Disruption of speech motor adaptation with repetitive transcranial magnetic stimulation of the articulatory representation in primary motor cortex.
When auditory feedback perturbation is introduced in a predictable way over a number of utterances, speakers learn to compensate by adjusting their own productions, a process known as sensorimotor adaptation. Despite multiple lines of evidence indicating the role of primary motor cortex (M1) in motor learning and memory, whether M1 causally contributes to sensorimotor adaptation in the speech domain remains unclear. Here, we aimed to assay whether temporary disruption of the articulatory representation in left M1 by repetitive transcranial magnetic stimulation (rTMS) impairs speech adaptation. To induce sensorimotor adaptation, the frequencies of first formants (F1) were shifted up and played back to participants when they produced "head", "bed", and "dead" repeatedly (the learning phase). A low-frequency rTMS train (.6 Hz, subthreshold, 12 min) over either the tongue or the hand representation of M1 (between-subjects design) was applied before participants experienced altered auditory feedback in the learning phase. We found that the group who received rTMS over the hand representation showed the expected compensatory response for the upwards shift in F1 by significantly reducing F1 and increasing the second formant (F2) frequencies in their productions. In contrast, these expected compensatory changes in both F1 and F2 did not occur in the group that received rTMS over the tongue representation. Critically, rTMS (subthreshold) over the tongue representation did not affect vowel production, which was unchanged from baseline. These results provide direct evidence that the articulatory representation in left M1 causally contributes to sensorimotor learning in speech. Furthermore, these results also suggest that M1 is critical to the network supporting a more global adaptation that aims to move the altered speech production closer to a learnt pattern of speech production used to produce another vowel.


Impact of the 2019/2020 Australian Megafires on Air Quality and Health.
The Australian 2019/2020 bushfires were unprecedented in their extent and intensity, causing a catastrophic loss of habitat, human and animal life across eastern-Australia. We use a regional air quality model to assess the impact of the bushfires on particulate matter with a diameter less than 2.5 μm (PM2.5) concentrations and the associated health impact from short-term population exposure to bushfire PM2.5. The mean population Air Quality Index (AQI) exposure between September and February in the fires and no fires simulations indicates an additional ∼437,000 people were exposed to "Poor" or worse AQI levels due to the fires. The AQ impact was concentrated in the cities of Sydney, Newcastle-Maitland, Canberra-Queanbeyan and Melbourne. Between October and February 171 (95% CI: 66-291) deaths were brought forward due to short-term exposure to bushfire PM2.5. The health burden was largest in New South Wales (NSW) (109 (95% CI: 41-176) deaths brought forward), Queensland (15 (95% CI: 5-24)), and Victoria (35 (95% CI: 13-56)). This represents 38%, 13% and 30% of the total deaths brought forward by short-term exposure to all PM2.5. At a city-level 65 (95% CI: 24-105), 23 (95% CI: 9-38) and 9 (95% CI: 4-14) deaths were brought forward from short-term exposure to bushfire PM2.5, accounting for 36%, 20%, and 64% of the total deaths brought forward from all PM2.5. Thus, the bushfires caused substantial AQ and health impacts across eastern-Australia. Climate change is projected to increase bushfire risk, therefore future fire management policies should consider this.


A contra-lateral comparison of the visual effects of a photochromic vs. non-photochromic contact lens.
To compare the effects of a photochromic contact lens vs. a non-photochromic control lens on visual function. A subject-masked, prospective contralateral eye design was used. Sixty-one subjects were enroled based on age (using a 2:1 allocation ratio for ages 18-39 and 40-65 years, respectively). The study lenses were senofilcon A with photochromic additive (Test) that filtered over the entire lens, compared to a non-photochromic Control with no tint. The Test lens was partially activated during testing with a steady-state transmittance of approximately 62%. Eligible subjects were tested using both study lenses, with Test and Control lens randomized by eye. Five visual function outcomes were tested: photostress recovery (PSR), glare disability (GD), glare discomfort (GDC), chromatic contrast (CC) and vernier acuity (VA). Iris colour and macular pigment density were assessed as control variables. PSR was measured as the time needed to recover sight of a target after an intense xenon flash exposure; GD was evaluated as the energy needed to veil a central target by a surrounding xenon annulus; GDC was measured using bio-imaging of the squint response and by self-report using a 9-item Likert scale; CC was measured as thresholds for a yellow grating target superposed on a 460-nm background; VA was determined by measuring vernier offsets of light lines through apertures. Based on our stimulus conditions, PSR was 43% faster using the Test vs. the Control. The eye wearing the Test had 38% less squint (GDC) compared to the Control. GD was improved by 36% in the Test vs. Control and CC was enhanced by 48% with the Test. There was no significant difference in VA. There was a beneficial influence on visual function when comparing the photochromic with the non-photochromic contact lens. This benefit was seen specifically with respect to PRT, GDC, GD and CC thresholds.


Synaptic profile of nucleus tractus solitarius neurons involved with the peripheral chemoreflex pathways.
The glomus cells in the carotid bodies (CB) detect alterations in pH and pCO₂ and low pO₂ level in arterial blood. The carotid sinus nerve conveys the information related to the oxygen level to 2nd-order neurons in the nucleus tractus solitarius (NTS) via tractus solitarius (TS), which is part of the chemoreflex pathways. It has been demonstrated that in 2nd-order NTS neurons receiving inputs from the aortic depressor nerve (ADN), the TS stimulation presents high temporal fidelity. However, the temporal properties of synaptic activity in NTS neurons receiving inputs from CB were not yet fully investigated. Herein using patch-clamp recordings in NTS brainstem slices, we studied TS-evoked excitatory postsynaptic currents (TS-eEPSCs) on morphologically identified 2nd-order NTS neurons that receive afferent inputs from the CB and compared with 2nd-order ADN-NTS neurons recorded in the same experimental conditions. The amplitudes of TS-eEPSCs were similar in both groups, but the latencies and standard deviation (SD) of latency were significantly higher in the CB-NTS neurons (latency: 4±0.2 ms, SD: 0.49±0.03 ms) than in ADN-NTS neurons (latency: 3.3±0.3 ms, SD: 0.19±0.02 ms; P=0.049 for latency and P<0.001 for SD of latency). In a series of double-labeling experiments, we confirmed that some CB-NTS 2nd-order neurons send direct projections to the rostral ventrolateral medulla (RVLM). We conclude that: (a) CB-NTS 2nd-order neurons present temporally distinct postsynaptic currents when compared with ADN-NTS 2nd-order neurons; (b) low SD of latency of TS-eEPSCs is not necessarily a characteristic of all 2nd-order neurons in the NTS; and (c) the presence of direct connections between these 2nd-order neurons in the NTS and RVLM is indicative that these synaptic properties of CB-NTS neurons are relevant for the processing of respiratory and autonomic responses to chemoreflex activation.


Epidermoid cyst in association with subcutaneous meningioma.
A 17-year-old female presented with a non-tender, firm and fixed swelling in the right frontal region. Skull x-rays revealed soft tissue shadow and mild hyperostosis of the underlying frontal bone. Histopathological examination after excision showed it to be a meningioma with an epidermoid cyst.


Intraocular pressure-lowering effect of omidenepag isopropyl in latanoprost non-/low-responder patients with primary open-angle glaucoma or ocular hypertension: the FUJI study.
Omidenepag isopropyl (OMDI) is the prodrug of omidenepag, a selective, non-prostaglandin, prostanoid EP2 receptor agonist, which has been shown to lower intraocular pressure (IOP) in patients with glaucoma and ocular hypertension (OHT). This study evaluated the efficacy and safety of OMDI ophthalmic solution 0.002% in patients with primary open-angle glaucoma or OHT who were non-/low responders to latanoprost. Open-label, multicenter, Phase 3 study (NCT02822742). Following 1-4-week washout, patients were treated with latanoprost ophthalmic solution 0.005% during an 8-week run-in period. Patients with ≤15% IOP reduction at the end of the run-in (indicating non-/low response) received OMDI 0.002% (one drop once daily for 4 weeks). The primary endpoint was the change from baseline in mean diurnal IOP at Week 4. In total, 26 patients were treated with OMDI; two withdrew owing to lack of efficacy. The mean diurnal IOP at baseline (end of latanoprost run-in) was 23.1 mmHg (7.6% IOP reduction from end of washout) indicating non-/low response to latanoprost. After 4 weeks of OMDI treatment, mean diurnal IOP was significantly reduced from baseline (-2.99 mmHg; P < 0.0001). No serious adverse events were reported. Adverse events occurred in five patients (19.2%); adverse drug reactions (anterior chamber cell, conjunctival hyperemia, and erythema of eyelid) occurred in two patients (7.7%) and were mild in severity. In this study, OMDI 0.002% demonstrated a clinically significant reduction in IOP and was well tolerated in patients with primary open-angle glaucoma and OHT who were non-/low responders to latanoprost.


Advantages of, and Adaptations to, Enhanced Recovery Protocols for Perioperative Care during the COVID-19 Pandemic.
This review formulates the rationale for using enhanced recovery protocols (ERPs) to standardize and optimize perioperative care during this high-risk time to minimize poor outcomes owing to provider, patient, and system vulnerabilities. n/a METHODS OF STUDY SELECTION: A literature review using key Medical Subject Headings terms was performed-according to methods described by the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines-on studies that described enhanced recovery and coronavirus disease (COVID-19). Modifications to our existing ERPs related to the COVID-19 pandemic should include new accommodations for patient education, preoperative COVID-19 testing, prehabilitation, and intraoperative infection as well as thromboembolism risk reduction. ERPs are evidence-based, best practice guidelines applied across the perioperative continuum to mitigate surgical stress, decrease complications, and accelerate recovery. These benefits are part of the high-value-care equation needed to solve the clinical, operational, and financial challenges of the current COVID-19 pandemic. The factors driving outcomes on ERPs, such as the provision of minimally invasive surgery, warrant careful consideration. Tracking patient outcomes and improving care in response to outcomes data are key to the success of clinical care protocols such as ERPs. Numerous emerging clinical registries and reporting systems have been activated to provide outcomes data on the impact of COVID-19. This will inform and change surgical practice as well as provide opportunity to learn if the advantages that surgeons, patients, and the healthcare system might gain from using ERPs during a pandemic are meaningful.


IMOUTA: a proposal for patient care handoffs.
An increased frequency of patient handoffs has occurred as a result of the new resident work-hour restrictions that have recently been instituted. Inadequate handoff of patient care has been associated with adverse patient events due to residents being unprepared for events that happen during cross cover periods. The objective of our study was to develop and test the effectiveness of a patient handoff method in an otolaryngology residency program. Single-blinded controlled clinical trial. A standardized, anonymous questionnaire was developed that scored on-call residents' understanding of their patients' diagnoses, hospital courses, active concerns, and treatment plans. For the first 45 days, residents used their traditional handoff. This handoff was prepared by the residents, relaying relevant patient information without any structured format. For the next 45 days, the residents followed the acronym of IMOUTA for handoffs. This mnemonic was developed to help residents identify data (I), medical course (M), outcomes possible tonight (OU), responsibilities to do tonight (T), and opportunity to ask questions and give morning feedback in the AM (A). The questionnaires were then compared at the end of the study. The residents who used the IMOUTA acronym scored significantly higher on their perceived knowledge of patients diagnoses (P = 0.001), hospital courses (P <0.001), active concerns (P <0.001), and treatment plans (P <0.001). Residents felt significantly better prepared for call duties when using the IMOUTA acronym. This standardized system of patient handoff may also be valuable to other residency programs.


Why are anti-smoking health-information interventions less effective among low-socioeconomic status groups? A systematic scoping review.
This paper identifies and synthesises explanations proposed in the literature for the (in)effectiveness of institutional anti-smoking health-information interventions (HII) among low-socioeconomic status (SES) adults in high-income countries. We searched eight databases for relevant papers from various disciplines: Studies published in English since 2009, on the effectiveness among low-SES adults of anti-smoking HIIs, aimed at changing knowledge/behaviour, and conducted by official institutions, were included. Through a scoping review, we synthesised: study design, SES indicator, intervention type, intervention source, study population, outcomes, low-SES effects, equity effects, proposed explanations and whether these were studied empirically. Thirty-eight studies were included in this scoping review. Seventeen suggested explanations for the (in)effectiveness of the HIIs in low-SES adults, but only nine assessed them empirically. Thematic analysis yielded six themes: message engagement, material conditions, cognition, risk perception, social environment and self-efficacy. Explanations for intervention results are not always present, and empirical evidence for explanations is often not provided. Including such explanations and testing their empirical merits in future research can provide the crucial information needed for developing more effective anti-smoking HIIs for low-SES adults. To our knowledge, this is the first review to explore the explanations proposed for why anti-smoking HIIs are (in)effective among low-SES adults. It contains insights for future studies aiming to provide empirical evidence on the causes of this (in)effectiveness, and concludes that such research is yet largely missing, but crucial to the quest for more effective and equitable anti-smoking interventions.


Maintenance of specificity by sprouting and regenerating peripheral nerves. I. Normal variability.
Inter-animal variability in the spinal representation of a single hindlimb muscle, tibialis anterior (TA), in the cat, was examined by retrograde transport of intramuscularly injected HRP, dissection of the lumbosacral plexus and reflex testing after acute section of spinal nerves L5, L6, S1 and S2 sparing L7. No variability between the two sides of the same animal was seen. The transverse position of the TA motor nucleus and the number of labeled cells was constant between the two sides in each animal. Inter-animal variability was considerable, however, in that the number of motor neurons and rostrocaudal extent of the motor neuron column supplying TA varied considerably from animal to animal. According to the relationship between the position of the lumbosacral plexus and the distribution of spinal nerves, 3 classes of representation of the plexus were found: prefixed, postfixed and intermediate. In animals in which the lumbosacral plexus was prefixed, more than one half of labeled cells were rostral to the L7 segment; in those with postfixed plexus more than half the cells were caudal to L7. Section of L5, L6, S1 and S2 spinal nerves weakened the tibialis anterior tendon reflex in 'prefixed plexus' animals but abolished that reflex in 'postfixed' plexus animals, in spite of the presence of labeled motor neurons projecting through the spared L7 nerve. This suggests that some of the afferents and efferents comprising the TA tendon reflex may travel in different spinal roots or that a particular distribution of motor axons within a muscle is required for the maintenance of this particular reflex activity.


Characterization and immobilization of Pycnoporus cinnabarinus carboxylic acid reductase, PcCAR2.
Carboxylic acid reductases (CARs) are well-known for their eminent selective one-step synthesis of carboxylic acids to aldehydes. To date, however, few CARs have been identified and characterized, especially from fungal sources. In this study, the CAR from the white rot fungus Pycnoporus cinnabarinus (PcCAR2) was expressed in Escherichia coli. PcCAR2's biochemical properties were explored in vitro after purification, revealing a melting temperature of 53 °C, while the reaction temperature optimum was at 35 °C. In the tested buffers, the enzyme showed a pH optimum of 6.0 and notably, a similar activity up to pH 7.5. PcCAR2 was immobilized to explore its potential as a recyclable biocatalyst. PcCAR2 showed no critical loss of activity after six cycles, with an average conversion to benzaldehyde of more than 85% per cycle. Immobilization yield and efficiency were 82% and 76%, respectively, on Ni-sepharose. Overall, our findings contribute to the characterization of a thermotolerant fungal CAR, and established a more sustainable use of the valuable biocatalyst.


Damned if they do, damned if they don't: the need for a comprehensive public policy to address the inadequate management of pain.
Amy Dilcher examines the need for a comprehensive pain policy and argues that opioids--highly effective drugs for pain management--should be legally and practicably accessible to medical professionals and their patients, as and when needed to provide relief from pain. The article synthesizes a number of perspectives regarding the regulation of pain management and demonstrates that the inadequate treatment of pain stems from a multitude of barriers. After reviewing Congressional action on the topic, Ms. Dilcher concludes with recommendations for a more comprehensive pain policy that would enhance the management of pain.


A genome-wide set of congenic mouse strains derived from DBA/2J on a C57BL/6J background.
In the analysis of complex traits, congenic strains are powerful tools because they allow characterization of a single locus in the absence of genetic variation throughout the remainder of the genome. Here, we report the construction and initial characterization of a genome-wide panel of congenic strains derived from the donor strain DBA/2J on the background strain C57BL/6J. For many strains, we have carried out high-density SNP genotyping to precisely map the congenic interval and to identify any contaminating regions. Certain strains exhibit striking variation in litter size and in the ratio of females to males. We illustrate the utility of the set by "Mendelizing" the complex trait of myocardial calcification. These 65 strains cover more than 95% of the autosomal genome and should facilitate the analysis of the many genetic trait differences that have been reported between these parental strains.


Molecular variants and derivatives of insulin for improved glycemic control in diabetes.
Insulin is a historic molecule. It presents many first instances, such as the first protein to be fully sequenced, one of the first proteins to be crystallized in pure form, one among the early proteins whose structure was investigated using X-ray crystallography, the first protein to be chemically synthesized and the first Biotech drug. Therefore, the development of insulin in the early years is intricately intertwined with the progress in molecular and structural biology. In recent years, development of a range of insulin analogs has led to better control of glucose levels, thus preventing secondary complications and improving the quality of life in diabetic patients. Such analogs were obtained by modification of the native insulin sequence. They vary with regard to their pharmacokinetic profile, stability, tissue specificity and mode of administration. In addition, alterations involving incorporation of various chemical moieties in insulin and its co-crystallization with insoluble derivatives are used to modulate the time-action profile of the drug. This article traces the development of molecular variants and derivatives of insulin. It discusses future directions for further improvement in their properties to produce still better insulin therapeutics for tight glycemic control.


Network pharmacology to explore the mechanism of scutellarin in the treatment of brain ischaemia and experimental verification of JAK2/STAT3 signalling pathway.
Scutellarin is used to treat brain ischaemia. However, its underlying mechanism of action remains unclear. This study aimed to elucidate the potential mechanism of action of scutellarin in brain ischaemia through network pharmacology and experimental verification. The JAK2/STAT3 signalling pathway was identified and experimentally verified. Expression of JAK2/STAT3 signalling related proteins in TNC-1 astrocytes with BV-2 microglia-conditioned medium (CM), CM + lipopolysaccharide (LPS) (CM + L), and CM pretreated with scutellarin + LPS (CM + SL) was analysed by Western Blot and immunofluorescence staining. Expression levels of JAK2, p-JAK2, STAT3, and p-STAT3 were evaluated in astrocytes pre-treated with AG490. Middle cerebral artery occlusion (MCAO) in rats was performed in different experimental groups to detect expression of the above biomarkers. Network pharmacology suggested that the JAK2/STAT3 signalling pathway is one of the mechanisms by which scutellarin mitigates cerebral ischaemic damage. In TNC-1 astrocytes, p-JAK2 and p-STAT3 expression were significantly up-regulated in the CM + L group. Scutellarin promoted the up-regulation of various markers and AG490 neutralised the effect of scutellarin. In vivo, up-regulation of p-JAK2 and p-STAT3 after ischaemia is known. These results are consistent with previous reports. Scutellarin further enhanced this upregulation at 1, 3, and 7 d after MCAO. Scutellarin exerts its therapeutic effects on cerebral ischaemia by activating the astrocyte JAK2/STAT3 signalling, which provides a firm experimental basis for its clinical application.


Risk factors of pediatric venoarterial extracorporeal membrane oxygenation-related gastrointestinal bleeding after open-heart surgeries.
To analyze the risk factors for gastrointestinal (GI) bleeding in congenital heart disease (CHD) patients supported with venoarterial extracorporeal membrane oxygenation (V-A ECMO) after open-heart surgery. A retrospective analysis was performed on children with (GI group: 26 cases) and without (control group: 122 cases) GI bleeding during ECMO at Shanghai Children's Medical Center from 2017 to 2020. Clinical data were analyzed and compared between groups to search for risk factors for GI bleeding. A total of 148 cases were included in the study. The overall incidence of GI bleeding was 17.6% (26/148). The in-hospital mortality rate in the GI group was 61.5% (16/26) versus 45.9% (56/122) in the control group. Twenty-six patients suffered cardiac arrest before ECMO support. The GI bleeding incidence among extracorporeal cardiopulmonary resuscitation (ECPR) patients was 50.0% (13/26) versus 28.7 (35/122) among non-ECPR patients, p = 0.035. The activated clotting time (ACT) was 201.40 s (180.47 to 247.27) in the GI group versus 177.63 s (167.79 to 203.13) (p = 0.050) in the control group. The lowest antithrombin level (Min AT) was 27.00 ± 13.07% versus 37.62 ± 15.18 (p = 0.001). The pH and lactate levels before ECMO (Pre PH and Pre Lac) were lower in the GI group than in the control group. (7.31 ± 0.23 vs. 7.35 ± 0.17, p = 0.035 and 12.2 ± 6.11 vs. 7.78 ± 6.67, p = 0.003). Liver function during ECMO support was statistically worse in the GI group than in the control group. Multivariate analysis showed that Pre Lac (OR = 1.106 [1.018-1.202], p = 0.0016) was an independent risk factor for GI bleeding. ROC analysis of Pre Lac and GI bleeding showed an area under the curve (AUC) of 0.700 (95% CI: 0.600-0.800, p = 0.002) and a cutoff value of 9.30 mmol/L (sensitivity, 73.1%; specificity, 62.7%). As the first study in this field, the probability of GI bleeding and related mortality was found to be high in children supported with V-A ECMO after open-heart surgery. A higher lactate level before ECMO was an independent risk factor for GI bleeding.


Polyvictimization and psychopathology among children and adolescents: A systematic review of studies using the Juvenile Victimization Questionnaire.
Exposure to child abuse can lead to lasting mental health problems. Extant research has found that different types of child abuse tend to co-occur and overlap, which merits the investigation of the effects of exposure to multiple types of childhood mistreatment. The aim of this study was to systematically review the evidence on the associations between multiple different types of interpersonal victimization or polyvictimization, and indicators of psychopathology among children ages 0-17. The review included studies across all economic strata and research on nationally representative, community, and at-risk samples, using the same standardized assessment tool (i.e. the Juvenile Victimization Questionnaire or JVQ). The review was conducted using peer-reviewed evidence published up until August 2019 from Scopus, EMBASE, PsycINFO, Medline, CINAHL, and ERIC. Out of 4998 relevant references screened, 255 met the inclusion criteria, 22 of which aimed to address childhood polyvictimization and psychopathology. A total of 21 of the 22 included studies identified a significant positive association between polyvictimization and various indicators of psychopathology comprising both externalizing (e.g. anger), internalizing problems (e.g. depression) and total psychological distress. A range of studies demonstrated that polyvictimization was a stronger risk factor for psychopathology than individual (sub)types of victimization. Based on the study findings, we provide a set of recommendations for future research on polyvictimization and psychopathology. The present systematic review was the first to review the evidence on the associations between polyvictimization (as measured by the JVQ) and child and adolescent psychopathology in the global research literature. As a novel approach, the present review included both normative and high-risk samples. The results showed that polyvictimization is a substantial risk factor for mental health problems spanning both inner-directed and outer-directed mental health difficulties. However, the inconsistency in methods of defining and measuring polyvictimization severely undermines the scientific impact of this body of work. Additional well-designed, longitudinal studies that take account of the context-specific nature of polyvictimization are required to better establish the causal relationships between childhood polyvictimization and psychopathology so as to improve prevention and intervention efforts.


Fear extinction learning improvement in PTSD after EMDR therapy: an fMRI study.
Objective: Neurobiological models of Posttraumatic Stress Disorder (PTSD) implicate fear processing impairments in the maintenance of the disorder. Eye Movement Desensitization and Reprocessing (EMDR) is one of the most efficient psychotherapies to treat PTSD. We aimed at exploring the brain mechanisms of the fear circuitry involved in PTSD patients' symptom remission after EMDR therapy. Method: Thirty-six PTSD participants were randomly assigned to either EMDR group receiving EMDR therapy or Wait-List (WL) group receiving supportive therapy. Participants underwent a behavioural fear conditioning and extinction paradigm during functional magnetic resonance (fMRI). In the EMDR group, patients were scanned at baseline, before EMDR and one week after remission. In the WL group, patients were scanned at baseline and within the same time interval as the EMDR group. Results: In the EMDR group after treatment, fear responses in the late extinction were significantly lower than before therapy. In parallel, significant functional activity and connectivity changes were found in the EMDR group versus the WL during the late extinction. These changes involve the fear circuit (amygdalae, left hippocampus), the right inferior frontal gyrus, the right frontal eye field and insula (pFWE < .05). Conclusion: These functional modifications underlie a significant improvement of fear extinction learning in PTSD patients after EMDR therapy.


The association of cannabis use late in pregnancy with engagement and retention in perinatal substance use disorder care for opioid use disorder: A cohort comparison.
Prenatal use of cannabis and opioids are increasing and very concerning. Engagement and retention in comprehensive, perinatal substance use disorder (PSUD) care are associated with better outcomes for mothers and babies. We compared the characteristics and engagement in care among women with opioid use disorder who used cannabis late in pregnancy versus those who didn't. The primary outcome, "overall engagement and retention in PSUD care" included: utilization of substance use treatment prenatally, negative screening/toxicology at delivery (excluding cannabis), and attendance at expected prenatal and postpartum visits. Cannabis use late in pregnancy was objectively assessed at delivery via maternal urine drug screen and/or neonatal meconium/cord toxicology. Between-group comparisons utilized chi square, t-test or Mann-Whitney. Associations were assessed using Spearman Rho and two multivariate, binary logistic regressions for cannabis use and the primary outcome. 18.0% (85/472) consumed cannabis late in pregnancy. Women of color, younger women, and those diagnosed with concurrent cannabis use disorder were more likely to consume cannabis. Engagement and retention in PSUD care was not associated with cannabis use, but rather, with prescribed pharmacotherapy for psychiatric disorders. The use of prescribed buprenorphine+naloxone was associated with cannabis avoidance late in pregnancy. Cannabis use late in pregnancy, compared to none, did not impact engagement and retention in our PSUD program. Adjunctive psychotropic medication and/or buprenorphine+naloxone prescription were associated with cannabis avoidance suggesting the use and interactions of pharmacotherapies in an opioid dependent population is complex. A shared decision-making process during PSUD care is warranted.


Atypical retention of infraoccluded primary molars with permanent successor teeth.
Infraocclusion of primary molar teeth is relatively common. The majority of infraoccluded primary molars with permanent successors exfoliate naturally. There are currently no evidence based guidelines for the treatment of infraoccluded primary molars with permanent successor teeth. The three cases presented demonstrate atypical retention of infraoccluded primary molars, following a conservative approach. In case 1 taking a conservative approach over 5 years, the infraocclusion became gradually more severe. Tilting of the adjacent teeth and the centre-line shift caused by leaving the affected tooth in place during dental and alveolar development was significant. In Case 2 the severely infraoccluded 55 required surgical removal and exposure of the underlying permanent successor (15). Case 3 showed a maxillary premolar (14) and first permanent molar (16) tilted toward the partially erupted, ectopic, rotated 15. Surgical removal of the impacted maxillary primary molar was required. Although there is evidence available to support the conservative treatment of such cases, it does not always lead to a favourable outcome. Detrimental effects on the adjacent teeth and occlusion were observed and surgical intervention was required.


Assessment of magnification of digital radiographs in total HIP arthroplasty.
Total hip arthroplasty (THA) preoperative planning requires the calibration of X-ray. We evaluate the magnification in standard pelvis hip X-ray and determine its relation with biometric factors. The magnification of 140 THA X-ray were calculated with the known femoral head (MFFH) and acetabular component (MFAC). Gender, age, height, weight, and BMI were correlated to the magnification. The MFFH and MFAC were 113.2 ± 4,4 and 113,4 ± 3,6 respectively. No significant differences by gender and no correlation with height, weight or BMI. The X-ray magnification should be calibrated in every institution to improve the accuracy of preoperative planning.


Optimization of the aromatase inhibitory activities of pyridylthiazole analogues of resveratrol.
Aromatase is an established target not only for breast cancer chemotherapy, but also for breast cancer chemoprevention. The moderate and non-selective aromatase inhibitory activity of resveratrol (1) was improved about 100-fold by replacement of the ethylenic bridge with a thiadiazole and the phenyl rings with pyridines (e.g., compound 3). The aromatase inhibitory activity was enhanced over 6000-fold by using a 1,3-thiazole as the central ring and modifying the substituents on the 'A' ring to target the Met374 residue of aromatase. On the other hand, targeting the hydroxyl group of Thr310 by a hydrogen-bond acceptor on the 'B' ring did not improve the aromatase inhibitory activity.


Quality of life and its predictors among patients with chronic kidney disease: A hospital-based cross sectional study.
Quality of life (QoL) is increasingly being considered as an important measure of how disease affects patients' lives, especially for long-term diseases like chronic kidney disease (CKD). Even though there is no statistically significant association between stages of CKD and QoL, it is decreased in patients with early stages of the disease. Hence, this study aimed to assess QoL and its predictors among patients with CKD at Tikur Anbessa Specialized Hospital (TASH). A cross sectional study was conducted at the nephrology clinic of TASH. A total of 256 patients were recruited through systematic random sampling. Data were collected using the Medical Outcomes Study Short Form 36-Items (SF-36). The data were entered into Epi Info 188.8.131.52 and analyzed using SPSS version 20.0 statistical software. Descriptive statistics like frequency, percent, mean and standard deviation were used to summarize patients' baseline characteristics. Student's unpaired t-test and ANOVA were conducted to compare two groups and more than two groups in the analysis of QoL, respectively. Multivariable linear regression was employed to investigate the potential predictors of QoL. Quality of life was decreased in all stages of CKD. A reduction in physical functioning (p = 0.03), bodily pain (p = 0.004), vitality (p = 0.019) and social functioning (p = 0.002) was observed progressively across stages of CKD. High income status and greater than 11g/dl hemoglobin level were found to be predictors of all high score SF-36 domains. High family income (β 15.33; 95%CI: 11.33-19.33, p<0.001), higher educational status (β 7.9; 95%CI: 4.10-11.66, p<0.001), and hemoglobin ≥11g/dl (β 8.36; 95%CI: 6.31-10.41, p<0.001) were predictors of better QoL in the physical component summary, whereas absence of CKD complications (β 2.75; 95%CI: 0.56-4.94, p = 0.014), high family income (β 10.10; 95%CI: 5.10-15.10, p<0.001) and hemoglobin ≥11g/dl (β 4.54, 95%CI: 2.01-7.08, p = 0.001) were predictors of better QoL in the mental component summary. In this setting, QoL decreased in CKD patients in the early stages of the disease. Study participants with low income and hemoglobin level were considered to have worse quality of life in both physical and mental component summaries.


Exercise handout and one-on-one hand therapy for management of stiffness after plaster cast immobilization of simple phalangeal and metacarpal fractures in children: A randomized, noninferiority trial.
This is a noninferior, single-blind, randomized controlled trial. Joint stiffness is common after plaster cast immobilization for simple phalanx and metacarpal fractures in children. The limited literature suggests this joint stiffness in children resolves without one-on-one therapy; however, without robust studies confirming that there is no detrimental effect from withdrawing treatment, many children are still referred. The purpose of this study was to determine if an educational handout for self-management of stiffness is noninferior to one-on-one hand therapy for achieving full range of motion (ROM). Participants were randomly assigned to group one who received the handout or group two who received hand therapy in addition to the handout. The ROM was measured by composite flexion and total active motion (TAM). The noninferiority margin was 10% difference between the two groups in the proportion of participants who achieved full ROM at two weeks after cast removal. Sixty participants in each group completed the study. Group difference for composite flexion was 1.7% (95% CI: -3.9% to 7.2%), demonstrating noninferiority. Group difference for TAM was inconclusive at 8.3% (95% CI: -2.1% to 18.7%). Sensitivity analysis adjusting for participants with full composite flexion at the baseline resulted in the group difference for composite flexion of 3.1% (95% CI: -3.6% to 9.8%), maintaining noninferiority, but group difference for TAM at 10.4% (95% CI: 0.0% to 20.9%), was inconclusive with the handout group significantly worse. An educational handout is noninferior to hand therapy for achieving full ROM in composite flexion but not TAM. This needs to be taken into consideration for changing clinical practise.


Ablation of Complex Fractionated Electrograms With or Without ADditional LINEar Lesions for Persistent Atrial Fibrillation (The ADLINE Trial).
For persistent atrial fibrillation (AF) ablation, different strategies including complex fractionated atrial electrograms (CFAE) ablation and linear lesions (LL) have been used in addition to pulmonary vein isolation (PVI). However, it is still a matter of debate if extended substrate modification improves long-term outcome. The aim of this study was to determine the benefit of LL in addition to PVI and CFAE ablation regarding freedom from arrhythmia recurrence in patients with persistent AF. The study was a prospective randomized trial including 90 patients with persistent and longstanding persistent AF. All patients underwent PVI and CFAE ablation. If AF did not terminate to atrial tachycardia (AT) or sinus rhythm, patients were randomized to direct current cardioversion (Group 1; n = 45) or LL (Group 2; n = 45). Primary endpoint was freedom from any atrial arrhythmia off antiarrhythmic drugs at 12 months. (NCT02059369) RESULTS: Baseline characteristics were similar between the two groups with more than half of the patients having structural heart disease. The primary endpoint was reached in 37% in Group 1 (G1) and 16% in Group 2 (G2; P = 0.03). After a total number of 1.4 ± 0.5 (G1) versus 1.7 ± 0.4 (G2; P = 0.01) procedures, freedom from any arrhythmia was reached in 54% in G1 and 65% in G2 (P = 0.35). In persistent AF ablation, LL in addition to PVI and CFAE show a significantly lower success rate after a single procedure compared to PVI and CFAE. Following LL, significantly more patients needed a reablation to reach a similar success rate during a 12-month follow-up.


Basic mechanisms of rTMS: Implications in Parkinson's disease.
Basic and clinical research suggests a potential role for repetitive transcranial magnetic stimulation (rTMS) in the treatment of Parkinson's disease. However, compared to the growing number of clinical studies on its putative therapeutic properties, the studies on the basic mechanisms of rTMS are surprisingly scarce. Animal studies have broadened our understanding of how rTMS affects brain circuits and the causal chain in brain-behavior relationships. The observed changes are thought to be to neurotransmitter release, transsynaptic efficiency, signaling pathways and gene transcription. Furthermore, recent studies suggest that rTMS induces neurogenesis, neuronal viability and secretion of neuroprotective molecules. The mechanisms underlying the disease-modifying effects of these and related rTMS in animals are the principle subject of the current review. The possible applications for treatment of Parkinson's disease are discussed.


Accumulation of cyanide and thiocyanate in haemodialysis patients.
Cyanide is a toxic agent, and its detoxification product, thiocyanate, may be a major pathogenetic substance in uraemia. Recent studies examining the myeloperoxidase(MPO)/thiocyanate system have suggested a link between thiocyanate and atherosclerosis. However, inaccuracies in conventional assays for cyanide and thiocyanate have limited the understanding of their metabolism in haemodialysis (HD) patients. We used high-performance liquid chromatography to measure cyanide in erythrocytes and thiocyanate in plasma in 43 HD patients and in a group of 46 healthy controls that included 15 current smokers. To clarify the metabolic conversion of cyanide to thiocyanate in uraemic patients, we also measured cysteine and sulfate. We then used stepwise regression analysis to analyse factors that determine erythrocyte cyanide and plasma thiocyanate. Mean cyanide and thiocyanate were significantly greater in HD patients than in non-smoking controls. However, cyanide was far below lethal concentrations in dialysis patients. Thiocyanate was six to seven times greater in HD patients than in non-smoking controls, and decreases in thiocyanate following dialysis were only 19.3+/-3.5%. Multiple regression analysis showed a positive correlation between cyanide and thiocyanate in controls, but a negative correlation in HD patients. In patients, an inverse relationship between thiocyanate and BUN was also observed. The elevation of thiocyanate in patients undergoing dialysis probably is secondary to both limited efficiency of HD and deranged metabolism of cyanide and thiocyanate. Because thiocyanate is a preferred substrate for MPO, it may play a role in uraemic complications including cardiovascular events.


Spatial organization of acute myocardial ischemia.
Myocardial ischemia is a pathological condition initiated by supply and demand imbalance of the blood to the heart. Previous studies suggest that ischemia originates in the subendocardium, i.e., that nontransmural ischemia is limited to the subendocardium. By contrast, we hypothesized that acute myocardial ischemia is not limited to the subendocardium and sought to document its spatial distribution in an animal preparation. The goal of these experiments was to investigate the spatial organization of ischemia and its relationship to the resulting shifts in ST segment potentials during short episodes of acute ischemia. We conducted acute ischemia studies in open-chest canines (N=19) and swines (N=10), which entailed creating carefully controlled ischemia using demand, supply or complete occlusion ischemia protocols and recording intramyocardial and epicardial potentials. Elevation of the potentials at 40% of the ST segment between the J-point and the peak of the T-wave (ST40%) provided the metric for local ischemia. The threshold for ischemic ST segment elevations was defined as two standard deviations away from the baseline values. The relative frequency of occurrence of acute ischemia was higher in the subendocardium (78% for canines and 94% for swines) and the mid-wall (87% for canines and 97% for swines) in comparison with the subepicardium (30% for canines and 22% for swines). In addition, acute ischemia was seen arising throughout the myocardium (distributed pattern) in 87% of the canine and 94% of the swine episodes. Alternately, acute ischemia was seen originating only in the subendocardium (subendocardial pattern) in 13% of the canine episodes and 6% of the swine episodes (p<0.05). Our findings suggest that the spatial distribution of acute ischemia is a complex phenomenon arising throughout the myocardial wall and is not limited to the subendocardium.


Multidetector row computed tomography can identify and characterize the occlusive culprit lesions in patients early (within 24 hours) after acute myocardial infarction.
The reliable noninvasive assessment of occluded disrupted plaques and thromboses in culprit vessels could constitute an important step forward in risk stratification of patients early after acute myocardial infarction (AMI). However, noninvasive identification of patency of culprit vessels remains a challenging issue. This prospective study was designed to identify the occluded culprit vessels by multidetector row computed tomography (MDCT) and to compare the stenotic and occlusive culprit lesions by MDCT in patients early (within 24 hours) after AMI. We enrolled 62 patients with first Q-wave AMI (54 males). Multidetector row computed tomography was performed 16.5 +/- 7.1 hours after the onset of chest pain without any complication. Coronary angiography was done within 6 hours after MDCT. Patients were divided into 2 groups according to angiographic findings: stenotic group (35 patients) and occluded group (27 patients). The following MDCT data were collected: luminal artery stenosis, remodeling index, plaque burden, and lesion attenuation. Compared to coronary angiography, MDCT detected occluded culprit vessels with sensitivity, specificity, negative predict value, and positive predict value of 92.6%, 88.6%, 93.9%, and 86.2%, respectively. Compared with the stenotic group, culprit lesions in the occlusive group had significantly longer length (18.9 +/- 9.7 vs 11.9 +/- 6.2 mm; P = .024) and higher MDCT lesion attenuation (38.8 +/- 15.6 vs 29.2 +/- 12.9 Hounsfield unit; P = .008). Multidetector row computed tomography attenuation was negatively correlated with thrombolysis in myocardial infarction flow (Spearman rho = -0.46; P < .001). Multidetector row computed tomography could accurately and safely identify occluded culprit lesions in patients early after AMI, providing important information to aid in risk stratification.


[The role of echoendoscopic biopsy in diagnosing tuberculosis of pancreas].
The diagnosis of an abdominal mass using imaging techniques is difficult for clinicians and radiologists. We report a case of an atypical peripancreatic mass, mimicking a carcinoma on abdominal computed tomography and which was only diagnosed after an echoendoscopic biopsy of the mass was performed. It is difficult to differentiate abdominal tuberculosis from a neoplasm, especially if there is no pulmonary tuberculosis. Usually, the diagnosis of abdominal tuberculosis is only confirmed histologically, after surgical resection of the mass. Echoendoscopic biopsy confirmed the infectious nature of the mass and prevented complicated and difficult surgery.


Test-retest variability and reliability of 123I-IBZM SPECT measurement of striatal dopamine D2 receptor availability in healthy volunteers and influence of iterative reconstruction algorithms.
123I-IBZM single photon emission computed tomography (SPECT) is a widely used method to measure D(2) receptor availability. However, test-retest variability and reliability have not been reported yet. This study aimed to further characterize 123I-IBZM SPECT in healthy volunteers (HVs), by assessing (1) pseudoequilibrium interval after bolus injection; (2) normal specific uptake ratio (SUR) values using filtered-backprojection (FBP); and the iterative reconstruction algorithm ordered-subsets expectation maximization (OSEM); (3) test-retest variability and reliability (intraclass correlation coefficient); and (4) influence of OSEM on test-retest variability and reliability. Ten HVs (Group A) were scanned twice 48 h apart for test-retest variability and reliability measurements, and n = 4 of them were sequentially scanned over time. Eighteen HVs (Group B) were scanned once at pseudoequilibrium. For reconstruction FBP was used. Test-retest scans were reconstructed in addition using OSEM. SPECT-MRI coregistration was used for region of interest drawing. Pseudoequilibrium was achieved at 90 min postinjection (p.i.) and maintained until the end of the SPECT session (n = 4), and mean SUR at this time point was 0.96 +/- 0.14 (Groups A + B, n = 28). Mean SUR at test was 0.96 +/- 0.19 and at retest 0.94 +/- 0.19 (Group A, n = 10). Using FBP, test-retest variability was (12.7 +/- 9.6)% and reliability was 0.74. Using OSEM with 18 equivalent iterations, test-retest variability and reliability were improved to (6.5 +/- 5.2)% and 0.84, respectively. 123I-IBZM SPECT imaging using the bolus injection and a single scan at 90 min p.i. is a reproducible method showing acceptable test-retest variability and reliability. Test-retest variability and reliability can be substantially improved using OSEM with 12-36 equivalent iterations.


Cytotoxic effect of Argentine medicinal plant extracts on human hepatocellular carcinoma cell line.
Methanolic extracts from Achyrocline satureioides (Dc.) Lam, Aristolochia macroura Gomez, Lithraea molleoides (Vell.) Engl., Schinus molle L., unlike those from Celtis spinosa Spreng, Chenopodium ambrosioides L., Petiveria alliacea L., and Plantago major L. showed cytotoxic activity against a human hepatocellular carcinoma cell line, Hep G2. Schinus molle L. was the most active (IC50=50+/-7 microg/ml). These results call for further studies of these extracts.


Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank.
The genetic architecture underlying Familial Hypercholesterolemia (FH) in Middle Eastern Arabs is yet to be fully described, and approaches to assess this from population-wide biobanks are important for public health planning and personalized medicine. We evaluate the pilot phase cohort (n = 6,140 adults) of the Qatar Biobank (QBB) for FH using the Dutch Lipid Clinic Network (DLCN) criteria, followed by an in-depth characterization of all genetic alleles in known dominant (LDLR, APOB, and PCSK9) and recessive (LDLRAP1, ABCG5, ABCG8, and LIPA) FH-causing genes derived from whole-genome sequencing (WGS). We also investigate the utility of a globally established 12-SNP polygenic risk score to predict FH individuals in this cohort with Arab ancestry. Using DLCN criteria, we identify eight (0.1%) 'definite', 41 (0.7%) 'probable' and 334 (5.4%) 'possible' FH individuals, estimating a prevalence of 'definite or probable' FH in the Qatari cohort of ~ 1:125. We identify ten previously known pathogenic single-nucleotide variants (SNVs) and 14 putatively novel SNVs, as well as one novel copy number variant in PCSK9. Further, despite the modest sample size, we identify one homozygote for a known pathogenic variant (ABCG8, p. Gly574Arg, global MAF = 4.49E-05) associated with Sitosterolemia 2. Finally, calculation of polygenic risk scores found that individuals with 'definite or probable' FH have a significantly higher LDL-C SNP score than 'unlikely' individuals (p = 0.0003), demonstrating its utility in Arab populations. We design and implement a standardized approach to phenotyping a population biobank for FH risk followed by systematically identifying known variants and assessing putative novel variants contributing to FH burden in Qatar. Our results motivate similar studies in population-level biobanks - especially those with globally under-represented ancestries - and highlight the importance of genetic screening programs for early detection and management of individuals with high FH risk in health systems.


Intranasal Osteopontin for Rodent Germinal Matrix Hemorrhage.
Germinal matrix hemorrhage (GMH) is the most common and devastating neurological problem of premature infants. Current treatment is largely ineffective and GMH has been nonpreventable. Osteopontin (OPN) is an endogenous protein that has been shown to be neuroprotective, however, it has not been tested in GMH. P7 neonatal rats were subjected to stereotactic ganglionic eminence collagenase infusion. Groups were as follows: (1) sham, (2) GMH + vehicle, (3) GMH + intranasal OPN. Seventy-two hours later, the animals were evaluated using righting reflex, blood-brain barrier (BBB) permeability by Evans blue dye leakage, brain water content, and hemoglobin assay. Intranasal OPN improved outcomes after GMH by attenuation of brain swelling, BBB function, re-bleeding, and neurological outcomes. OPN may play an important role in enhancing neuroprotective brain signaling following GMH. These observed effects may offer novel possibilities for therapy in this patient population.


Three-dimensional coculture of endometrial cancer cells and fibroblasts in human placenta derived collagen sponges and expression matrix metalloproteinases in these cells.
Collagen gel constitutes a valuable tool for the study of cell-matrix interactions; however, it is sometimes difficult to use the gel, in which tumor and stromal cells are cocultured, for immunohistochemistry, because it is easily broken during the process of fixation and embedding in paraffin, especially after long-term culture. To examine the interaction between endometrial cancer cells and fibroblasts in tumor invasion, we carried out three-dimensional (3-D) coculture of various endometrial cancer cell lines and fibroblasts in human placenta derived collagen sponges and analyzed the expression and localization of matrix metalloproteinases (MMP) and plasminogen activators (PA) in these cells by immunohistochemistry. After 4 weeks of culture on the collagen sponges, endometrial cancer cells composed stratiform or glandular structures on the layer of extracellular matrix, which was composed from fibloblasts and extracellular matrix. Compared to Ishikawa cells, which were rarely invasive, HEC-1A and HEC-1BE and cocultured fibroblasts showed high invasiveness and strong expression of some proteins. In cell line HEC-1BE, MMP-1, -7, and -9, MT1-MMP, tissue inhibitors of metalloproteinases 2, and uPA showed intensive staining in both cancer cells and fibroblasts by immunohistochemistry. HEC-1A cells and cocultured fibroblasts showed expression patterns similar to those of HEC-1BE. These results suggested that expression of MMPs and uPA was accelerated in fibroblasts surrounded by cancer cells. We believe that our 3-D coculture system has merit in that the interaction between cancer cells and stromal cells can be visually analyzed by immunohistochemistry and that experiments for a long period, at least 2 weeks, are possible. Furthermore, it is expected that some animal, e.g., nude mouse, experiments can be replaced by experiments using this culture system.


A novel electrogenerated chemiluminescence sensor for pyrogallol with core-shell luminol-doped silica nanoparticles modified electrode by the self-assembled technique.
The core-shell luminol-doped SiO2 nanoparticles were synthesized and immobilized on the surface of chitosan film coating graphite electrode by the self-assembled technique. Then, a novel electrogenerated chemiluminescence (ECL) sensor for pyrogallol was developed based on its ECL enhancing effect for the core-shell luminol-doped silica nanoparticles. The ECL analytical performances and the sensing mechanism of this ECL sensor for pyrogallol were investigated in detail. The corresponding results showed that: compared with the conventional ECL reaction procedures by luminol ECL reaction system, the electrochemical (EC) reaction of pyrogallol and its subsequent chemiluminescence (CL) reaction occurred in the different spatial region whilst offering a high efficiency to couple the EC with the CL reaction to form the ECL procedures. In this case, this new sensing scheme offered more potential to improve the analytical performances of the ECL reaction. Under the optimum experimental conditions, this ECL sensor showed less than 5% decrease in continuums over 100 times ECL measurements, the detection limit was 1.0 x 1.0(-9) mol/L for pyrogallol. The linear range extended from 3.0 x 10(-9) mol/L to 2.0 x 10(-5) mol/L for pyrogallol.


Malnutrition in the elderly: a narrative review.
The focus of nutrition is often on healthy diets and exercise to minimise the risk of developing lifestyle diseases such as cancer, diabetes and cardiovascular disease. However, during the shift into older years often the nutrition priorities change towards meeting increased nutrient needs with less energy requirements, and minimising lean muscle loss. There are several causes of general malnutrition in the elderly that lead to depletion of muscle including starvation (protein-energy malnutrition), sarcopenia and cachexia. The prevalence of protein-energy malnutrition increases with age and the number of comorbidities. A range of simple and validated screening tools can be used to identify malnutrition in older adults, e.g. MST, MNA-SF and 'MUST'. Older adults should be screened for nutritional issues at diagnosis, on admission to hospitals or care homes and during follow up at outpatient or General Practitioner clinics, at regular intervals depending on clinical status. Early identification and treatment of nutrition problems can lead to improved outcomes and better quality of life.


The role of glutathione in cadmium ion detoxification: coordination modes and binding properties--a density functional study.
In this investigation the reduced form of glutathione molecule (GSH) was considered as a model in the coordination chemistry of Cd(2+) and group thiol-containing peptides. Three different forms of GSH, corresponding to the prevalent ones in gas-phase and in aqueous solution, were taken into account in the metallation process. The obtained complexes were characterized at the density functional B3LYP level with the purpose to give better insight in the chelation mechanism of GSH with heavy metal ions in living organisms. Solvent effects, whether with explicit water molecules or with polarizable continuum model (PCM), were considered on the most stable cadmium-complexes obtained by every GSH charged species examined.


[Fatigue fracture of the femoral shaft. Contribution of x-ray computed tomography].
A case of stress fracture of the femoral shaft is reported. The part of CT scan imaging is emphasized in the diagnosis and follow-up of this rare location.


β2-adrenergic receptor regulates ER-mitochondria contacts.
Interactions between the endoplasmic reticulum (ER) and mitochondria (Mito) are crucial for many cellular functions, and their interaction levels change dynamically depending on the cellular environment. Little is known about how the interactions between these organelles are regulated within the cell. Here we screened a compound library to identify chemical modulators for ER-Mito contacts in HEK293T cells. Multiple agonists of G-protein coupled receptors (GPCRs), beta-adrenergic receptors (β-ARs) in particular, scored in this screen. Analyses in multiple orthogonal assays validated that β2-AR activation promotes physical and functional interactions between the two organelles. Furthermore, we have elucidated potential downstream effectors mediating β2-AR-induced ER-Mito contacts. Together our study identifies β2-AR signaling as an important regulatory pathway for ER-Mito coupling and highlights the role of these contacts in responding to physiological demands or stresses.


68Ga-DOTATATE-PET shows promise for diagnosis of recurrent or persistent medullary thyroid cancer: A systematic review.
Many patients with Medullary Thyroid Cancer (MTC) will have persistent or recurrent disease after surgery requiring lifelong surveillance with imaging and tumor markers. The objective of this study is to evaluate the efficacy of 68Ga-DOTATATE-PET (or 68Ga labelled equivalent radiopharmaceutical) versus 18F-FDG-PET for detecting persistent and/or metastatic recurrent MTC. Relevant studies were identified by conducting searches in Embase and PubMed and five studies were included in the final review. Five studies investigated per-patient sensitivity of 18F-FDG-PET and 68Ga-DOTATATE-PET in MTC patients. Four studies investigated the correlation between calcitonin and number of lesions detected by 18F-FDG-PET and 68Ga-DOTATATE-PET, and three investigated the correlation between CEA and number of lesions detected by 18F-FDG-PET and 68Ga-DOTATATE-PET. There was no significant difference in number of lesions detected by 18F-FDG -PET compared with 68Ga-DOTATATE-PET. When compared directly to 18F-FDG-PET, there is a general trend towards favoring 68Ga-DOTATATE-PET in per-patient sensitivities, and incidence of lesion detection.


Evaluation of obstetric management of women with macrosomic foetuses in two Level 3 maternity hospitals in France and identification of predictive factors for obstetric and neonatal complications.
Foetal macrosomia is associated with high maternal and neonatal morbidity; however, obstetric management of suspected macrosomia has not been well defined. This study aimed to analyse obstetric management in a population of women who delivered macrosomic new-borns and assess maternal and neonatal outcomes and risk factors for complications in such cases. This two-centre retrospective study conducted in France over a 10-year period comprised 1724 women who had delivered macrosomic new-borns (defined as those whose weight was > 90th percentile according to the Association of Users of Computerised Records in Perinatology, Obstetrics, and Gynaecology curve) from 37SA. In this study, the caesarean section and instrumental extraction rates were 24.1% and 15.7%, respectively, and the postpartum haemorrhage rate was 7%. The rate of shoulder dystocia was 23.1% (including brachial plexus injuries, 0.4%; and clavicular fractures, 2.0%). Significant risk factors for caesarean section were maternal height < 160 cm, nulliparity, history of caesarean section, excessive uterine height, induction of labour and duration of labour > 10 h. The risk factors for shoulder dystocia were maternal height < 160 cm and instrumental extraction. The study findings may help determine predictive factors for an unfavourable outcome at the time of delivery of a macrosomic foetus, thus allowing clinical teams to better anticipate and manage potential complications.


Representations of parenting autistic children: A critical interpretive synthesis.
Many taken-for-granted expectations for parents in Western societies are situated in normative assumptions. Social constructions of 'good' parenting may be a poor fit for parents whose children's development varies from a so-called typical trajectory. Normative assumptions about parenting can have harmful effects for parents of autistic children. This paper examines representations of parenting autistic children in contemporary research and considers the potential effects of these representations on these parents' occupational possibilities. Informed by a critical occupational perspective, a critical interpretive synthesis (CIS) of 27 research articles focussed on parenting autistic children was conducted. Three major discursive threads were identified regarding how parents of autistic children are represented in research: gendered assumptions, caregiving as all-consuming, and disruption of normative expectations of parenting. Normative discourses about parenting were (re)produced within this body of research which may perpetuate limitations in the occupational possibilities of parents of autistic children. Critical investigation into contemporary research is necessary to challenge taken for granted expectations for parents of children with autism, to mitigate harmful effects for parents, to inform transformative OT practices and policies, and to promote equitable service provision.


Synthesis and antitumoral activity of novel 3-(2-substituted-1,3,4-oxadiazol-5-yl) and 3-(5-substituted-1,2,4-triazol-3-yl) beta-carboline derivatives.
Several novel 1-substituted-phenyl beta-carbolines bearing the 2-substituted-1,3,4-oxadiazol-5-yl and 5-substituted-1,2,4-triazol-3-yl groups at C-3 were synthesized and evaluated for their in vitro anticancer activity. The assay results pointed thirteen compounds with growth inhibition effect (GI(50)<100 microM) for all eight different types of human cancer cell lines tested. The beta-carbolines 7a and 7h, bearing the 3-(2-metylthio-1,3,4-oxadiazol-5-yl) group, displayed high selectivity and potent anticancer activity against ovarian cell line with GI(50) values lying in the nanomolar concentration range (GI(50)=10 nM for both compounds). The 1-(N,N-dimethylaminophenyl)-3-(5-thioxo-1,2,4-triazol-3-yl) beta-carboline (8g) was the most active compound, showing particular effectiveness on lung (GI(50)=0.06 microM), ovarian and renal cell lines. The potent anticancer activity presented for synthesized compounds 7a, 7h, and 8g, together with their easiness of synthesis, makes these compounds promising anticancer agents.


A prospective head-to-head comparison of 68 Ga-NOTA-3P-TATE-RGD and 68 Ga-DOTATATE in patients with gastroenteropancreatic neuroendocrine tumours.
The aim of this study was to compare 68 Ga-NOTA-3P-TATE-RGD, a dual somatostatin receptor 2- and integrin αVβ3-targeting tracer, to 68 Ga-DOTATATE in a single group of patients with gastroenteropancreatic (GEP)-neuroendocrine tumours (NETs). Thirty-five patients with histologically confirmed GEP-NETs (5 grade 1, 28 grade 2, and 2 grade 3 tumours) were prospectively enrolled with informed consent. The primary tumour mainly originated from the pancreas and rectum. All patients were scanned with both 68 Ga-NOTA-3P-TATE-RGD PET/CT and 68 Ga-DOTATATE PET/CT within a week and compared on a head-to-head basis. Sixteen patients also had conventional 18F-FDG PET/CT. Images were evaluated semi-quantitatively using maximum standardized uptake values (SUVmax) of tumour and tumour-to-background ratio. All patients had at least one positive lesion on each of the two scans. A total of 1190 and 1106 lesions were detected on 68 Ga-NOTA-3P-TATE-RGD images and 68 Ga-DOTATATE images, respectively (P = 0.152). 68 Ga-NOTA-3P-TATE-RGD PET/CT revealed significantly more lesions in the liver than 68 Ga-DOTATATE PET/CT (634 vs. 532, P = 0.021). Both tracers produced comparable results for detecting primary tumours (20 vs. 20, P = 1.000), lymph node metastases (101 vs. 102, P = 0.655), and bone metastases (381 vs. 398, P = 0.244). The tumour SUVmax in 12 patients was significantly higher for 68 Ga-NOTA-3P-TATE-RGD than for 68 Ga-DOTATATE (27.2 ± 13.6 vs. 19.5 ± 10.0, P < 0.001); among them, 9 had 18F-FDG PET/CT and all were found to be FDG-positive. The remaining 23 patients had significantly higher 68 Ga-DOTATATE uptake than 68 Ga-NOTA-3P-TATE-RGD uptake (22.3 ± 16.4 vs. 11.9 ± 7.5, P < 0.001); among them, 7 had 18F-FDG PET/CT and 6 were FDG-negative. Generally, 68 Ga-DOTATATE demonstrated higher tumour SUVmax than 68 Ga-NOTA-3P-TATE-RGD (20.8 ± 16.0 vs. 14.2 ± 8.9, P < 0.001), including primary tumours, liver lesions, lymph node lesions, and bone lesions. However, the tumour-to-background ratio of liver lesions was significantly higher when using 68 Ga-NOTA-3P-TATE-RGD compared with that when using 68 Ga-DOTATATE (8.4 ± 5.5 vs. 4.7 ± 3.7, P < 0.001). 68 Ga-NOTA-3P-TATE-RGD performed better than 68 Ga-DOTATATE in detection of liver metastases with a higher tumour-to-background ratio. Moreover, 68 Ga-NOTA-3P-TATE-RGD tended to demonstrate higher uptake over 68 Ga-DOTATATE in FDG-avid NETs. Dual SSTR2 and Integrin αvβ3 Targeting PET/CT Imaging (NCT02817945, registered 5 November 2018). URL OF REGISTRY: https://clinicaltrials.gov/ct2/show/NCT02817945.


Computed tomography and plain film appearance of a bony sequestration: significance and differential diagnosis.
Bony sequestration has been reported in osteomyelitis, eosinophilic granuloma, and fibrosarcoma. Thirty-eight examples of radiographically apparent bony sequestra were collected to examine the validity of this differential diagnosis. Apparent sequestra were found in osteomyelitis (59%), fibrosarcoma or fibrosarcoma-like entities (13%), eosinophilic granuloma (8%), and osteoid osteoma (21%). Although osteoid osteoma does not contain a true bony sequestrum, the partially calcified nidus was radiographically mistaken for a sequestrum in eight (21%) of our cases and, therefore, should be considered when an apparent sequestrum is visualized. Computed tomography enhanced visualization of a sequestrum in 19 of 22 cases and is recommended as an adjunct to conventional radiography when the presence of a sequestrum will alter therapy.


Tomato SlIDA has a critical role in tomato fertilization by modifying reactive oxygen species homeostasis.
Anther development and pollen tube elongation are key steps for pollination and fertilization. The timing and spatial distribution of reactive oxygen species (ROS) and programmed cell death are central to these processes, but the regulatory mechanism of ROS production is not well understood. Inflorescence deficient in abscission (IDA) is implicated in many plant development and responses to environmental stimuli. However, their role in reproductive development is still unknown. We generated tomato knockout lines (CR-slida) of an IDA homolog (SlIDA), which is expressed in the tapetum, septum and pollen tube, and observed a severe defect in male gametes. Further analysis indicated that there was a programmed cell death defect in the tapetum and septum and a failure of anther dehiscence in the CR-slida lines, likely related to insufficient ROS signal. Liquid chromatography-tandem mass spectrometry identified mature SlIDA as a 14-mer EPIP peptide, which was shown to be secreted, and a complementation experiment showed that application of a synthetic 14-mer EPIP peptide rescued the CR-slida defect and enhanced the ROS signal. Moreover, the application of the ROS scavengers diphenyleneiodonium or Mn-TMPP suppressed peptide function. Collectively, our results revealed that SlIDA plays an essential role in pollen development and pollen tube elongation by modulating ROS homeostasis.


Anesthesia for Stüve-Wiedemann syndrome: a rare adult patient case report.
Stüve-Wiedemann syndrome (SWS) is a rare genetic disorder characterized by skeletal dysplasia and severe dysautonomia, evidencing a difficult airway approach and likely increased malignant hyperthermia susceptibility. Developmental dysmorphism classically worsens with age, therefore translating in a poor prognosis. In this article, we describe a case of a 27-year-old woman diagnosed with SWS proposed for abscess drainage under dissociative anesthesia. This patient has outlived the life expectancy described for SWS, acknowledging the importance of reporting this rare adult clinical case in what SWS anesthetic management is concerned.


Models for hydrogen exchange from folded proteins. II.
The kinetics of hydrogen exchange from folded proteins can be molded as a function of two continuous distributions of rate constants, kcx and kn, representing exchange from the folded and unfolded conformations, respectively. This model can account for the temperature dependence of soybean trypsin inhibitor at pH 3 and pH 6.5. The physical significance of this model, especially the shape and breadth of the kn distribution, are discussed.


Overlapping spatial clusters of sugar-sweetened beverage intake and body mass index in Geneva state, Switzerland.
Obesity and obesity-related diseases represent a major public health concern. Recently, studies have substantiated the role of sugar-sweetened beverages (SSBs) consumption in the development of these diseases. The fine identification of populations and areas in need for public health intervention remains challenging. This study investigates the existence of spatial clustering of SSB intake frequency (SSB-IF) and body mass index (BMI), and their potential spatial overlap in a population of adults of the state of Geneva using a fine-scale geospatial approach. We used data on self-reported SSB-IF and measured BMI from residents aged between 20 and 74 years of the state of Geneva (Switzerland) that participated in the Bus Santé cross-sectional population-based study (n = 15,423). Getis-Ord Gi spatial indices were used to identify spatial clusters of SSB-IF and BMI in unadjusted models and models adjusted for individual covariates (education level, gender, age, nationality, and neighborhood-level median income). We identified a significant spatial clustering of BMI and SSB-IF. 13.2% (n = 2034) of the participants were within clusters of higher SSB-IF and 10.7% (n = 1651) were within clusters of lower SSB-IF. We identified overlapping clusters of SSB-IF and BMI in specific areas where 11.1% (n = 1719) of the participants resided. After adjustment, the identified clusters persisted and were only slightly attenuated indicating that additional neighborhood-level determinants influence the spatial distribution of SSB-IF and BMI. Our fine-scale spatial approach allowed to identify specific populations and areas presenting higher SSB-IF and highlighted the existence of an overlap between populations and areas of higher SSB-IF associated with higher BMI. These findings could guide policymakers to develop locally tailored interventions such as targeted prevention campaigns and pave the way for precision public health delivery.


Choleresis and hepatic transport mechanisms. IV. Influence of bile salt choleresis on the hepatic transport of the organic cations, D-tubocurarine and N4 -acetyl procainamide ethobromide.
The influence of the bile salts taurocholate and dehydrocholate on the hepatic transport of two quaternary ammonium compounds, D-tubocurarine (dTc) and N4 -acetylprocainamide ethobromide (APAEB) was investigated in rats. The biliary excretion of APAEB and dTc in vivo was not enhanced by 106 mumoles/h of taurocholate or dehydrocholate. Infusion of 268 mumoles/h dehydrocholate caused an inhibition of the plasma disappearance and hepatic transport of dTc. This inhibition, which presumably occurred at the hepatic uptake level, was also observed in isolated perfused rat liver experiments. In animals with an intact renal function, the high dose of dehydrocholate caused a decreased biliary excretion and an increased renal excretion of dTc. The observed concentration gradients, plasma/liver cytosol and bile/liver cytosol 20 min after injection of both drugs were 1.6 and 23 for APAEB and 2.2 and 190 for dTc. These concentration ratios were based on free drug concentrations; corrections were made for plasma protein binding, intracellular binding and bilary micelle binding. No substantial binding of both compounds to ligandin and Z proteins was found. From the amount in the liver 20 min after injection of both drugs 70% of APAEB and 90% of dTc was bound to cellular particles. The rate limiting step in hepatic transport of APAEB from plasma into bile was concluded to be the hepatic uptake, which may explain the lack of effect of bile salt induced choleresis on its biliary excretion.


Recovery of baseline lung function after pulmonary exacerbation in children with primary ciliary dyskinesia.
Spirometry in children with cystic fibrosis (CF) frequently fails to return to baseline after treatment for a pulmonary exacerbation. It is unclear whether the same is true for children with primary ciliary dyskinesia (PCD). To determine in children with PCD treated with intravenous antibiotics for a pulmonary exacerbation: (1) the proportion who recover to baseline forced expiratory volume at 1 sec (FEV1 ) within 3 months after treatment and (2) to try to identify factors which are associated with failure to regain pre-exacerbation FEV1 . Cohort study using the PCD database for children at the Royal Brompton Hospital, 2003-2013. We selected the first pulmonary exacerbation treated with intravenous antibiotics. The best FEV1 within 3 months after treatment was compared to the best FEV1 in the 12 months before treatment (baseline). Recovery to baseline was defined as any FEV1 after treatment that was greater than or equal to 90% of the baseline FEV1 . 32/150 children (21%) had at least one pulmonary exacerbation. 23/30 (77%) regained baseline spirometry within 3 months of treatment. There was no difference between responders and non-responders in any baseline characteristics. Around 25% of children with PCD fail to recover to baseline lung function within 3 months following treatment for a pulmonary exacerbation, similar to CF. Better treatment strategies are needed, and the results also suggest that prevention of exacerbations would be a useful end-point in clinical trials. Pediatr Pulmonol. 2016;51:1362-1366. © 2016 Wiley Periodicals, Inc.


Central and peripheral involvement in hemodialysed subjects: neurophysiological and nephrological relationships.
Nerve conduction velocity and visual evoked potential studies were conducted in 31 patients with chronic renal failure undergoing periodic hemodialysis. The results indicate damage to the central nervous system, such as delayed P100 wave, even in the absence of clinical signs, and to the peripheral nervous system, such as distal sensorimotor neuropathy. The degree of peripheral involvement correlates with the duration of dialysis and with some blood chemistry values but not with the evoked potential parameters. There is no correlation between central and peripheral nervous damage, which presumably points to a difference in pathogenesis.


Mortality related to general anaesthesia and sedation in dogs under UK primary veterinary care.
To quantify and explore risk factors in dogs seen at primary care UK veterinary clinics for general anaesthetic (GA)/sedative-related death overall, in addition to neuter-specific procedures. A nested case-control study within UK primary care veterinary electronic patient record surveillance programme, VetCompass, including over 300 UK veterinary practices. A total of 157,318 dogs undergoing GA/sedative events. Cases included dogs undergoing GA/sedative events between January 2010 and December 2013 with GA/sedative-related death recorded within 48 hours or 2 weeks of the event. Controls were randomly selected from dogs undergoing GA/sedation that did not die within these time periods. Risks of GA/sedative-related death for all surgeries and neuter-specific surgeries were estimated. Demographic and clinical associations with GA/sedative-related death were reported as odds ratios following multivariable logistic regression modelling. Statistical significance was set at 5%. From 157,318 dogs with a GA/sedative event, there were 159 (0.10%) within 48 hours and 219 (0.14%) GA/sedative-related deaths within 2 weeks. Within 89,852 dogs that underwent a neuter surgery, there were eight GA/sedative related (0.009%). Greater age, poorer American Society of Anaesthesiologists health status scores and more urgent procedures were associated with greater odds of death. Compared with mixed breeds, Rottweilers and West Highland White Terriers had greater odds and Cocker Spaniels had lower odds of GA/sedative-related death. The overall risk for GA/sedative related death was relatively low, particularly among the subset of dogs undergoing castration or ovariohysterectomy surgery. Associations and risk estimates may assist shared decision-making in clinical practice and provide benchmarks for audit.


Panoramic evaluation of mesiodistal axial inclinations of maxillary anterior teeth in orthodontically treated subjects.
The objectives of this study were to evaluate, through panoramic radiographs, the mesiodistal axial inclinations of the maxillary anterior teeth at the beginning and end of nonextraction orthodontic treatment, and to compare the results with the mesiodistal axial inclinations of a control sample with normal (acceptable) occlusions. The experimental sample consisted of 40 white patients (20 male, 20 female; mean age, 14 years) with Class I maloccusions who were treated orthodontically with a standard edgewise (not preadjusted) technique without extractions. The mean treatment period was 1.6 years. The control sample comprised 42 white subjects (14 male, 28 female; age range, 12-17 years) with untreated normal (acceptable) occlusions. Panoramic radiographs were taken of the patients at the beginning (T1) and end (T2) of treatment. The mean values of the mesiodistal axial inclination at T1 were compared with the mean values at T2, and both were compared with the mesiodistal axial inclinations of the control sample. The mesiodistal axial inclinations of the maxillary anterior teeth of the experimental group at T1 were different from those of the control group for 50% of the evaluated teeth. In contrast, the inclinations at T2 were consistent with the normal anatomical configuration of the controls. The panoramic radiograph is an effective tool for evaluating the mesiodistal axial inclinations of maxillary anterior teeth.


Characterisation of a glutamine- and proline-rich protein (QP protein) from Theileria parva.
We have isolated a clone from a Theileria parva infected lymphocyte cDNA library which has the potential to encode a protein of 480 amino acids. This protein is particularly rich in glutamine and proline and has some short repeated amino acid motifs based on the sequences QPXP and QPXQ. We have called it the 'QP protein'. Southern blotting suggests that the QP protein gene is present as a single copy in the T. parva Muguga genome. Northern blotting revealed that the gene is transcribed in both schizonts and piroplasms. We have expressed part of the QP protein as a fusion with glutathione S-transferase in Escherichia coli and used this product to raise an anti-QP protein serum. Western blots of T. parva lysates using this serum showed a major polypeptide of approximately 100 kDa and two further polypeptides of approximately 67 and 72 kDa. Indirect immunofluorescence assays using the anti-QP protein serum on infected cells showed that the protein is associated with the schizont. The pattern of staining in the indirect immunofluorescence assays and the structure of the protein suggest that it is a component of the schizont membrane.


Initiating nasal continuous positive airway pressure in preterm neonates at 5 cm as against 7 cm did not decrease the need for mechanical ventilation.
The optimum starting nasal continuous positive airway pressure (nCPAP) for infants on bubble nCPAP is unknown. We compared whether an initial bubble nCPAP of 7 cm rather than 5 cm of water prevented the need for mechanical ventilation among preterm neonates with respiratory distress. Preterm neonates born at 27-34 weeks with the onset of respiratory distress within 24 hours of birth were randomised to receive high or standard nCPAP at either 7 cm or 5 cm of water, respectively. The primary outcome was the need for mechanical ventilation in the first week of life. The baseline characteristics were comparable between the two groups. The proportion of infants who required mechanical ventilation during the first week of life was similar between the two groups (standard 29/133, 21.8% versus high 30/138, 21.7%), with a relative risk of 0.99 and range of 0.56-1.77. The secondary outcomes were similar between the two groups, including mortality before discharge, pulmonary air leaks, need of surfactant therapy, bronchopulmonary dysplasia and duration of nCPAP. Initiating nCPAP at a higher pressure of 7 cm in preterm neonates with respiratory distress, rather than the standard 5 cm, did not decrease the need for mechanical ventilation during the first week of life.


Performance evaluation of a green process for microalgal CO2 sequestration in closed photobioreactor using flue gas generated in-situ.
In the present study, carbon-dioxide capture from in situ generated flue gas was carried out using Chlorella sp. in bubble column photobioreactors to develop a cost effective process for concomitant carbon sequestration and biomass production. Firstly, a comparative analysis of CO2 sequestration with varying concentrations of CO2 in air-CO2 and air-flue gas mixtures was performed. Chlorella sp. was found to be tolerant to 5% CO2 concentration. Subsequently, inhibitory effect of pure flue gas was minimized using various strategies like use of high initial cell density and photobioreactors in series. The final biofixation efficiency was improved by 54% using the adopted strategies. Further, sequestered microalgal biomass was analyzed for various biochemical constituents for their use in food, feed or biofuel applications.


Development of nursing theory and science in vulnerable populations research.
Inequalities with respect to the distribution of societal resources can predispose people to vulnerability, which has led to a growing concern across America. The Federal Government has taken a leadership role and has launched several initiatives to combat health inequalities experienced by vulnerable populations. The National Institute of Health and all of its institutes, including the National Institute of Nursing Research, have written strategic plans to reduce, and ultimately, eliminate such health disparities. Nursing research has been conducted in the setting of vulnerable populations; several theoretical models for studying vulnerability have been created; and interventional studies designed to reduce health disparities have been implemented. This introduction includes the following: (a) a definition of the concept of vulnerability and health disparities; (b) a discussion of the conceptual models of vulnerability and health disparity and their applications; (c) a description of the impact of federal funding on vulnerable populations research; (d) a synopsis of the contributions made by nurse researchers in the field of vulnerable populations research; and (e) an overview of the volume.


2-(4-Chlorophenyl)-1,3-dicyano-6,7-dihydro-4-imino-9,10-dimethoxybenzo[a]quinolizine-water (2/5).
Crystals of the title compound, C(23)H(17)ClN(4)O(2).2.5H(2)O, contain channels filled with highly disordered water molecules. The best structure refinement was obtained by removing the solvent contribution from the intensity data and refining against a solvent-free model. The central six-membered ring of the quinolizine molecule has a slightly distorted screw-boat conformation.


Acupressure can reduce preoperative anxiety in adults with elective surgery: A systematic review and meta-analysis of randomised controlled trials.
Preoperative anxiety is prevalent amongst adults with elective surgery and is associated with multiple detrimental perioperative physiological effects. Increasing studies support the effectiveness of acupressure in managing preoperative anxiety. However, the magnitude of acupressure's positive association with preoperative anxiety is still unclear due to a lack of rigorous evidence synthesis. To estimate the efficacy of acupressure on preoperative anxiety and physiological parameters amongst adults scheduled for elective surgery. Systematic review and meta-analysis. Search terms were combined for acupressure and preoperative anxiety in PubMed, Cochrane Library, EMBASE, CINAHL, China National Knowledge Infrastructure, and WanFang Data Knowledge Service Platform to search for eligible randomised controlled trials from the inception of each database through September 2022. Pairs of researchers independently screened and extracted data from included studies. The risk of bias was assessed using the Cochrane risk of bias tool Version 2.0. Meanwhile, random-effects meta-analysis of overall effects and prespecified subgroup (i.e., surgery types, intervention providers, and acupressure stimulation tools) was conducted using Review Manager Software 5.4.1. Meta-regression was performed to explore study-level variables that may contribute to heterogeneity using STATA 16. Of 24 eligible randomised controlled trials, there were a total of 2537 participants from 5 countries contributed to this synthesis. When comparing acupressure with usual care or placebo, acupressure showed a large effect size for preoperative anxiety (SMD = -1.30; 95%CI = -1.54 to -1.06; p < 0.001; I2 = 86%). The significant mean reduction of heart rate, and systolic and diastolic blood pressure was -4.58 BPM (95%CI = -6.70 to -2.46; I2 = 89%), -6.05 mmHg (95%CI = -8.73 to -3.37; p < 0.001; I2 = 88%), and -3.18 mmHg (95%CI = -5.09 to -1.27; p = 0.001; I2 = 78%), respectively. Exploratory subgroup analyses showed significant differences in surgery types and acupressure stimulation tools, whilst the intervention providers (i.e., healthcare professionals and self-administered) showed no statistically significant difference for acupressure therapy. None of the predefined participants and study-level characteristics moderated preoperative anxiety through meta-regression. Acupressure appears efficacious as a therapy for improving preoperative anxiety and physiological parameters amongst adults with elective surgery. Self-administered acupressure, which is effective with a large effect, may be considered as an evidence-based approach to managing preoperative anxiety. Hence, this review aids in the development of acupressure in different types of elective surgeries and the improvement of the rigour of acupressure therapy.


3Rs-Related and Objective Indicators to Help Assess the Culture of Care.
Within animal research and testing, the need for an effective Culture of Care is widely recognized and described in terms of an establishment-wide commitment to improving the implementation of the 3Rs, animal welfare, scientific quality, care of the staff, and transparency for all stakeholders, including the public. Ideally, each establishment would determine what the Culture of Care means for them, and be able to assess and potentially benchmark their own culture. Some establishments already do this, using various indicators and formal or informal assessments. This paper provides examples of these approaches to assessing the Culture of Care, including surveys and surrogate measures. Many currently-used criteria and indicators tend to be human-centric and subjective, and we suggest using further objective indicators and animal-centric, 3Rs-based criteria. It is preferable to consider each of the 3Rs separately when assessing culture, and some indicators are suggested to facilitate this. Several documents produced by regulators in the UK and European Union are good sources of objective indicators of a good Culture of Care. This concept paper aims to complement the literature on assessing the Culture of Care, providing ideas and sources of information to help identify relevant and measurable criteria.


Distribution characteristics of phosphorus in the sediments and overlying water of Poyang lake.
Phosphorus (P) is a key indicator of the aquatic organism growth and eutrophication in lakes. The distribution and speciation of P and its release characteristics from sediments were investigated by analyzing sediment and water samples collected during high flow and low flow periods. Results showed that the average concentrations (ranges) of total phosphorus (TP) in the surface and deep water were 0.06 mg L(-1) (0.03-0.13 mg L(-1)) and 0.15 mg L(-1) (0.06-0.33 mg L(-1)), respectively, while the average concentration (range) of TP in sediments was 709.17 mg kg(-1) (544.76-932.11 mg kg(-1)). The concentrations of TP and different forms of P varied spatially in the surface sediments, displaying a decreasing trend from south to north. P also varied topographically from estuarine areas to lake areas. The vertical distribution of TP and different forms of P were observed to decrease as depth increased. The P concentrations during the low flow period were higher than those during the high flow period. Inorganic phosphorus (IP) was the dominant form of P, accounting for 61%-82% of TP. The concentration of bioavailable phosphorus in sediments was relatively large, indicating a high risk of release to overlying water. The simulation experiment of P release from sediments showed that the release was relatively fast in the first 0-5 min and then decreased to a plateau after 1 hr. Approximately 84-89% of the maximum amount of P was released during the first hour.


ADME/PK as part of a rational approach to drug discovery.
Rational drug discovery requires an early appraisal of all factors impacting on the likely success of a drug candidate in the subsequent preclinical, clinical and commercial phases of drug development. The study of absorption, distribution, metabolism, excretion and pharmacokinetics (ADME/PK) has developed into a relatively mature discipline in drug discovery through the application of well-established in vitro and in vivo methodologies. The availability of improved analytical and automation technologies has dramatically increased our ability to dissect out the fundamentals of ADME/PK through the development of increasingly powerful in silico methods. This is fuelling a shift away from the traditional, empirical nature of ADME/PK towards a more rational, in cerebro approach to drug design.


The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase.
Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically. To address this unmet clinical need, we previously developed a cell-based assay of STAT3 transcriptional activity and performed an unbiased and high-throughput screen of small molecules known to be biologically active in humans. We identified the antimicrobial drug pyrimethamine as a novel and specific inhibitor of STAT3 transcriptional activity. Here, we show that pyrimethamine does not significantly affect STAT3 phosphorylation, nuclear translocation, or DNA binding at concentrations sufficient to inhibit STAT3 transcriptional activity, suggesting a potentially novel mechanism of inhibition. To identify the direct molecular target of pyrimethamine and further elucidate the mechanism of action, we used a new quantitative proteome profiling approach called proteome integral solubility alteration coupled with a metabolomic analysis. We identified human dihydrofolate reductase as a target of pyrimethamine and demonstrated that the STAT3-inhibitory effects of pyrimethamine are the result of a deficiency in reduced folate downstream of dihydrofolate reductase inhibition, implicating folate metabolism in the regulation of STAT3 transcriptional activity. This study reveals a previously unknown regulatory node of the STAT3 pathway that may be important for the development of novel strategies to treat STAT3-driven cancers.


Tracing of motoneurones and primary afferent projections after intracellular staining with Lucifer Yellow: dye-coupling.
Intracellular injection of the fluorescent dye Lucifer Yellow CH into single motoneurones of the isolated perfused frog spinal cord resulted in backfilling of presynaptic fibres originating from dorsal roots and ventrolateral funiculi. The dye transfer from primary sensory fibres into motoneurones was observed following application of Lucifer Yellow to the central end of the cut dorsal root. The dye-coupling coincides with electrical coupling at sensory-motor synapses presumably through gap junctions. The fluorescent primary afferent fibres were traced from the dorsal roots to the motor nucleus where they terminate the chains of swellings. Most swellings are located in dorsal horn and in the intermediate zone approximately 100-100 micrometers from the somata of motoneurones. A few varicosities are located ion the cell bodies of the motoneurones.


CTX-M-1 and CTX-M-15-producing Escherichia coli in dog faeces from public gardens.
Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli are increasingly reported in dogs. The objective of this study was to provide data on the prevalence of ESBL-producing E. coli in dog faecal deposits in public gardens. A total of 209 faecal deposits collected in nine public gardens in Copenhagen, Denmark were screened by selective enrichment followed by plating on MacConkey agar supplemented with cefotaxime. Presumptive ESBL-producing E. coli were confirmed by MALDI-TOF MS and polymerase chain reaction (PCR) for detection of common cefotaxime resistance determinants (bla TEM, bla SHV, bla CTX-M and bla CMY-2). ESBL-producers were further characterized by multilocus sequence typing (MLST) and antimicrobial susceptibility testing using broth microdilution. Plasmids harbouring ESBL genes were characterized by S1 nuclease pulsed field gel electrophoresis, PCR-based replicon typing, and pMLST. Cefotaxime-resistant E. coli were detected in four (1.9 %) samples. Three samples harboured CTX-M-1-producing isolates, and one sample contained two CTX-M-15-producing isolates displaying distinct colony morphology. All isolates belonged to distinct sequence types (STs), including one E. coli lineage previously associated to a human-specific pathotype (ST59). bla CTX-M-1 was carried on IncI1 plasmids classified as ST3 or ST58 by pMLST, whereas bla CTX-M-15 was located on IncF/Y and non-typeable plasmids in the two strains isolated from the same sample. The study shows that dog faeces are a vector for dissemination of CTX-M-producing E. coli within urban areas. The risk derived from human exposure to dog faeces in public gardens depends on the prevalence of these bacteria in the local dog population as well as on the owners' practice to remove and dispose their dog's faeces.