Staging bipolar disorder: what data and what models are needed?
Although bipolar disorder is increasingly recognised as a spectrum of multisystem disorders (ie, bipolar disorders), proposed staging models and theories of bipolar disease progression often fail to incorporate longitudinal data or data from multiple domains of dysfunction. We propose that bipolar disorders are best thought of as syndromes, with different trajectories of development and progression for various symptoms and demographic groups. This inherent complexity might be better suited to non-traditional modelling techniques, potentially derived from chaos theory. In this Personal View, we propose an allostatic load framework to account for biomarkers of physiological symptom progression. We then suggest integration of two potential domains of biobehavioural markers: sleep and wake and circadian rhythm regulation and the behavioural activation system. A satisfactory model should account for the effects of developmental stage as well as demographic characteristics, including but not limited to sex, culture, ethnicity, and socioeconomic status. The ultimate goal of a staging model has to be to inform the development of targeted, stage-appropriate interventions to reduce the substantial burden of bipolar disorders on individuals and societies.


Programmatic Assessment of Professionalism in Psychiatry Education: A Literature Review and Implementation Guide.
Programmatic assessment is being adopted as a preferred method of assessment in postgraduate medical education in Australia. Programmatic assessment of professionalism is likely to receive increasing attention. This paper reviews the literature regarding the assessment of professionalism in psychiatry. A search using the terms 'professionalism AND psychiatry' was conducted in the ERIC database. Only original articles relevant to professionalism education and assessment in psychiatry were selected, rather than theoretical or review papers that applied research from other fields of medicine to psychiatry. Articles regarding the need for professionalism education in psychiatry were included as they provided a rationale for curriculum development in this field as a precursor to assessment. Key findings from the literature were summarised in light of the author's own experience as an educator and assessor of both medical students and trainees in psychiatry, and incorporated into a guide to implementing programmatic assessment of professionalism in psychiatry. Within psychiatry, the specific evidence base for use of particular tools in assessing professionalism is limited. However, used in conjunction with psychiatrists' views about what is important in professionalism education, as well as knowledge from other medical disciplines regarding professionalism assessment tools, this evidence can inform implementation of programmatic assessment of professionalism in undergraduate, postgraduate and continuing professional development settings. Given the emergent nature of such assessment initiatives, they should be subjected to rigorous evaluation.


The use of Apatite II™ to remove divalent metal ions zinc(II), lead(II), manganese(II) and iron(II) from water in passive treatment systems: column experiments.
The conventional passive treatments for remediation of acid mine drainage using calcite are not totally efficient in the removal of certain heavy metal ions. Although pH increases to 6-7 and promotes the precipitation of trivalent and some divalent metals as hydroxides and carbonates, the remaining concentrations of some divalent metals ions do not fulfill the environmental regulations. In this study, Apatite II™, a biogenic hydroxyapatite, is used as an alternative reactive material to remove Zn(II), Pb(II), Mn(II) and Fe(II). Apatite II™ reacted with acid water releasing phosphate and increasing pH up to 6.5-7, inducing metals to precipitate mainly as metal-phosphates: zinc precipitated as hopeite, Zn(3)(PO(4))(2)·4H(2)O, lead as pyromorfite, Pb(5)(PO(4))(3)OH, manganese as metaswitzerite, Mn(3)(PO(4))(2)·4H(2)O and iron as vivianite, Fe(3)(PO(4))(2)·8H(2)O. Thus, metal concentrations from 30 to 75 mg L(-1) in the inflowing water were depleted to values below 0.10 mg L(-1). Apatite II™ dissolution is sufficiently fast to treat flows as high as 50 m/a. For reactive grain size of 0.5-3mm, the treatment system ends due to coating of the grains by precipitates, especially when iron and manganese are present in the solution.


Baseline PSMA-PET/CT as a predictor of PSA persistence following radical prostatectomy in high-risk nonmetastatic prostate cancer patients receiving neoadjuvant therapy.
The precise staging and proper management of high-risk prostate cancer (PCa) continues to be a challenge. We aimed to demonstrate the prognostic value of baseline prostate-specific membrane antigen-ligand positron emission tomography/computed tomography (PSMA-PET/CT) in high-risk, nonmetastatic PCa patients who received neoadjuvant hormonal or chemohormonal treatment followed by radical prostatectomy (RP). We performed retrospective analyses of 70 patients with high-risk, nonmetastatic PCa confirmed by biopsy between 2018 and 2021. All patients underwent neoadjuvant therapy followed by RP and pelvic lymph node dissection (PLND); PSMA-PET/CT was performed before initiation of neoadjuvant therapy. Acquired image information and clinical characteristics/outcomes were examined for possible associations. Among 70 high-risk PCa patients, median age was 69 years old and median prostate specific antigen (PSA) at presentation was 58.5 ng/mL. Thirty (42.9%) patients had uptake of the PSMA tracer only in the primary PCa lesions and 40 (57.1%) patients had PSMA-positive lesions in regional or distant sites. Sixteen (32%) localized PCa patients defined by pre-PET magnetic resonance imaging were found to have locally advanced PCa based on PSMA-PET/CT. Fifteen (30%) localized PCa patients and 7 (35%) locally advanced PCa patients were upstaged to metastatic PCa. The sensitivity and specificity of PSMA-PET/CT for the detection of lymph node involvement were 90.9% and 69.5%, respectively, with a positive prediction value of 35.7% and negative prediction value of 97.6%. The diagnostic accuracy was 72.9%. Univariate analysis showed upstaging, tumor stage, and metastasis location based on PSMA-PET/CT are predictors to PSA persistence after surgery, while multivariate logistic regression analysis showed only the tumor stage based on PSMA-PET/CT remained an independent predictor of the outcome. This study further highlights the accuracy and necessity of PSMA-PET/CT in newly diagnosed, high-risk, nonmetastatic PCa patients.


Investigation of fragmentation pathways of norpimarane diterpenoids by mass spectrometry combined with computational chemistry.
Norpimarane diterpenes possess plentiful bioactivities and are widely distributed in herbs, such as Flickingeria fimbriata. Rapid characterization of these natural products in complicated plant extracts is of great importance, and electrospray ionization tandem mass spectrometry is a powerful tool for chemical constituent profiling. However, limited researches on their fragmentation mechanisms seriously hinder identification via mass spectrometry. Three norpimarane diterpenes isolated from F. fimbriata via multiple types of column chromatography served as reference compounds, and collision-induced dissociation experiments were performed on them with a series of variable collision energies. Plausible fragmentation pathways were proposed based on product ions. To further validate the fragmentation mechanisms, the proton affinity and product ion energy were simulated by density functional theory at the B3LYP/6-31+G(d, p) level. Three main cleavage reactions induced skeleton breakage and resulted in characteristic ions, methyl (CH3 -20) migration, hydrogen arrangement and Retro-Diels-Alder reaction, among which methyl migration was firstly proposed for pimarane diterpenes. A series of common diagnostic ions were identified, such as m/z 133.1012, 121.1012, 119.0805 and 107.0855. Additionally, the constructed fragmentation mechanisms were successfully applied for fragment ion rationalization of previously reported isopimarane diterpenes. Fragmentation mechanisms of norpimarane diterpenes have been uncovered. Carbocation located at the C ring tends to result in methyl (CH3 -20) migration which has been rarely reported before. This characteristic dissociation reaction allows multiple diagnostic ions to be rationalized and aids in rationalizing fragmentation patterns of other diterpenes. The uncovered mechanisms also shed light on rapid identification of norpimarane diterpenes.


Tuberculosis: pH-Responsive Isoniazid-Loaded Nanoparticles Markedly Improve Tuberculosis Treatment in Mice (Small 38/2015).
On page 5066, J. I. Zink, M. A. Horwitz, and co-workers use confocal microscopy to demonstrate the avid uptake of RITC-labeled mesoporous silica nanoparticles loaded with the anti-tuberculosis drug isoniazid (shown here in red) by human macrophages (nuclei stained blue with DAPI) infected with GFP-expressing Mycobacterium tuberculosis (shown here in green).


Disability weight measurement for the severity of different diseases in Wuhan, China.
Measurement of the Chinese burden of disease with disability-adjusted life-years (DALYs) requires disability weight (DW) that quantify health losses for all non-fatal consequences of disease and injury. The Global Burden of Disease (GBD) 2013 DW study indicates that it is limited by lack of geographic variation in DW data and by the current measurement methodology. We aim to estimate DW for a set of health states from major diseases in the Wuhan population. We conducted the DW measurement study for 206 health states through a household survey with computer-assisted face-to-face interviews and a web-based survey. Based on GBD 2013 DW study, paired comparison (PC) and Population health equivalence (PHE) method was used and different PC/PHE questions were randomly assigned to each respondent. In statistical analysis, the PC data was analyzed by probit regression. The probit regression results will be anchored by results from the PHE data analyzed by interval regression on the DW scale units between 0 (no loss of health) and 1 (loss equivalent to death). A total of 2610 and 3140 individuals were included in the household and web-based survey, respectively. The results from the total pooled data showed health state "mild anemia" (DW = 0.005, 95% UI 0.000-0.027) or "allergic rhinitis (hay fever)" (0.005, 95% UI 0.000-0.029) had the lowest DW and "heroin and other opioid dependence, severe" had the highest DW (0.699, 95% UI 0.579-0.827). A high correlation coefficient (Pearson's r = 0.876; P < 0.001) for DWs of same health states was observed between Wuhan's survey and GBD 2013 DW survey. Health states referred to mental symptom, fatigue, and the residual category of other physical symptoms were statistically significantly associated with a lower Wuhan's DWs than the GBD's DWs. Health states with disfigurement and substance use symptom had a higher DW in Wuhan population than the GBD 2013 study. This set of DWs could be used to calculate local diseases burden for health policy-decision in Wuhan population. The DW differences between the GBD's survey and Wuhan's survey suggest that there might be some contextual or culture factors influencing assessment on the severity of diseases.


Cephalic vein guide wire technique for implantation of permanent pacemakers.
This report describes a modified cephalic vein guide wire technique for the implantation of permanent pacemakers. The procedure was attempted in 11 patients only when pacing leads could not be passed directly into the exposed cephalic vein. Eight bipolar DDD (two leads), two unipolar DDD, and one bipolar VVI (one lead) pulse generators were implanted successfully, with only one relatively minor complication. The cephalic vein guide wire technique provides easy access to the subclavian vein and may allow implantation of most single- and dual-chamber pacemakers with only a cephalic vein cutdown.


Assessing public aesthetic preferences towards some urban landscape patterns: the case study of two different geographic groups.
Landscape aesthetics is closely linked to people's daily life, and a large body of studies has been conducted to understand the public's landscape preferences. These studies commonly focused on comprehensive landscape configuration, yet limited emphasis was placed on the patterns of individual landscape features. This research explored people's preferences towards the composition and patterns of some specific urban features. Questionnaire-based survey was conducted in two cities: Cambridge, UK and Nanjing, China and more than 180 responses were collected, respectively. Respondents from both sites showed similar preferences towards freely growing trees, individual houses, gable roofs and mixed design of green spaces. On the other hand, respondents from Cambridge and Nanjing have different preferences towards the height of trees, the size of green spaces, and the height diversity of buildings. This survey also proved that the factors of age, education, status and length of living have larger influences on landscape preferences than the factors of gender, and major. Furthermore, strong correlations were found between people's aesthetic preferences towards comparative landscape patterns, building types, tree shapes and roof structures. The existence of generally shared landscape preferences makes it feasible to conduct international and standardized projects for acquiring comparable and transferable criteria. The methodology and findings of this research provides landscape planners and decision makers with useful reference to compare, evaluate and improve urban landscape configurations to meet people's needs.


The effects of systemic and intratumoral interleukin-12 treatment in C6 rat glioma model.
Cytokine based immunotherapy has long been an exciting field for many investigators aiming to provide an effective alternative treatment modality for glioma management. Among these cytokines, interleukin-12 (IL-72) plays a crucial role in mediating inflammatory and antitumoral activity on the host defence. We have investigated the therapeutic role of systemic and local delivery of IL-12 in C6 rat glioma model and compared these two modalities. The donor C6 glioma cells were injected stereotactically to 32 Wistar rats and right frontal tumor formation was established in all subjects. The rats were evenly divided into four groups as intratumoral (i.t.) control group (Group IA), intraperitoneal (i.p.) control group (Group IB), i.t. treatment group (Group II) and i.p. treatment group (Group III). Magnetic resonance imaging were performed to 72 rats (three from each group) on the seventh post-inoculation day. Recombinant mouse IL-12 (rmIL-12) was administered via i.t. (0.1 microg 5 microl/day/rat) and i.p. (0.1 microg 20 microl/day/rat) routes to treatment groups between days 9 and 11 following tumor inoculation, for 3 consecutive days. The rats which were unresponsive to the external stimuli, unable to feed themselves or having severe neurological impairment were decapitated and the specimens were histopathologically examined. The subjects of Group ILL (i.p.) showed a statistically significant prolongation in survival time (mean = 39 days) when compared to the control group (mean = 31.7 days) (p = 0.035) and Group II (i.t.) (mean = 24.5 days) (p = 0.005). Histopathologic examination of Group III revealed markedly increased intratumoral and peritumoral lymphocyte infiltration compared with the other groups. This study demonstrated that systemic administration of IL- 12 in C6 glioma model in rats prolongs the survival, probably by stimulating the cellular immunity leading to lymphocytic infiltration.


Short-term pre- and post-operative stress prolongs incision-induced pain hypersensitivity without changing basal pain perception.
Chronic stress has been reported to increase basal pain sensitivity and/or exacerbate existing persistent pain. However, most surgical patients have normal physiological and psychological health status such as normal pain perception before surgery although they do experience short-term stress during pre- and post-operative periods. Whether or not this short-term stress affects persistent postsurgical pain is unclear. In this study, we showed that pre- or post-surgical exposure to immobilization 6 h daily for three consecutive days did not change basal responses to mechanical, thermal, or cold stimuli or peak levels of incision-induced hypersensitivity to these stimuli; however, immobilization did prolong the duration of incision-induced hypersensitivity in both male and female rats. These phenomena were also observed in post-surgical exposure to forced swimming 25 min daily for 3 consecutive days. Short-term stress induced by immobilization was demonstrated by an elevation in the level of serum corticosterone, an increase in swim immobility, and a decrease in sucrose consumption. Blocking this short-term stress via intrathecal administration of a selective glucocorticoid receptor antagonist, RU38486, or bilateral adrenalectomy significantly attenuated the prolongation of incision-induced hypersensitivity to mechanical, thermal, and cold stimuli. Our results indicate that short-term stress during the pre- or post-operative period delays postoperative pain recovery although it does not affect basal pain perception. Prevention of short-term stress may facilitate patients' recovery from postoperative pain.


Humoral immune response following prime and boost BNT162b2 vaccination in people living with HIV on antiretroviral therapy.
People living with HIV (PLWH) with low CD4 T-cell counts may be at a higher risk for severe coronavirus disease 2019 (COVID-19) outcomes and in need of efficient vaccination. The World Health Organization (WHO) now recommends prioritizing PLHIV for COVID-19 vaccination. Data on immune responses after messenger RNA (mRNA) vaccination in PLHIV in relation to CD4 counts are scarce. We aimed at assessing the humoral immune response in PLHIV after mRNA vaccination against COVID-19. We examined a cohort of PLHIV after prime (n = 88) and boost (n = 52) vaccination with BNT162b2. We assessed levels of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein-specific immunoglobulin G (IgG)/IgA and circulating neutralizing antibodies in plasma and correlated results to the cellular immune status. BNT162b2-vaccinated health care workers served as controls. All PLWH had a viral load of ≤ 200 HIV-1 RNA copies/mL and 96.5% had a viral load of < 50 copies/mL. Anti-S IgG and neutralizing antibody responses after BNT162b2 priming were significantly lower in PLHIV having a CD4:CD8 T-cell ratio of < 0.5. However, we observed robust humoral immunity in the majority of PLWH receiving antiretroviral therapy (ART) irrespective of CD4 T-cell nadir, current CD4 count or CD4:CD8 ratio after full BNT162b2 vaccination. Nevertheless, HIV-negative controls produced significantly higher mean anti-S IgG concentrations with less variability. The majority of PLWH mounted robust responses after complete BNT162b2 vaccination but overall amounts of antibodies directed against the SARS-CoV-2 receptor-binding domain were variable. The impact on clinical efficacy remains unclear.


Posterior lens capsulectomy during primary cataract surgery in children.
Concern continues about the best and safest method to surgically manage cataracts in children. Posterior capsulectomy and anterior vitrectomy with a vitreous suction cutter eliminates the need for secondary surgery. It is the best method to avoid development of amblyopia resulting from gradual posterior lens capsule opacification. However, cystoid macular edema is reported to occur more frequently with this approach as opposed to leaving the posterior lens capsule intact. Amblyopia, however, at this time may be a greater risk to final visual acuity than cystoid macular edema.


Identification of genetic counseling service delivery models in practice: a report from the NSGC Service Delivery Model Task Force.
Increasing demand for genetic services has resulted in the need to evaluate current service delivery models (SDMs) and consider approaches that improve access to and efficiency of genetic counseling (GC). This study aimed to describe SDMs currently used by the GC community. The NSGC membership was surveyed regarding the use of four SDMs: in-person GC, telephone GC, group GC, and telegenetics GC. Variables related to access and components of use were also surveyed, including: appointment availability, time-per-patient, number of patients seen, billing, and geographic accessiblity. Seven hundred one usable responses were received. Of these, 54.7 % reported using an in-person SDM exclusively. The remainder (45.3 %) reported using multiple SDMs. Telephone, group and telegenetics GC were used often or always by 8.0 %, 3.2 % and 2.2 % of respondents, respectively. Those using an in-person SDM reported the ability to see the highest number of patients per week (p < 0.0001) and were the most likely to bill in some manner (p < 0.0001). Those using telegenetic and telephone GC served patients who lived the furthest away, with 48.3 % and 35.8 %% respectively providing GC to patients who live >4 h away. This study shows that genetic counselors are incorporating SDMs other than traditional in-person genetic counseling, and are utilizing more than one model. These adaptations show a trend toward shorter wait time and shorter length of appointments. Further study is indicated to analyze benefits and limitations of each individual model and factors influencing the choice to adopt particular models into practice.


New mothers' thoughts of harm related to the newborn.
There are few published studies of new mothers' experiences of intrusive thoughts of harm related to the newborn. Evidence-based information about the normal phenomenology of intrusive thoughts of harm related to the newborn is needed to facilitate appropriate clinical decision-making. The objective of this project was to assess the phenomenology, prevalence, correlates, and behavioural sequelae of maternal thoughts of harm related to the newborn. One hundred women were recruited during pregnancy. Participants were assessed prenatally and at 4 and 12 weeks postpartum using questionnaires and a semi-structured interview about unwanted thoughts of harm related to the newborn. Postpartum intrusive thoughts of accidental harm to the infant were universal, and close to half of the sample reported unwanted thoughts of intentionally harming their infant. Compared with intentional harm thoughts, accidental harm thoughts were more frequent and more time consuming, but less distressing. High parenting stress and low social support predicted the occurrence of thoughts of intentional harm. Little evidence of an association between these thoughts and aggressive parenting was found. Unwanted intrusive thoughts of harming one's infant are a relatively normative experience during the early postpartum period, particularly in association with greater parenting stress and low social support.


(13)C-(13)c homonuclear recoupling in solid-state nuclear magnetic resonance at a moderately high magic-angle-spinning frequency.
Two-dimensional (13)C-(13)C correlation experiments are widely employed in structure determination of protein assemblies using solid-state nuclear magnetic resonance. Here, we investigate the process of (13)C-(13)C magnetisation transfer at a moderate magic-angle-spinning frequency of 30 kHz using some of the prominent second-order dipolar recoupling schemes. The effect of isotropic chemical-shift difference and spatial distance between two carbons and amplitude of radio frequency on (1)H channel on the magnetisation transfer efficiency of these schemes is discussed in detail.


High-performing executive teams.
What are the five dysfunctions of an executive team, and how can you, as the CEO, overcome them? This foldout section offers strategies to revitalize your C-suite.


An affordable implantable vagus nerve stimulator system for use in animal research.
In this research, a vagus nerve stimulator has been developed and miniaturized for use in epilepsy research. The board contains all the components necessary for its operation during the standard duration of the experiments, being possible to control it once implanted and even being able to reuse it. The VNS system has been designed for rodents since the VNS devices available for human are not only too large for laboratory animals, but also too expensive. With this solution the expenditure on materials made by laboratories is greatly reduced and bioethical considerations were kept in mind. The system was validated in hamsters. This article is part of the theme issue 'Advanced neurotechnologies: translating innovation for health and well-being'.


CT evaluation of severe renal inflammatory disease in children.
We have performed CT scans on 15 children and 2 young adults with severe renal inflammatory disease. Most children with urinary tract infections do not require such evaluation. We have, however, found CT helpful in defining the nature of renal abnormality and in defining the extent of disease in selected patients who either presented as diagnostic dilemmas or who did not respond initially to proper medical treatment. We therefore use CT scanning as our initial examination in such problem patients.


Cardiovascular Testing and Imaging in Pregnant Women.
Cardiovascular disease is a major contributor to maternal morbidity and mortality and frequently preventable. Women with known cardiovascular disease should undergo cardiac evaluation before pregnancy. Many women with pregnancy-associated cardiac complications are not previously known to have cardiac disease. Women at high risk or who have signs or symptoms suggestive of heart failure, angina, or arrhythmias should undergo prompt evaluation. This article describes various diagnostic imaging modalities that can be used in pregnancy, including indications, strengths, and limitations.


Integrated metabolic and epigenetic mechanisms in cardiomyocyte proliferation.
Heart disease continues to be the leading cause of mortality worldwide, primarily attributed to the restricted regenerative potential of the adult human heart following injury. In contrast to their adult counterparts, many neonatal mammals can spontaneously regenerate their myocardium in the first few days of life via extensive proliferation of the pre-existing cardiomyocytes. Reasons for the decline in regenerative capacity during postnatal development, and how to control it, remain largely unexplored. Accumulated evidence suggests that the preservation of regenerative potential depends on a conducive metabolic state in the embryonic and neonatal heart. Along with the postnatal increase in oxygenation and workload, the mammalian heart undergoes a metabolic transition, shifting its primary metabolic substrate from glucose to fatty acids shortly after birth for energy advantage. This metabolic switch causes cardiomyocyte cell-cycle arrest, which is widely regarded as a key mechanism for the loss of regenerative capacity. Beyond energy provision, emerging studies have suggested a link between this intracellular metabolism dynamics and postnatal epigenetic remodeling of the mammalian heart that reshapes the expression of many genes important for cardiomyocyte proliferation and cardiac regeneration, since many epigenetic enzymes utilize kinds of metabolites as obligate cofactors or substrates. This review summarizes the current state of knowledge of metabolism and metabolite-mediated epigenetic modifications in cardiomyocyte proliferation, with a particular focus on highlighting the potential therapeutic targets that hold promise to treat human heart failure via metabolic and epigenetic regulations.


Cardiac arrhythmias in Chagas' heart disease.
Chagas' disease is a chronic parasitosis affecting most Latin American countries. Its most important clinical manifestation is a late developing chronic myocarditis and, much less frequently, an early acute myocarditis. Chagasic myocardial damage is microfocal and disseminated throughout the heart. In most cases, the coexistence of areas of myocytic degeneration, inflammatory infiltration, and fibrosis suggests a permanent evolving process. Commonly, chronic chagasic myocarditis resembles a dilated cardiomyopathy, with characteristic ECG abnormalities (atrial and ventricular extrasystoles, intraventricular and/or AV conduction disturbances, and primary ST-T wave changes). Since myocardial damage is scattered throughout the heart, the ECG abnormalities (arrhythmias, conduction disturbances, and repolarization changes) are also representative of the widespread cardiac involvement. Thus, sick sinus syndrome, atrial extrasystoles, intraatrial conduction disturbances, and atrial fibrillation or flutter are common findings in different stages of the disease. At the ventricular level, both conduction disturbances and arrhythmias are conspicuous expressions of the myocardial damage. Right bundle branch block alone or in combination with left anterior hemiblock are the most common conduction defects. Further compromise of the conduction system can lead to different degrees of AV block. Chagas' disease is the main cause of bundle branch block and AV block in endemic areas. In advanced cases of Chagas' heart disease, ventricular premature contractions are extremely frequent, multiform, and repetitive (couplets and runs of ventricular tachycardia), and show R on T phenomenon. These arrhythmias are usually aggravated by increased sympathetic tone, implying an enhanced risk of cardiac sudden death among chagasic patients, which is sometimes the first manifestation of the illness. Chronic chagasic myocarditis is the leading cause of cardiovascular death, mostly as a consequence of heart failure and sudden death, in areas where the disease is endemic.


[ADP ribosylation of proteins and its role in regulating functional cellular activity].
New data are presented on ADP-ribosylation of nuclear proteins, which is one of the paths of their postsynthetic modifications. The importance of this reaction for DNA cell cycle regulation are discussed. The structure of mono- and poly(ADPRib), the properties of their synthesis and degradation catalyzing enzymes, and the nature of the modified proteins are considered.


Genome-wide analysis reveals specificities of Cpf1 endonucleases in human cells.
Programmable clustered regularly interspaced short palindromic repeats (CRISPR) Cpf1 endonucleases are single-RNA-guided (crRNA) enzymes that recognize thymidine-rich protospacer-adjacent motif (PAM) sequences and produce cohesive double-stranded breaks (DSBs). Genome editing with CRISPR-Cpf1 endonucleases could provide an alternative to CRISPR-Cas9 endonucleases, but the determinants of targeting specificity are not well understood. Using mismatched crRNAs we found that Cpf1 could tolerate single or double mismatches in the 3' PAM-distal region, but not in the 5' PAM-proximal region. Genome-wide analysis of cleavage sites in vitro for eight Cpf1 nucleases using Digenome-seq revealed that there were 6 (LbCpf1) and 12 (AsCpf1) cleavage sites per crRNA in the human genome, fewer than are present for Cas9 nucleases (>90). Most Cpf1 off-target cleavage sites did not produce mutations in cells. We found mismatches in either the 3' PAM-distal region or in the PAM sequence of 12 off-target sites that were validated in vivo. Off-target effects were completely abrogated by using preassembled, recombinant Cpf1 ribonucleoproteins.


Virtual connection, real support? A study of loneliness, time on social media and psychological distress among men.
In an age of increasing loneliness and associated poor mental health, research uncovering the extent to which social connection can be achieved digitally is paramount. This is particularly important among men, who experience unique barriers to achieving meaningful social connections due to masculine norms including independence and self-reliance. Loneliness is a known determinant of both psychological distress and greater time on social media, however relationships among these constructs are yet to be studied specifically among men. This study aimed to examine a novel mediation model to uncover whether time on social media mediates the association between loneliness and psychological distress, alongside a moderating effect of age. A community sample of 979 men of mean age 36.0 years (range = 18-78, SD = 13.11) took part via an online survey involving measures of study constructs. Results highlighted a novel moderated mediation effect: for younger men only, loneliness predicts psychological distress via time spent on social media. Men experiencing loneliness appear to turn to social media in attempt at digital connection, however for younger men in particular, often this fails to ameliorate links between loneliness and psychological distress. Implications for public health messaging, clinical work with men and future interventional studies are discussed.


Critical care: A concept analysis.
The terms critical care and the Intensive Care Unit (ICU) are often used interchangeably to describe a place of care. Defining critical care becomes challenging because of the colloquial use of the term. Using concept analysis allows for the development of definition and meaning. The aim of this concept analysis is to distinguish the use of the term critical care to develop an operational definition which describes what constitutes critical care. Walker and Avant's eight-step approach to concept analysis guided this study. Five databases (CINAHL, Scopus, PubMed, ProQuest Dissertation Abstracts and Medline in EBSCO) were searched for studies related to critical care. The search included both qualitative and quantitative studies written in English and published between 1990 and 2022. Of the 439 papers retrieved, 47 met the inclusion criteria. The defining attributes of critical care included 1) a maladaptive response to illness/injury, 2) admission modelling criteria, 3) advanced medical technologies, and 4) specialised health professionals. Antecedents were associated with illness/injury that progressed to a level of criticality with a significant decline in both physical and psychological functioning. Consequences were identified as either death or survival with/without experiencing post-ICU syndrome. Describing critical care is often challenging because of the highly technical nature of the environment. This conceptual understanding and operational definition will inform future research as to the scope of critical care and allow for the design of robust evaluative instruments to better understand the nature of care in the intensive care environment.


Breast reconstruction using the profunda artery perforator (PAP) flap: Technical refinements and evolution, outcomes, and patient satisfaction based on 116 consecutive flaps.
When a deep inferior epigastric artery flap is not suitable, the profunda artery perforator (PAP) flap can be a good alternative for autologous breast reconstruction. Popularity of the PAP flap is expanding, but it is still only slowly being adopted worldwide. We report our experience with 116 consecutive PAP flaps showing refinements and evolution of the technique towards improvement in outcomes and patients' satisfaction. We prospectively collected data from consecutive PAP flap breast reconstructions performed from 2016 to 2019. Patients' demographics, pre-, intra-, postoperative data, and revision procedures were analyzed. The BREAST-Q and a specific questionnaire investigating outcomes at the donor site were completed preoperatively and 12 months postoperatively. One-hundred and sixteen PAP flaps were performed in 86 patients, 64 unilateral and 22 bilateral breast reconstructions. Mean body mass index was 24.72 kg/m2 (range 18.9-29.2) and mean flap weight was 251.30 g (range 152-455 g). Complications included donor site hematoma (1.7%), seroma (2.6%), fat necrosis (1.7%), and wound dehiscence (2.6%). No arterial/venous thrombosis nor flap losses were recorded. Patients reported high satisfaction in all BREAST-Q domains, with mean postoperative scores being higher than preoperative ones, suggesting a positive effect in quality of life and satisfaction. Scores were significant in the satisfaction with breast domain (p = 0.0016). Breast reconstruction with PAP flap yields a high success, low complications, and excellent cosmetic outcomes in the breast and donor sites. It improves patients' satisfaction and quality of life; hence, it can be considered an excellent option for autologous breast reconstruction.


Biochemical characterization of the boar sperm 42 kilodalton protein tyrosine kinase: its potential for tyrosine as well as serine phosphorylation towards microtubule-associated protein 2 and histone H 2B.
The majority of cellular responses to changing environmental conditions is regulated by protein kinases. Spermatozoa have many special properties, including motility with demonstrated chemotaxis, the ability to undergo capacitation, and the acrosome reaction, which are in part controlled by extracellular signals and in which sperm kinases are considered to be involved. We have previously reported that there is a protein kinase activity, which phosphorylates the synthetic substrate poly-(Glu, Tyr) with a Km value of 2.3 microM, and is inhibited by the tyrosine kinase inhibitor tyrphostin, in the protein extract from boar spermatozoa (Berruti and Porzio, 1992: Biochim Biophys Acta 1118:149-154). Now we have demonstrated that the enzyme is cytosolic, is active as a monomer of M(r) 42,000, is stimulated by Mg2+ > Mn2+ but not by Ca2+, is renaturable, and can phosphorylate native protein substrates such as microtubule-associated protein 2 (MAP2) and histone H2B both on the tyrosine and serine residues. N-terminal sequence analysis suggests that it is a novel protein. These new findings imply that the boar sperm 42 kD kinase may be a novel member of the emerging class of dual-specificity protein kinases, and they raise the intriguing question of its function in the protein kinase network mediating signal transduction in mammalian spermatozoa.


A highly effective catalyst system for the Pd-catalyzed amination of vinyl bromides and chlorides.
[reaction: see text] A highly efficient synthesis of enamines and imines by Pd-catalyzed amination of vinyl bromides or chlorides with amines is described using the Pd2(dba)3/P(i-BuNCH2CH2)3N catalyst system.


Identification of potential active-site residues in the hydroxynitrile lyase from Manihot esculenta by site-directed mutagenesis.
The hydroxynitrile lyase from cassava (Manihot esculenta Crantz) (EC 18.104.22.168) catalyzes the decomposition of the achiral alpha-hydroxynitrile acetone cyanohydrin into HCN and acetone during cyanogenesis of damaged plants. This enzyme can also be used for stereoselective synthesis of a wide array of (S)-cyanohydrins by addition of HCN to aldehydes or ketones. Optically active cyanohydrins are interesting intermediates for the synthesis of alpha-hydroxy acids, alpha-hydroxy ketones, or beta-ethanolamines, all of which are important building blocks in organic synthesis. Inhibition of hydroxynitrile lyase from M. esculenta (MeHNL) by serine- and histidine-modifying reagents suggests involvement of active site seryl and histidyl residues. Furthermore, serine 80 of MeHNL is part of the active site motif Gly-X-Ser-X-Gly/Ala, often considered as the hallmark of catalytic triads having independently evolved in four groups of enzymes: the alpha/beta hydrolase fold enzymes, subtilisins, the cysteine proteases, and the eukaryotic serine proteases. By site-directed mutagenesis, three residues critical for enzyme activity have been identified: serine 80, aspartic acid 208, and histidine 236. These residues may be directly involved in MeHNL-catalyzed decomposition of cyanohydrins, providing evidence for a catalytical triad in HNLs, too. The order of the catalytic triad residues in the primary sequence of MeHNL is nucleophile-histidine-acid, suggesting that MeHNL belongs to the alpha/beta hydrolase fold group of enzymes. In contrast to all other enzymes having a catalytical triad, HNLs catalyze no net hydrolytic reactions.


Exogenous glucocorticoids increase macrophage secretion of apo E by cholesterol-independent pathways.
Macrophage apo E synthesis and secretion has been previously demonstrated to be regulated by intracellular free cholesterol levels and is decreased by cytokines and other inflammatory stimuli associated with macrophage activation. In a recent study, the opposing effects of TGF beta and GM-CSF were reported with the former increasing and the latter decreasing apo E secretion and apo E mRNA levels. In an attempt to further understand the mechanisms by which TGF beta increased apo E expression in mouse peritoneal macrophages, the present study was performed to determine whether pharmacological agents could up-regulate apo E secretion by a mechanism independent of intracellular free cholesterol levels. Agents which resulted in increased apo E secretion were subdivided based on their effects on cAMP elevation. In addition to TGF beta, dexamethasone resulted in significant increases in apo E secretion. The 2-4-fold enhancement in apo E secretion by both TGF beta and dexamethasone occurred without concomitant changes in intracellular cAMP or free cholesterol. Other agents which increased apo E secretion included cholera toxin and 8-bromo-cAMP. While these agents did not affect intracellular cholesterol levels, cholera toxin did increase macrophage cAMP. The changes in apo E secretion by dexamethasone and 8-bromo-cAMP were associated with elevations in apo E mRNA. Dexamethasone-treated macrophages had 6-fold increases in apo E mRNA by 48 h when compared with control macrophages. Macrophages stimulated with 8-bromo-cAMP for 48 h demonstrated a more modest but statistically significant (P < 0.001) 2.2-fold increase. Similar effects of dexamethasone, cholera toxin, TGF beta, and 8-bromo-cAMP on apo E secretion were also apparent in macrophage-derived foam cells. In addition to increasing apo E secretion in macrophages and foam cells, dexamethasone and 8-bromo-cAMP inhibited the down-regulation of apo E secretion mediated by LPS and GM-CSF. Finally, the increased apo E secretion by exogenous glucocorticoids or TGF beta was not species specific as similar effects were observed in rabbit peritoneal macrophages. Therefore, while macrophage activation results in decreased apo E synthesis, macrophages exposed to anti-inflammatory agents including dexamethasone, TGF beta, or following cAMP elevation demonstrate increased apo E secretion by a cholesterol-independent mechanism.


Glucose-dependent insulinotropic peptide impairs insulin signaling via inducing adipocyte inflammation in glucose-dependent insulinotropic peptide receptor-overexpressing adipocytes.
Glucose-dependent insulinotropic peptide (GIP) exerts multiple biological effects via the G-protein-coupled receptor GIPR, including glucose-stimulated insulin production and secretion, cell proliferation, and antiapoptosis in pancreatic β-cells. In an obese state, the circulating level of GIP is elevated. GIPR-knockout mice are resistant to high-fat-diet-induced obesity. The rising evidence suggests a potential role of GIP in adipocyte biology and lipid metabolism. In our study, we overexpressed GIPR in 3T3-L1 CAR adipocytes and demonstrated that GIP impaired the physiological functions of adipocytes as a consequence of increased production of inflammatory cytokines and chemokines and phosphorylation of IkB kinase (IKK)-β through activation of the cAMP-PKA pathway. Activation of Jun N-terminal kinase (JNK) pathway was also observed during GIP-induced inflammatory responses in adipocytes. The inhibition of JNK blocked GIP-stimulated secretion of inflammatory cytokines and chemokines, as well as phosphorylation of IKKβ. In addition, GIP-induced inflammatory response increased basal glucose uptake but inhibited insulin-stimulated glucose uptake. Moreover, GIP-induced adipocyte inflammation impaired insulin signaling in adipocytes as demonstrated by a reduction of AKT phosphorylation. Our results suggest that GIP might be one of the stimuli attributable to obesity-induced insulin resistance via the induction of adipocyte inflammation.


Association of a novel point mutation in MSH2 gene with familial multiple primary cancers.
Multiple primary cancers (MPC) have been identified as two or more cancers without any subordinate relationship that occur either simultaneously or metachronously in the same or different organs of an individual. Lynch syndrome is an autosomal dominant genetic disorder that increases the risk of many types of cancers. Lynch syndrome patients who suffer more than two cancers can also be considered as MPC; patients of this kind provide unique resources to learn how genetic mutation causes MPC in different tissues. We performed a whole genome sequencing on blood cells and two tumor samples of a Lynch syndrome patient who was diagnosed with five primary cancers. The mutational landscape of the tumors, including somatic point mutations and copy number alternations, was characterized. We also compared Lynch syndrome with sporadic cancers and proposed a model to illustrate the mutational process by which Lynch syndrome progresses to MPC. We revealed a novel pathologic mutation on the MSH2 gene (G504 splicing) that associates with Lynch syndrome. Systematical comparison of the mutation landscape revealed that multiple cancers in the proband were evolutionarily independent. Integrative analysis showed that truncating mutations of DNA mismatch repair (MMR) genes were significantly enriched in the patient. A mutation progress model that included germline mutations of MMR genes, double hits of MMR system, mutations in tissue-specific driver genes, and rapid accumulation of additional passenger mutations was proposed to illustrate how MPC occurs in Lynch syndrome patients. Our findings demonstrate that both germline and somatic alterations are driving forces of carcinogenesis, which may resolve the carcinogenic theory of Lynch syndrome.


[Population models in the study of neurogenic domnants of arterial hypertension. Report 2. The peculiarities of arterial hypertension matched with personal motivational priorities].
The peculiarities of primary arterial hypertension in persons with opposite types of motivational priorities were studied. The features and prevalence of the disease in two populations were analyzed. Group 1 consisted of 141 subjects whose profession and working conditions required maximum realization of the market-oriented motivational dominant ("socially active persons"); Group 2 consisted of 147 "altruistic" type subjects who lacked the first group's motivational dominant. The study found a higher prevalence of the disease and a lower level of psychological health as part of quality of life in Group 1 (p = 0.018); the disease in this group was more intensive and significant structural and functional left ventricular transformation was typical. The absence of pernicious habits and healthy life-style should not be considered primary factors of a more favorable clinical course of the disease in the "altruistic" group.


Absence of TRIC-B from type XIV Osteogenesis Imperfecta osteoblasts alters cell adhesion and mitochondrial function - A multi-omics study.
Osteogenesis Imperfecta (OI) is a heritable collagen-related bone dysplasia characterized by bone fractures, growth deficiency and skeletal deformity. Type XIV OI is a recessive OI form caused by null mutations in TMEM38B, which encodes the ER membrane intracellular cation channel TRIC-B. Previously, we showed that absence of TMEM38B alters calcium flux in the ER of OI patient osteoblasts and fibroblasts, which further disrupts collagen synthesis and secretion. How the absence of TMEM38B affects osteoblast function is still poorly understood. Here we further investigated the role of TMEM38B in human osteoblast differentiation and mineralization. TMEM38B-null osteoblasts showed altered expression of osteoblast marker genes and decreased mineralization. RNA-Seq analysis revealed that cell-cell adhesion was one of the most downregulated pathways in TMEM38B-null osteoblasts, with further validation by real-time PCR and Western blot. Gap and tight junction proteins were also decreased by TRIC-B absence, both in patient osteoblasts and in calvarial osteoblasts of Tmem38b-null mice. Disrupted cell adhesion decreased mutant cell proliferation and cell cycle progression. An important novel finding was that TMEM38B-null osteoblasts had elongated mitochondria with altered fusion and fission markers, MFN2 and DRP1. In addition, TMEM38B-null osteoblasts exhibited a significant increase in superoxide production in mitochondria, further supporting mitochondrial dysfunction. Together these results emphasize the novel role of TMEM38B/TRIC-B in osteoblast differentiation, affecting cell-cell adhesion processes, gap and tight junction, proliferation, cell cycle, and mitochondrial function.


Clinical risk factors for post-stroke urinary incontinence during rehabilitation.
Urinary incontinence (UI) is a common problem after stroke. Risk factors for UI seem to be multifactorial. There is still controversy in which risk factors contribute to UI. The aim of this study was to investigate risk factors for UI in stroke patients during rehabilitation. Study investigated 150 participants after the first stroke consecutively admitted to a post-acute inpatient rehabilitation program. They were divided into continence and incontinence group according to continence status on rehabilitation admission. Data about sociodemographic factors, functional status, comorbidities, current medications, type and localisation of stroke were collected. Compared with the continence group, incontinent participants had significantly worse cognitive status and upper limb function (P ≤ 0.005), more common global aphasia, neglect, visual field defect, agitation/confusion and deficits in somatic sensation (P ≤ 0.014). There were no differences between the groups regarding comorbidities, but incontinent participants received a larger number of current medications (P = 0.020). Incontinent participants had stroke located more common in the right hemisphere, corticosubcortical region and in the total anterior circulation region (P ≤ 0.051). In the multivariate analysis, Brunnstrom recovery stages of the affected upper limb [odds ratio (95% confidence interval: 1.61 (1.27-2.03)], agitation/confusion [5.36 (1.74-16.54)], global aphasia [5.06 (1.40-18.26)] and faecal impaction [3.41 (1.15-10.09)] were independent risk factors for UI. Findings suggest that communicative and cognitive problems, affected upper limb function and faecal impaction are the most important clinical risk factors for UI after stroke. Knowledge of these risk factors may help in the management of UI during rehabilitation of stroke patients.


Diurnal changes in the expression of genes encoding for arginine vasotocin and pituitary pro-opiomelanocortin in the rainbow trout (Oncorhynchus mykiss): correlation with changes in plasma hormones.
Using quantitative in-situ hybridization, this study monitored diurnal changes in the abundance of the gene transcripts of two corticotropin-releasing peptides, arginine vasotocin (AVT) and isotocin in hypothalamic neurones, and of pro-opiomelanocortin (POMC) mRNA in the pituitary of the rainbow trout (Oncorhynchus mykiss). A significant diurnal pattern of gene expression was only displayed in the hypothalamus by the parvocellular AVT neurones of the preoptic nucleus. Abundance of AVT mRNA in these neurones was low at lights on (06.00 h), increased during the morning to reach a plateau of peak values between 14.00 h and 22.00 h, and then declined during the dark phase. This pattern was the inverse of that shown by plasma cortisol values. Changes in AVT transcript abundance are also considered in terms of the reported diurnal change in circulating AVT concentration. Pituitary and hypothalamic AVT peptide content did not change. Transcripts of both POMC genes (POMC-A and POMC-B) were monitored in pituitary corticotropes and melanotropes. Only POMC-A mRNA was detected in corticotropes where it showed no diurnal change in abundance. Transcripts of both POMC genes were found in the melanotropes, although, judging from autoradiographic intensity, POMC-A mRNA predominated. Both genes showed diurnal differences in their transcription with POMC-A mRNA showing peak values at 10.00 h and a nadir at 02.00 h, while POMC-B mRNA showed an inverse pattern. The results indicate that the two POMC genes can be independently regulated.


Variations in hemodynamic parameters and ECG in healthy, conscious, freely moving telemetrized beagle dogs.
Interpretation of the dynamic cardiovascular parameters on safety pharmacology studies is a challenging process; sometimes, it is difficult to separate normal physiological variations from the effects of the test drug. Data from healthy control Beagle dogs (41 males and 25 females) implanted with telemetry transmitters (DSI, St. Paul, MN) from 34 studies performed from 2003 to 2005 were analyzed. Telemetry data were collected for a 30-s period every 10 min for 24 h after sham dosing. One-hour averages were analyzed. Prior to dosing, heart rate (HR) was 95.6 +/- 26.6 bpm; mean, systolic, and diastolic blood pressure (BP) were 105.3 +/- 12.7, 142.5 +/- 5.3, and 84.7 +/- 11.1 mmHg, respectively. PR, QRS, QT, and corrected (Van de Water) QT intervals were 121 +/- 13, 33 +/- 3, 217 +/- 23, and 245 +/- 18 ms, respectively. Seasonal and slight diurnal patterns were noticed only in HR; BP and body temperature were more stable. PR and QT intervals were inversely related to HR; in addition, the duration of PR was influenced by the light cycle. A comparison of three QT correction formulas demonstrated that Van de Water's formula provided the optimal results in Beagle dogs over a wide range of HR.


Effects of Cysteine-Stabilised Peptide Fraction of Aqueous Extract of Morinda lucida Leaf on Selected Cardiovascular Disease Indices in Mice.
This study evaluated the effects of cysteine-stabilised peptide fraction (CSPF) of aqueous extract of Morinda lucida leaf on selected cardiovascular disease indices in mice. Sixty adult Swiss Albino mice were randomly divided into 6 groups (n = 10). Group A served as control and received 5% DMSO. Half of the mice in groups B, C, D, E and F received 31.25, 62.5, 125, 250, and 500 mg/kg body weight of CSPF respectively for 7 days while the other half received the various doses for 28 days. After the experimental period, selected cardiovascular disease indices were determined in the mice. The results revealed that CSPF significantly reduced (p < 0.05) atherogenic index, plasma concentrations of total cholesterol and LDL-cholesterol but significantly increased (p < 0.05) plasma HDL-cholesterol concentration at higher doses after 28 days of administration. Plasma lactate dehydrogenase, aspartate aminotransferase and alkaline phosphatase activities were not significantly altered (p > 0.05) at all doses of the CSPF after 7 and 28 days of administration compared to controls. After 7 days of CSPF administration, the activities of heart Ca2+, Mg2+-ATPase and Na+-K+-ATPase were not significantly altered (p > 0.05) but heart Mg2+-ATPase activity was significantly increased (p < 0.05) at 250 mg/kg body weight compared to controls. Also, 28 days of CSPF administration at all doses had no significant effect (p > 0.05) on the activities of heart Mg2+-ATPase and Na+-K+-ATPase of mice compared to controls but heart Ca2+-Mg2+-ATPase activity was significantly increased (p < 0.05) at the highest dose with no significant alteration (p > 0.05) at other doses compared to controls. Generally, CSPF administration had no significant effect (p > 0.05) on haematological parameters after 7 and 28 days. These results suggest that CSPF may not predispose subjects to cardiovascular diseases.


Antibody responses to influenza vaccines containing A/New Jersey/8/76.
Studies were undertaken with whole virus, subunit and adsorbed subunit influenza vaccines containing the A/New Jersey/8/76 strain to compare the antibody response induced by immunization with these vaccines. There were no significant differences in the haemagglutination-inhibiton (HI) antibody responses to A/New Jersey/8/76 induced by these vaccines in the adult groups under study. Vaccinees over 23 years of age produced good HI antibody responses to one dose of vaccine. Neuraminidase antibody and complement-fixing (CF) antibody responses were determined for the A/Victoria/3/75 component of bivalent vaccines. There were significant increases in neuraminidase inhibiting (NI) antibody titres but no increase in the complement-fixing antibody titres after vaccination.


Reoperation for composite graft infection after aortic root replacement.
Composite graft infection after aortic root replacement is a serious complication and requires surgical reintervention with a high mortality rate. We report two cases of composite graft infection 3 months and 44 months after the primary operation. Each successfully underwent redo aortic root replacement with a new composite graft and a Freestyle stentless bioprosthesis, respectively. Both patients are currently well and without recurrence of infection 35 months and 48 months postoperatively.


Surgical treatment of synchronous multiple primary lung cancers: experience of 92 patients.
According to our previous study, the concurrent detection of p53 and epidermal growth factor receptor mutations significantly improves the clonality assessment and impact management of patients with multiple primary lung cancer. Nevertheless, the treatment, outcome, and safety of patients with this complex disease remain controversial. This series of cases detail our experiences with surgical resections in 92 patients during the past 16 years. A database of 1651 patients was evaluated for unilateral and bilateral synchronous multiple primary lung cancers. The relationships among the location of tumors, number of tumors, tumor size, tumor histology, vascular invasion, regional lymph node metastasis, extranodal extension, type of surgery, mortality, and survival were analyzed. The 5-year survival for all synchronous multiple primary lung cancers was 35.3%. The overall surgical mortality was 1.1%. Notably, lymph node metastasis, extranodal extension, vascular invasion, tumors with adenosquamous carcinoma or different histology, and poor survival were observed. Multivariate analysis showed that only the occurrence of lymph node metastasis remained a statistically significant prognostic factor. The 5-year survivals were 15.5% [corrected] and 52.5% [corrected] for patients with and without lymph node metastasis, respectively (P < .001). An aggressive surgical approach is safe and justified in patients with synchronous multiple primary lung cancers and node-negative diseases. The status of this particular form of non-small cell lung cancers might be considered in the conventional TNM staging system for more accurate prediction of patient prognosis.


Photonic labyrinths: two-dimensional dynamic magnetic assembly and in situ solidification.
Creating novel structures by self-assembly processes and fixing the resultant assemblies are both critical to the design and fabrication of functional materials through bottom-up approaches. We demonstrate magnetically induced self-assembly of 2D photonic labyrinth structures and their solidification through a sol-gel method. The photonic labyrinth structures can be patterned into more regular arrangements using nonmagnetic substrates. This work may provide a platform for fabricating novel materials and devices with complex morphologies and spatial configurations.


The impact of COVID-19 pandemic on out-of-hospital cardiac arrest system-of-care: Which survival chain factor contributed the most?
In many communities, out-of-hospital cardiac arrest (OHCA) survival outcomes decreased after the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to identify and compare the impacts of each survival chain factor on the change of survival outcomes after COVID-19. Using a Korean out-of-hospital cardiac arrest registry, we analyzed OHCA patients whose arrest was not witnessed by emergency medical service (EMS) providers between 2017 and 2021. Because lack of hospital and survival information in 2021, the 2021 data were used only to identify the expected trend. We developed a prediction model for survival to discharge using patients from 2017 to 2019 (Pre-COVID-19 set) and validated it using patients from 2020 (post-COVID-19 set). Using Utstein elements, a stepwise logistic regression model was constructed, and discrimination and calibration were evaluated by c-statistics and scaled Brier score. Using the distribution change of predictors from one year before the pandemic (2019) to post-COVDI-19, we calculated the magnitude of survival difference according to each predictor's distribution change using the marginal standardization method. Among 83,273 patients (mean age 67.2 years and 64.3% males), 61,180 and 22,092 patients belonged to pre-COVOD-19 and post-COVID-19 sets. Survival to discharge was 5019 (8.2%) in pre-COVID-19 set and 1457 (6.6%) in post-COVID-19 set. The proportion of bystander cardiopulmonary resuscitation was 59.0% in the pre-COVID-19 set and 61.0% in the post-COVID-19 set. The median (interquartile range) response time was 7 (5-9) minutes in the pre-COVID-19 set and 8 (6-10) minutes in the post-COVID-19 set. The area under the receiver operating characteristic (AUROC) curve (95% confidence interval) was 0.907 (0.902-0.912) in the pre-COVID-19 set, and 0.924 (0.916-0.931) in the post-COVID-19 set, and scaled Brier score were 0.39 in pre-COVID-19 sets, and 0.40 in the post-COVID-19 set. Among various predictors, EMS factors showed the highest impact. Response time and on-scene management of EMS showed the highest impact on decreased survival. A similar trend was also expected in the 2021. The effort to create a rapid response system for OHCA patients could have priority for the recovery of survival outcomes in OHCA patients in the post-COVID-19 period. Further studies to recover survival outcomes of OHCA are warranted.


High-rate automated deposition system for the manufacture of complex multilayer coatings.
A previously described automated thin-film deposition system based on rf-magnetron sputtering could deposit quite complex optical multilayer systems with good precision and with no one in attendance [Sullivan and Dobrowolski, Appl. Opt. 32, 2351-2360 (1993)]. However, the deposition rate was slow, and the uniform area on the substrate was limited. We describe an ac-magnetron sputtering process in which the same deposition accuracy has been combined with significantly better film uniformity and a fivefold or sevenfold increase in the deposition rate. This makes the equipment of commercial interest. Experimental results are presented for several difficult coating problems.


Anthropometric indices of fat distribution and cardiometabolic risk in Parkinson's disease.
To investigate the association between anthropometric indices of body fat distribution and cardiometabolic risk factors in a population of Parkinson's disease (PD) patients. One hundred and fifty-seven PD patients (57.3% males) were studied measuring: waist circumference (WC), waist-hip ratio (WHR), waist-to-height ratio (WtHR), body fat percentage (BF%) by impedance, fasting glucose, serum lipids. Information was collected also on diabetes, hypertension and metabolic syndrome (MetS). Increased cardiometabolic risk was defined by ≥2 MetS component traits other than abdominal adiposity. In the whole population, prevalence of overweight and obesity were 35.0% and 19.2%, respectively. However, prevalence of MetS and elevated cardiometabolic risk were 14.6% and 18.5%, respectively. Prevalence was similar between genders, with one exception: adverse fat distribution according to WC and WHR was more common in females (P < 0.001). Using a multivariable model (adjustments: age, smoking status and disease duration), indices were highly correlated with BF% in both genders. WC and WtHR were associated with the number of MetS criteria and elevated risk. The only cardiometabolic parameters associated with anthropometric indices were HDL in men and triglycerides in women. After adjusting also for BMI all the associations found with anthropometric indices disappeared. Despite their correlation with BF%, anthropometric indices of body fat distribution appear to poorly account for the reduced cardiometabolic risk of the PD patient. This finding suggests a low metabolic activity within the adipose tissue. The implications of fat distribution on the cardiometabolic risk of PD patients clearly deserves further investigation.


The effect of verbal commitment and treatment choice on medication compliance in a pediatric setting.
This experiment examined the manner in which verbal commitment and treatment choice affect medication compliance in a pediatric setting. Parents (N = 89) of children suffering from an inner ear infection (otitis media) were asked or not asked for a verbal promise to give their child all prescribed antibiotic medication (commitment manipulation) and allowed or not allowed to choose between two equally appropriate antibiotics as the treatment for their child (choice manipulation). Self-reports at follow-up visits, which were supported by urinalysis results, indicated that obtaining a verbal commitment significantly increased medication compliance. Verbal commitment also nonsignificantly increased the likelihood of a resolved infection at follow-up. Providing the parent with a choice of treatments had no effect on compliance or health outcome.


Relationship between Helicobacter pylori and Incident Hypertension as well as Blood Pressure: A Systematic Review and Meta-Analysis.
Helicobacter pylori (H. pylori) may be a risk factor for hypertension, but the reported studies have given conflicting results. This study aimed to explore the association between H. pylori infection and hypertension risk and blood pressure. PubMed, Embase, Web of Science, CNKI, Weipu, and Wanfang databases were searched for articles published up to June 2, 2021. Dual-selection and data abstraction were conducted. Random-effect models were used to measure pooled estimates. All data were analyzed with Stata 14.0 SE (StataCorp, College Station, TX, USA). A total of 55 studies with 198,750 individuals were included in the meta-analysis. Among them, 33 studies reported the relationship between H. pylori infection and the risk of hypertension, and 25 studies reported the association of H. pylori infection with systolic blood pressure (SBP) and diastolic blood pressure (DBP). Three studies reported both of the above. Meta-analysis showed that H. pylori infection increased the risk of hypertension by 32% (odd ratio: 1.32, 95% CI: 1.15-1.52). Compared with non-H. pylori-infection individuals, the subjects with H. pylori infection had elevated levels of SBP (WMD: 1.86, 95% CI: 1.21-2.50) and DBP (WMD: 1.12, 95% CI: 0.81-1.43). This meta-analysis suggested that H. pylori infection increased the risk of hypertension. This may provide a new strategy for hypertension prevention. However, the association between H. pylori infection and hypertension needs to be confirmed in further prospective cohort studies.


Macrophage migration inhibitory factor (MIF) is rendered enzymatically inactive by myeloperoxidase-derived oxidants but retains its immunomodulatory function.
Macrophage migration inhibitory factor (MIF) is an important player in the regulation of the inflammatory response. Elevated plasma MIF is found in sepsis, arthritis, cystic fibrosis and atherosclerosis. Immunomodulatory activities of MIF include the ability to promote survival and recruitment of inflammatory cells and to amplify pro-inflammatory cytokine production. MIF has an unusual nucleophilic N-terminal proline with catalytic tautomerase activity. It remains unclear whether tautomerase activity is required for MIF function, but small molecules that inhibit tautomerase activity also inhibit the pro-inflammatory activities of MIF. A prominent feature of the acute inflammatory response is neutrophil activation and production of reactive oxygen species, including myeloperoxidase (MPO)-derived hypochlorous acid and hypothiocyanous acid. We hypothesized that MPO-derived oxidants would oxidize the N-terminal proline of MIF and alter its biological activity. MIF was exposed to hypochlorous acid and hypothiocyanous acid and the oxidative modifications on MIF were examined by LC-MS/MS. Imine formation and carbamylation was observed on the N-terminal proline in response to MPO-dependent generation of hypochlorous and hypothiocyanous acid, respectively. These modifications led to a complete loss of tautomerase activity. However, modified MIF still increased CXCL-8/IL-8 production by peripheral blood mononuclear cells (PBMCs) and blocked neutrophil apoptosis, indicating that tautomerase activity is not essential for these biological functions. Pre-treatment of MIF with hypochlorous acid protected the protein from covalent modification by the MIF inhibitor 4-iodo-6-phenylpyrimidine (4-IPP). Therefore, oxidant generation at inflammatory sites may protect MIF from inactivation by more disruptive electrophiles, including drugs designed to target the tautomerase activity of MIF.


Oral 4-hydroxyandrostenedione, a new endocrine treatment for disseminated breast cancer.
Thirty-one post-menopausal female patients, with locally advanced or disseminated breast cancer were treated with the aromatase inhibitor 4-hydroxyandrostenedione given orally at a dose of 500 mg daily. Twenty-nine patients had assessable disease. Eight patients (28%) had objective evidence of partial response and six remain in remission 7-10 months later. A further four patients (14%) had stabilisation of disease and 11 patients (37%) had progressive disease in spite of treatment. Plasma oestradiol levels were measured throughout therapy in 16 patients and were lowered to 53% +/- 8% of baseline levels within 7 days of commencing 4-hydroxyandrostenedione. With regard to toxicity, one patient developed a transient skin rash and another patient some facial swelling. A further patient developed a transient leucopaenia and treatment was therefore discontinued. Twenty-seven of the 30 evaluable patients (90%) experienced no side effects. These results indicate that oral administration of 4-hydroxyandrostenedione is an acceptable new treatment for post-menopausal women with disseminated breast cancer.


Radioenzymatic assay for plasma dihydroxyphenylglycol (DHPG), dihydroxymandelic acid (DOMA) and dihydroxyphenylacetic acid (DOPAC).
An adaptation of the single-isotope radioenzymatic catecholamine assay technique allows simultaneous quantitation of free dihydroxyphenylglycol (DHPG), dihydroxymandelic acid (DOMA), and dihydroxyphenylacetic acid (DOPAC) in small volumes of plasma. Incubation of sample with catechol-O-methyltransferase and S-adenosylmethionine is followed by acidic extractions of metabolites and thin-layer chromatography. O-methylated products of the beta-hydroxylated metabolites DHPG and DOMA are further subjected to periodate cleavage to improve sensitivity. Quantitation by liquid scintillation counting with internal standardization results in a sensitivity of approximately 8, 30 and 70 pg for DHPG, DOMA and DOPAC. Normal values for these three metabolites in resting humans are (mean +/- S.D., pg/ml): 1010 +/- 280 for DHPG, 2090 +/- 720 for DOMA and 3270 +/- 1470 for DOPAC.


Blood-spinal cord barrier disruption proximal to a spinal cord transection in the rat: time course and pathways associated with protein leakage.
The effects of spinal cord transection on the blood-spinal cord barrier of the rat were examined at the ultrastructural level at sites 0.5 and 1.0 cm proximal to the injury. Using the vascular tracer horseradish peroxidase (HRP), the time course and pathways of barrier disruption were evaluated. At 0.5 cm, barrier disruption was noted from as early as 15 min and continued to 12 h after injury, whereas at 1.0 cm, evidence for vascular permeability was confined to between 15 min and 3 h. The presence of barrier breakdown to exogenous protein at a distance from the transection emphasizes that injury promotes a more generalized vascular response which likely contributes to subsequent edematous changes. The mechanism(s) involved in increased permeability appears to be primarily related to transendothelial vesicular transport of the tracer. There was no evidence for interendothelial leakage of the tracer across compromised tight junctions. In comparing these findings with those reported on sites distal to a transection, it is clear that there is an asymmetry in the vascular response to HRP. The pinocytotic index, an indicator of endothelial uptake of HRP, was significantly elevated (compared with control) distal to a transection from 3 h through 3 days after injury, attaining a maximum at 12 h. In contrast, the pinocytotic index proximal to a transection was significantly elevated compared to control values at only 1 h after injury. Furthermore, at 3 h after injury, when barrier disruption was most prominent, there was a smaller percentage of vessels exhibiting leakage to HRP proximal as opposed to distal to a transection.


Itaconic Acid Based Surfactants: I. Synthesis and Characterization of Sodium n-Octyl Sulfoitaconate Diester Anionic Surfactant.
A novel itaconate-based surfactant, namely sodium n-octyl sulfoitaconate diester (SOSID), has been synthesized from itaconic acid (IA) and n-octanol by sulfonation and esterification reaction processes. The effects of reaction temperature, reaction time, molar ratios of n-octanol to IA and the catalyst dosage on the esterification were investigated. The chemical structure of the surfactants SOSID was characterized by means of LC-MS and confirmed by FT-IR and 1H NMR spectroscopy. The surface tension γ and the critical micelle concentration (CMC) were determined as 25.02 mN/m and 4.0 × 10-4 mol/L by using surface tensiometer at 20 °C. Further investigations showed that SOSID possess excellent wetting, emulsifying and lime soap dispersing properties.


GM1 ganglioside counteracts cholinergic and behavioral deficits induced in the rat by intracerebral injection of vincristine.
The intracerebroventricular injection of 0.5 mg of vincristine sulphate in adult male Wistar rats caused within 11 days the impairment of motor and reflexive behavior, evaluated by the elevated platform and hanging wire tests, a decrease in food consumption and loss of body weight, a 45% decrease in hippocampal choline acetyltransferase (ChAT) activity and a 35% decrease in the rate of high-affinity choline uptake (HACU) in the injected side. The latter effects are due to the death of neurons in the respective hemiseptum. Intrafimbrial injection of vincristine caused the same decrease in ChAT activity without behavioral alterations. Daily i.p. administration of GM1 ganglioside, beginning immediately after the vincristine injection, prevented dose dependently the decrease in ChAT activity and HACU rate. Prevention was complete with the 60 mg/kg dose. The same dose was equally active on ChAT activity when given s.c. but was inactive p.o. The ChAT decrease was also prevented when GM1 treatment began 5 days after vincristine. GM1 60 mg/kg i.p. also reduced the behavioral toxicity of vincristine. The possibility that GM1 might prevent vincristine toxicity by antagonizing its disruption of neurofilaments and axonal flow is discussed.


Convergence of YAP/TAZ, TEAD and TP63 activity is associated with bronchial premalignant severity and progression.
Bronchial premalignant lesions (PMLs) are composed primarily of cells resembling basal epithelial cells of the airways, which through poorly understood mechanisms have the potential to progress to lung squamous cell carcinoma (LUSC). Despite ongoing efforts that have mapped gene expression and cell diversity across bronchial PML pathologies, signaling and transcriptional events driving malignancy are poorly understood. Evidence has suggested key roles for the Hippo pathway effectors YAP and TAZ and associated TEAD and TP63 transcription factor families in bronchial basal cell biology and LUSC. In this study we examine the functional association of YAP/TAZ, TEADs and TP63 in bronchial epithelial cells and PMLs. We performed RNA-seq in primary human bronchial epithelial cells following small interfering RNA (siRNA)-mediated depletion of YAP/TAZ, TEADs or TP63, and combined these data with ChIP-seq analysis of these factors. Directly activated or repressed genes were identified and overlapping genes were profiled across gene expression data obtained from progressive or regressive human PMLs and across lung single cell RNA-seq data sets. Analysis of genes regulated by YAP/TAZ, TEADs, and TP63 in human bronchial epithelial cells revealed a converged transcriptional network that is strongly associated with the pathological progression of bronchial PMLs. Our observations suggest that YAP/TAZ-TEAD-TP63 associate to cooperatively promote basal epithelial cell proliferation and repress signals associated with interferon responses and immune cell communication. Directly repressed targets we identified include the MHC Class II transactivator CIITA, which is repressed in progressive PMLs and associates with adaptive immune responses in the lung. Our findings provide molecular insight into the control of gene expression events driving PML progression, including those contributing to immune evasion, offering potential new avenues for lung cancer interception. Our study identifies important gene regulatory functions for YAP/TAZ-TEAD-TP63 in the early stages of lung cancer development, which notably includes immune-suppressive roles, and suggest that an assessment of the activity of this transcriptional complex may offer a means to identify immune evasive bronchial PMLs and serve as a potential therapeutic target.


Study on the interaction between NCP-(4-hydroxycoumarins) and bovine serum albumin by spectroscopic techniques.
The interaction between N-confused porphyrins-(4-hydroxycoumarins) diad (NCP-(4-hydroxycoumarins)) and bovine serum albumin (BSA) was studied using fluorescence and ultraviolet spectroscopy at different temperatures under imitated physiological conditions. The experimental results showed that the fluorescence of BSA was quenched by NCP-(4-hydroxycoumarins) through a combined quenching procedure. The binding constants, binding sites and corresponding thermodynamic parameters between NCP-(4-hydroxycoumarins) and BSA at different temperatures were obtained. According to Förster non-radiation energy transfer theory, the binding distance between BSA and NCP-(4-hydroxycoumarins) was calculated to be about 2.1 nm. The effect of NCP-(4-hydroxycoumarins) on the conformation of BSA was analyzed using synchronous fluorescence spectroscopy. In addition, the effect of some metal ions Cu(2+), Ca(2+), Mg(2+), and Ni(2+) on the binding constant between NCP-(4-hydroxycoumarins) and BSA was examined.


Novel naphthochalcone derivative accelerate dermal wound healing through induction of epithelial-mesenchymal transition of keratinocyte.
Wound healing is an intricate process whereby the skin repairs itself after injury. The epithelial-mesenchymal transition (EMT) is associated with wound healing and tissue regeneration. Naphthochalcone derivatives have various pharmaceutical properties. We investigated the effect of a novel naphthochalcone derivative, 2-(5-(2,4,6-trimethoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)naphthalen-1-ol (TDPN), on dermal wound healing in vivo and the migration of keratinocytes in vitro. We investigated the effect of TDPN on signaling pathway and epithelial-mesenchymal transition through protein and transcriptional expression. The TDPN treatment accelerated dermal closure about 3 days and remodeling of dermis. We found that treatment with TDPN induced the migration of keratinocytes but not cytotoxicity. TDPN induced the phosphorylation of ERK and AKT. TDPN-treated cells showed loss of adherence protein and showed induction of the transcriptional factor Slug, mesenchymal marker, and fibronectin. Moreover, TDPN treatment induced the expression of matrix metalloproteinase-1 (MMP-1), which degrades specific components of the extracellular matrix, thereby providing new substrates that facilitate migration and invasion. MMP expression is considered to be one of the major attributes acquired by cells after EMT. We propose that a novel naphthochalcone derivative TDPN is capable of promoting keratinocyte migration via the induction of EMT resulting acceleration of wound closure and matrix remodeling.


A high-conductance mode of a poly-3-hydroxybutyrate/calcium/polyphosphate channel isolated from competent Escherichia coli cells.
Reconstitution into planar lipid bilayers of a poly-3-hydroxybutyrate/calcium/polyphosphate (PHB/Ca(2+)/polyP) complex from Escherichia coli membranes yields cationic-selective, 100 pS channels (Das, S., Lengweiler, U.D., Seebach, D. and Reusch, R.N. (1997) Proof for a non-proteinaceous calcium-selective channel in Escherichia coli by total synthesis from (R)-3-hydroxybutanoic acid and inorganic polyphosphate. Proc. Natl. Acad. Sci. USA 94, 9075-9079). Here, we report that this complex can also form larger, weakly selective pores, with a maximal conductance ranging from 250pS to 1nS in different experiments (symmetric 150mM KCl). Single channels were inhibited by lanthanum (IC(50)=42+/-4microM, means+/-S.E.M.) with an unusually high Hill coefficient (8.4+/-1.2). Transition to low-conductance states (<250pS) was favored by increased membrane polarization (/V/ >or=50mV). High conductance states (>250pS) may reflect conformations important for genetic transformability, or "competence", of the bacterial cells, which requires the presence of the PHB/Ca(2+)/polyP complex in the membrane.


Trust about corona vaccine among health professionals working at Dilla University referral hospital, 2021.
Corona virus is continuing over a year ago throughout the world. To handle the spread and vitality of the virus, several investigations have been done and recently the vaccine has launched in order to effect soon. A vaccine has several controversial issues regarding the effectiveness and potential unwanted serious adverse effects. In low-and middle-income countries including Ethiopia, there is a huge knowledge gap and insufficiency of information about the corona vaccine. Trust is exceptionally crucial to utilize any vaccines apply on human being. This study aimed to assess trust about corona vaccine and its associated factors among health professionals working at Dilla University referral hospital, Southern Ethiopia, 2021. A hospital-based study employing cross-sectional design and simple random sampling technique was used to select health professionals who are working at Dilla University referral hospital from March 1-15, 2021. Trust about corona vaccine was assessed by a Likert scale type single standard questionnaire. A Binary Logistic regression at 95% CI, p < 0.05 was used to identify factors associated with the outcome variable. This study included 250 health professionals. From the total of respondents, 155(62%) indicated they would not trust COVID-19 vaccines. The most common reasons indicated through a closed series of 10 options for not trusting the vaccine included doubts in efficacy, novelty of the products, fast-tracking of the development and general indecisiveness. Men, people aged less than 32 years, who were single, who worked in a coronavirus treatment unit, who had a positive coronavirus test and no current history of physical illness were more likely to trust or demand the vaccine. The proportion of health professionals that trust COVID-19 vaccination is among the lowest in the world. Therefore, there is a need of awareness creation training and education about the corona vaccine for health professionals, particularly for those identified groups.


[Oxygen in emergency medicine--boon or bane?].
Oxygen is the best known and well accepted medication in emergency medicine. In most emergencies high doses of oxygen are an essential part of treatment and seemed to be nearly free of adverse effects. Studies of the last two decades show hints to possible adverse effects of hyperoxia during post-resuscitation-care and myocardial infarction. These results should be critically reviewed and may lead to a rational use of oxygen in emergency care.


Identification of sequence motifs at the breakpoint junctions in three t(1;9)(p36.3;q34) and delineation of mechanisms involved in generating balanced translocations.
Although approximately 1 in 500 individuals carries a reciprocal translocation, little is known about the mechanisms that result in their formation. We analyzed the sequences surrounding the breakpoints in three unbalanced translocations of 1p and 9q, all of which were designated t(1;9)(p36.3;q34), to investigate the presence of sequence motifs that might mediate nonhomologous end joining (NHEJ). The breakpoint regions were unique in all individuals. Two of three translocations demonstrated insertions and duplications at the junctions, suggesting NHEJ in the formation of the rearrangements. No homology was identified in the breakpoint regions, further supporting NHEJ. We found translin motifs at the breakpoint junctions, suggesting the involvement of translin in the joining of the broken chromosome ends. We propose a model for balanced translocation formation in humans similar to transposition in bacteria, in which staggered nicks are repaired resulting in duplications and insertions at the translocation breakpoints.


Early severe institutional deprivation is associated with a persistent variant of adult attention-deficit/hyperactivity disorder: clinical presentation, developmental continuities and life circumstances in the English and Romanian Adoptees study.
Early-life institutional deprivation is associated with attention-deficit/hyperactivity disorder (ADHD) later in childhood and adolescence. In this article, we examine, for the first time, the persistence of deprivation-related ADHD into young adulthood in a sample of individuals adopted as young children by UK families after periods in extremely depriving Romanian orphanages. We estimated rates of ADHD at age 15 years and in young adulthood (ages 22-25 years) in individuals at low (LoDep; nondeprived UK adoptees and Romanian adoptees with less than 6-month institutional exposure) and high deprivation-related risk (HiDep; Romanian adoptees with more than 6-month exposure). Estimates were based on parent report using DSM-5 childhood symptom and impairment criteria. At age 15, data were available for 108 LoDep and 86 HiDep cases, while in young adulthood, the numbers were 83 and 60, respectively. Data on education and employment status, IQ, co-occurring symptoms of young adult disinhibited social engagement (DSE), autism spectrum disorder (ASD), cognitive impairment, conduct disorder (CD), callous-unemotional (CU) traits, anxiety, depression and quality of life (QoL) were also collected. ADHD rates in the LoDep group were similar to the general population in adolescence (5.6%) and adulthood (3.8%). HiDep individuals were, respectively, nearly four (19%) and over seven (29.3%) times more likely to meet criteria, than LoDep. Nine 'onset' young adult cases emerged, but these had a prior childhood history of elevated ADHD behaviours at ages 6, 11 and 15 years. Young adult ADHD was equally common in males and females, was predominantly inattentive in presentation and co-occurred with high levels of ASD, DSE and CU features. ADHD was associated with high unemployment and low educational attainment. We provide the first evidence of a strong persistence into adulthood of a distinctively complex and impairing deprivation-related variant of ADHD. Our results confirm the powerful association of early experience with later development in a way that suggests a role for deep-seated alterations to brain structure and function.


A method for studying the population dynamics of Candida oleophila on oranges in the grove, using a selective isolation medium and PCR technique.
Populations of the biological control agent Candida oleophila on fruit in an orange grove were monitored by plating fruit washes and peel homogenates on a selective medium, followed by PCR analysis of DNA from yeast colonies resembling C. oleophila. The C. oleophila transformant ADGus-10 formed colonies on a selective medium that suppressed the development of 99% of the filamentous fungi and the indigenous yeasts, Aureobasium (a yeast-like fungus) and Rhodotorula. Only 6-8 indigenous yeasts/cm2 fruit surface gave rise to colonies that resembled C. oleophila on the selective medium. The identity of the C. oleophila transformant colonies was verified by PCR analysis of yeast DNA. The presence of a 599-bp band in the PCR product primed by beta-glucuronidase gene primers, confirmed the identity of C. oleophila transformant ADGus-10. Colony-forming units of C. oleophila were recovered efficiently from fortified washes of the fruit surface and from homogenates of wounds excised from fruit sprayed in the grove with C. oleophila.


Rugitermes tinto: A new termite (Isoptera, Kalotermitidae) from the Andean region of Colombia.
The imago and soldier castes of a new Rugitermes Holmgren, 1911 species, R. tinto sp. nov. are described. It is the ninth species of Rugitermes from South America and the first record of this genus from Colombia. Unlike its congeners, the soldier of R. tinto has very dark head capsule pigmentation and acute protuberances projecting from frontolateral ridges.


An improved method for the determination of acetaldehyde in human blood with minimal ethanol interference.
A sensitive method for the determination of acetaldehyde in human blood is described which involves the derivatization of acetaldehyde with semicarbazide followed by head-space gas chromatographic analysis of acetaldehyde in plasma samples after acid hydrolysis of the semicarbazone derivative. Quantitative recovery of acetaldehyde from human blood was achieved and interference from ethanol, a major problem associated with earlier methods, was negligible.


[Glycogen storage syndrome type 0 caused by GYS2 gene variation and phenotypic differences between two siblings].
To provide a basis for genetic counseling and clinical precision therapy by exploring the genetic etiology of a child with recurrent hypoglycemia convulsion accompanied by language retardation. Peripheral blood samples were obtained from the proband, his sister and his parents. Whole genomic DNA was extracted and analyzed by the whole exon gene sequencing and confirmed by Sanger sequencing. The proband and his sister were found to carry compound heterozygous variants c.731T>A (p.M244L) and c.928G>A (p.G244S) of the GYS2 gene, which had not been reported in the past, the c.731T>A (p.M244L) site was derived from the maternal heterozygous mutation, while c.928G>A (p.G244S) site from the father heterozygous mutation. The compound heterozygous variants c.731T>A (p.M244L) and c.928G>A (p.G244S) of the GYS2 gene were the genetic cause of glycogen storage syndrome type 0 in children, providing basis for family genetic counseling. When the patient had Hypoglycemia often accompanied with convulsions, which was easy to be misdiagnosed as seizures, and the antiepileptic treatment was ineffective. After genetic diagnosis, the seizure can be controlled by improving diet to maintain blood glucose stability.


Perception of disease burden and treatment satisfaction in patients with ulcerative colitis from outpatient clinics in Spain: UC-LIFE survey.
Ulcerative colitis (UC) conditions patients' everyday life. With this survey, we aimed to assess the perceived disease burden, preferred treatment attributes, and treatment satisfaction reported by Spanish UC patients. Consecutive unselected UC patients aged at least 18 years were recruited from outpatient hospital clinics. Patients completed the survey at home, returning it by postmail. With test-like questions, they described UC behavior, preferences, and satisfaction with treatment. Of 585 patients invited, 436 (75%) returned the survey (mean age 46 years, 53% men). Of these, 47.1% described their disease during the past year as 'controlled or nearly controlled', 28.0% as 'symptoms not impairing everyday life,' and 24.9% 'disruptive symptoms'. Only 8.7% reported the complete absence of symptoms during the previous year, and 18.8, 30.7, and 47.4%, respectively, described at least one hospital admission, emergency room visit, or nonscheduled visit because of UC activity. Urgency of defecation was the most disruptive symptom. The most important therapy attribute was continuous control of symptoms (44.6%). Most patients (78.8%) were 'very satisfied' or 'satisfied' with current treatment, even those reporting a high burden of symptoms. Half of the patients considered their UC as 'controlled or nearly controlled' and the degree of satisfaction with their therapies was high. However, they reported a high burden of symptoms and resource consumption during the previous year. These findings indicate that patients may get used to living with symptoms, underestimating the potential of therapy for achieving a complete remission. Urgency of defecation was mentioned as highly disrupting and should probably be included in scores and patient-reported outcomes.


Irreversible depigmentation of dark mouse hair by T-2 toxin (a metabolite of Fusarium sporotrichioides) and by calcium pantothenate.
T-2 toxin, a trichothecene metabolite of several Fusarium spp. causes depigmentation of dark mouse hair at the site of its application. Calcium pantothenate, though usually considered as antigreying factor, caused depigmentation at the site of its i.p. injections, at high concentration.


Hirudin or hirudin-like factor - that is the question: insights from the analyses of natural and synthetic HLF variants.
The hirudin-like factor 1 (HLF1) of Hirudo medicinalis belongs to a new class of leech-derived factors. In previous investigations, HLF1 did not exhibit anticoagulatory activities. Here, we describe the analysis of natural and synthetic variants of HLF1 and HLF-Hyb, a yet uncharacterized member of the HLF family. Modifications within the N terminus of HLF1 have a strong impact on its activity. Some variants of HLF1 exhibit thrombin-inhibiting activity comparable to hirudins, whereas others have reduced or no activity. The analyses of HLF-Hyb variants revealed a strong impact of the central globular domain on activity. Our results indicate a comparable mode of action of hirudins and thrombin-inhibiting HLF variants. Finally, we propose and discuss criteria for classifying hirudins and HLFs.


The Risk Factors for Developing Clustered Vertebral Compression Fractures: A Single-Center Study.
Vertebral compression fractures (VCFs) are common among elderly individuals, but clustered VCFs (C-VCFs) are rare and more severe. The risk factors for C-VCFs remain unclear. Thus, we investigated the clinical characteristics of C-VCFs to identify the imminent fracture risk and improve the treatment for such patients. We reviewed the records of patients with VCF at a single medical center between January 2011 and September 2020. Patients who had 4 or more VCFs within 1 year were categorized into the C-VCF group, and the remaining patients were paired into the control group at a ratio of 2:1. We collected demographic, clinical, laboratory, and radiologic information regarding these patients. Univariate analyses, stratified analyses, and multivariate logistic regression were performed to identify the risk factors for C-VCFs. A total of 156 patients were enrolled, of whom 52 were patients with C-VCF. Patients with C-VCF had more severe fractures and pain, with fractures occurring at uncommon sites of the spine. The independent risk factors for C-VCFs included glucocorticoid (GC) treatment (P < .001; hazard ratio [HR], 12.7), recent fracture history (P = .021; HR, 5.5), and lower trabecular bone score (TBS) (P = .044; HR, 1.6). TBS and bone mineral density had greater predictive values in patients without GC treatment (P < .001). Sex, age, and bone turnover biomarkers were not independent risk factors for C-VCFs. C-VCFs are rare adverse consequences of severe osteoporosis, for which GC treatment, recent fracture history, and lower TBS are unique risk factors that are valuable for the early identification and prevention of C-VCFs.


Dementia and intentional and unintentional poisoning in older people: a 10 year review of hospitalization records in New South Wales, Australia - CORRIGENDUM.
The authors would like to apologise for a typographical error in the abstract of the above mentioned article. In the results section of the abstract on the first page of the article, the first odds ratio that refers to 'aged care facilities' should be (OR 5.44; 95% CI 4.43-6.67) and the second odds ratio that refers to health service facilities should be (OR 4.56; 95%CI 4.06-5.13).


Component Distribution Regulation in Sn-Pb Perovskite Solar Cells through Selective Molecular Interaction.
Tin-lead (Sn-Pb) perovskite solar cells (PSCs) with near-ideal bandgap still lag behind the pure lead PSCs. Disordered heterojunctions caused by inhomogeneous Sn/Pb ratio in the binary perovskite film induce large recombination loss. Here, an Sn-Pb perovskite film is reported with homogeneous component and energy distribution by introducing hydrazine sulfate (HS) in Sn perovskite precursor. HS can form hydrogen bond network and coordinate with FASnI3 thus no longer bond with Pb2+ , which reduces the crystallization rate of tin perovskite to the level of lead analog. The strong bonding between SO4 2- and Sn2+ can also suppress its oxidation. As a result, the Sn-Pb PSCs with HS exhibit a significantly improved VOC of 0.91 V along with a high efficiency of 23.17%. Meanwhile, the hydrogen bond interaction network, strong bonding between Sn2+ and sulfate ion also improve the thermal, storage, and air stability of resulting devices.