional roles of vigilance states, and their behavioral manifestations. A modular and dynamic view highlights novel avenues for finer spatiotemporal interventions to improve sleep function.


Knowledge of iatrogenic premature ovarian insufficiency among Chinese obstetricians and gynaecologists: a national questionnaire survey.
With increasing cases of iatrogenic premature ovarian insufficiency (POI), more clinicians are required to counsel patients regarding the gonadotoxic effects of iatrogenic treatments. This survey aimed to explore obstetricians and gynaecologists' knowledge regarding iatrogenic POI. A national online questionnaire survey was conducted across China. Respondents were asked to select the iatrogenic condition(s) that can cause POI based on their experience and knowledge. Of the 5523 returned questionnaires, 4995 were analysed. Among tumour therapies causing POI, most respondents agreed that radiotherapy (73.5% of respondents) and chemotherapy (64.1%) are risk factors for POI. While only 6.5 and 7.8% of the gynaecological oncologists believed that tumour immunotherapy and tumour-targeting therapy, respectively, may cause ovarian impairment, 31.8 and 22.2% of the non-gynaecologic oncologists believed that these therapies could affect ovarian health. Most respondents believed that ovarian cystectomy (54.4%) was a risk factor for POI. In contrast, only a few respondents believed that hysterectomy with bilateral salpingectomy (39.6%) and uterine artery embolisation (33.5%) could cause ovarian impairment. Only 30.5% of respondents believed that immunosuppressants (ISs) increased the risk of POI. Views differed with experience and hospital setting. The knowledge of gonadal toxicity due to traditional tumour treatments is generally high among Chinese obstetricians and gynaecologists. A misunderstanding may exist in primary care hospitals and general gynaecologists regarding a link between novel tumour treatments and POI, owing to the lack of convincing evidence. Knowledge of POI caused by hysterectomy and ISs should be improved.


Biphasic regulation of adenylate cyclase by cholera toxin in neuroblastoma x glioma hybrid cells is due to the activation and subsequent loss of the alpha subunit of the stimulatory GTP binding protein (GS).
Exposure of neuroblastoma x glioma hybrid (NG108-15) cells to low concentrations of cholera toxin produced a stimulation of both basal and forskolin-amplified adenylate cyclase activity in membranes prepared from these cells. Higher concentrations of cholera-toxin reversed this effect. Mn2+ activation of adenylate cyclase indicated that this effect was not due to a modification of the intrinsic activity of this enzyme. Cholera toxin was demonstrated to produce a concentration and time-dependent loss of GS alpha from membranes of these cells. Loss of GS alpha from membranes of these cells was preceded by its ADP-ribosylation. The effects of cholera toxin were specific for GS alpha, as no alterations in levels of the pertussis toxin-sensitive G-proteins Gi2, Gi3 and Go, were noted in parallel. Equally, no alteration in levels of G-protein beta-subunit were produced by the cholera toxin treatment. These experiments demonstrate that cholera toxin-catalysed ADP-ribosylation does not simply maintain an activated population of GS at the plasma membrane and that alterations in levels of GS at the plasma membrane can modify adenylate cyclase activity.


Effects of patient education and progressive muscle relaxation alone or combined on adherence to continuous positive airway pressure treatment in obstructive sleep apnea patients.
The purpose of this study is to explore the effects of patient education and progressive muscle relaxation (PMR) alone or combined on adherence to continuous positive airway pressure (CPAP) treatment in obstructive sleep apnea (OSA) patients. One hundred and fifty-two Han Chinese OSA patients were randomly assigned to a control group (C), an education group (E), a PMR group (P), and an education + PMR group (E + P), with 38 patients each group. The adherence to CPAP was defined as 4 or more hours of CPAP usage per night and at least 9 of each 14 nights of ventilator use. The CPAP adherence rates, cumulative patient dropout rates, CPAP usage, and scores of daytime sleepiness, sleep quality, anxiety, and depression were compared among the groups at 4, 8, and 12 weeks of intervention. All study groups were comparable in baseline characteristics. Group E + P showed significant improvement in CPAP adherence, daytime sleepiness, and sleep quality compared with group C at 4, 8, and 12 weeks of intervention. Compared with group C, group E only showed significant improvement in CPAP adherence, daytime sleepiness, and sleep quality at 4 weeks of intervention, while group P showed no significant improvement over time. Scores of anxiety and depression were significantly improved in group E + P compared with group C at 12 weeks of intervention. Combined intervention with patient education and PMR can significantly improve CPAP adherence in OSA patients for at least 12 weeks. The intervention paradigm may serve as an important reference for future studies on CPAP adherence.


COMPLICATIONS OF SERIAL ANTERIOR CHAMBER PARACENTESIS FOR INCREASED INTRAOCULAR PRESSURE AFTER INTRAVITREAL INJECTIONS.
To report complications after serial anterior chamber (AC) paracentesis for sustained elevation of intraocular pressure after intravitreal injection. A retrospective interventional case series of five patients who had received AC paracentesis after intravitreal injection. Five patients presented with either decreased vision or increased pain after intravitreal injection with planned AC paracentesis. Of the five patients, three patients presented with profound hypotony due to persistent wound leak from the AC paracentesis site. Of these three, one resolved with pressure patch and cycloplegia. The other two patients required further intervention with either polyethylene glycol hydrogel or nylon suture for wound closure. The fourth patient presented with IOL optic prolapse into the AC that resolved with dilation. The fifth patient presented with vitreous prolapse through the AC paracentesis wound and was treated with YAG vitreolysis. A single AC paracentesis has been shown to demonstrate a favorable safety profile. Serial AC paracenteses may degrade the integrity of the peripheral cornea in patients with sustained elevation of intraocular pressure after repeated intravitreal injections.


Anxiety in children with hearing aids or cochlear implants compared to normally hearing controls.
The objectives of this study were to examine the levels of anxiety in hearing-impaired children with hearing aids or cochlear implants compared to normally hearing children, and to identify individual variables that were associated with differences in the level of anxiety. Large retrospective cohort study. Self-reports and parent-reports concerning general anxiety, social anxiety, and generalized anxiety disorder were used. The study group (mean age, 11.8 years) consisted of three age-matched subgroups: 32 children with cochlear implants, 51 children with conventional hearing aids, and 127 children without hearing loss. Levels of anxiety in children with cochlear implants and normally hearing children were similar. Early implantation was associated with lower levels of general and social anxiety. Remarkably, children with conventional hearing aids had higher levels of social anxiety, and their parents also reported more generalized anxiety disorder. The outcomes demonstrate that in their level of anxiety, children with cochlear implants might be more comparable to normally hearing children than to children with hearing aids. This positive finding can be the consequence of audiological factors or other aspects of the cochlear implant rehabilitation program.