Medical negligence in the U.K.--directions for research.
While the debate concerning compensation for victims of medical injury continues unabated, it is presented that many conclusions and recommendations are based on inadequate data. There is a need to examine, not only the legal requisites of a claim, but the factual circumstances surrounding claims. The direction of future studies must include an examination of: the relative experience of practitioners; frequency of medical specialties; demographic characteristics of patients; and the nature of the complaints.


Burnout in Critical Care Nurses.
Burnout syndrome is a contested diagnosis with wide ranging effects on critical care nurses, patients and families, and health care organizations. Multiple evaluation tools exist, and the core components of the theoretic burnout tools are vague and ambiguous and overlap legitimate mental health diseases, such as depression. Applied therapeutic interventions support decreased perceived burnout and staff turnover and improved overall well-being of nurses. Research postulates that decreased levels of burnout are associated with improved quality of patient care, communication, and trust, combined with decreases in patient morbidity and mortality, and ultimately, a decrease in the overall financial cost of care.


Influence of COVID-19 on the 10-year carbon footprint of the Nagoya University Hospital and medical research centre.
Amidst the climate crisis, a key goal of the medical sector is to reduce its large carbon footprint. Although the Coronavirus disease 2019 (COVID-19) pandemic greatly impacted the medical sector, its influence on carbon footprints remains unknown. Therefore, the aim of this study was to evaluate changes in the carbon footprint of a university hospital with a medical research centre over the past 10 years. Data on electricity, gas, and water usage, pharmaceutical and medical supply costs, and waste amounts were recorded for Nagoya University Hospital from April 2010 to March 2021. The relevant emission factors were obtained from the Japanese government and the overall monthly carbon footprint was reported according to the Greenhouse Gas Protocol. The effect of the COVID-19 pandemic on the carbon footprint was then compared for three types of emission sources. Moreover, a regression model was used to plot quadratic functions as approximate functions using monthly carbon emissions and monthly average external temperatures. Finally, the monthly carbon footprint was calculated per hospital admission. The overall carbon footprint of the hospital was 73,546 tCO2e in 2020, revealing an increase of 26.60% over the last 10 years. Carbon emissions from electricity consumption represented 26% of total emissions. The individual carbon footprints of pharmaceuticals, medical supplies, waste, and water usage also increased from 2010 to 2020. The overall monthly carbon footprint was positively correlated with the average monthly temperature (R2 = 0.7566, p < 0.001). Compared with 2019, the overall carbon footprint decreased by 2.19% in 2020. Moreover, the monthly carbon footprint per hospital admission increased significantly between 2018 (0.24 tCO2e/admission) and 2020 (0.26 tCO2e/admission) (p = 0.002). The overall carbon footprint of the hospital generally increased over the last decade. During the COVID-19 epidemic in 2020, the carbon footprint decreased slightly, likely because of the reduced number of patients. However, the carbon footprint per admission increased, which was attributed to more complicated patient backgrounds because of the ageing population. Therefore, evaluation of carbon emissions in the medical sector is urgently required in order to act on the climate crisis as soon as possible.


Posterior decompression and stabilization in a pregnant patient with traumatic lumbar fracture: A case report.
Spine fractures with or without spinal cord injury in the pregnant population are rare, with few reported cases. A 25-year-old primigravida at 24 weeks of gestation presented after falling off a fast-moving motorcycle one month prior. She had sustained a severe back injury and had difficulty walking. Magnetic resonance imaging showed an acute kyphosis secondary to comminuted anterior wedge compression fractures of the L2 and L3 vertebral bodies and L2/3 disc involvement with retropulsion of the fracture fragments into the central canal resulting in severe central canal stenosis. After multidisciplinary discussion, the patient underwent posterior decompression, reduction and stabilization with pedicle screws. The patient had good neurological recovery at discharge and the pregnancy progressed normally. Three months later, at 39 weeks of gestation, the patient had an uneventful spontaneous delivery of a healthy baby. This case illustrates the importance of multidisciplinary management of spinal cord injury in a pregnant patient.


Changes in the identification and management of mental health and domestic abuse among pregnant women during the COVID-19 lockdown: regression discontinuity study.
Domestic violence and abuse (DVA) and mental illness during pregnancy have long-lasting and potentially serious consequences, which may have been exacerbated during the COVID-19 pandemic. To investigate how the UK COVID-19 lockdown policy influenced the identification of DVA and depressive symptoms during pregnancy in health services in South-East London in Spring 2020, using eLIXIR (Early-Life Data Cross-Linkage in Research) maternity and mental routine healthcare data. We used a regression discontinuity approach, with a quasi-experimental study design, to analyse the effect of the transition into and out of the COVID-19 lockdown on the rates of positive depression screens, DVA recorded in maternity and secondary mental health services, and contact with secondary mental health services during pregnancy. We analysed 26 447 pregnancies from 1 October 2018 to 29 August 2020. The rate of DVA recorded in maternity services was low throughout the period (<0.5%). Within secondary mental health services, rates of DVA dropped by 78% (adjusted odds ratio 0.219, P = 0.012) during lockdown, remaining low after lockdown. The rate of women screening positive for depression increased by 40% (adjusted odds ratio 1.40, P = 0.023), but returned to baseline after lockdown lifted. Rates of DVA identification in secondary mental health services dropped during and after lockdown, whereas overall rates of DVA identified in maternity services were concerningly low. Healthcare services must adopt guidance to facilitate safe enquiry, particularly in remote consultations. Further research is vital to address the longer-term impact on women's mental health caused by the increase in depression during the lockdown.


Sleep Disturbance in Tourette's Disorder: Potential Underlying Mechanisms.
Sleep disturbance is common in TD. However, our understanding of the pathophysiological mechanisms involved is preliminary. This review summarizes findings from neuroimaging, genetic, and animal studies to elucidate potential underlying mechanisms of sleep disruption in TD. Preliminary neuroimaging research indicates increased activity in the premotor cortex, and decreased activity in the prefrontal cortex is associated with NREM sleep in TD. Striatal dopamine exhibits a circadian rhythm; and is influenced by the suprachiasmatic nucleus via multiple molecular mechanisms. Conversely, dopamine receptors regulate circadian function and striatal expression of circadian genes. The association of TD with restless legs syndrome and periodic limb movements indicates shared pathophysiology, including iron deficiency, and variants in the BTDB9 gene. A mutations in the L-Histidine Decarboxylase gene in TD, suggests the involvement of the histaminergic system, implicated in arousal, in TD. These biological markers have implications for application of novel, targeted interventions, including noninvasive neuromodulation, iron supplementation, histamine receptor antagonists, and circadian-based therapies for tic symptoms and/or sleep and circadian rhythms in TD.


Can biofuels finally take center stage?
Today, ethanol and biodiesel are predominantly produced from corn kernels, sugarcane or soybean oil. But researchers and investors are increasingly upbeat about another biofuel feedstock, lignocellulose--the most abundant biological material on earth.


Myelin lesions in the rabbit eye model as a bystander effect of herpes simplex and visna virus sensitization.
Rabbits were immunized with herpes simplex and visna virus in complete Freund's adjuvant. Uv-inactivated herpes virus and the purified visna virus protein p25 injected intraocularly into these rabbits elicited a moderate inflammatory cell infiltration in the epiretinal myelinated nerve fiber bundles accompanied by signs of demyelination. It is therefore apparent that also viral antigen can induce myelin lesions as a so-called "bystander effect" of a cell-mediated immune response (bystander demyelination).


NMDA receptor-mediated long-term alterations in epileptiform activity in experimental chronic epilepsy.
When epileptiform activity is acutely induced in vitro, transient partial blockade of N-methyl-d-aspartic acid (NMDA) receptor-mediated calcium influx leads to selective long-term depotentiation of the synapses involved in the epileptic activity as well as a reduction in the probability of further epileptiform activity. If such selective depotentiation occurred within foci of epileptic activity in vivo, the corresponding long-term reduction in seizure probability could form the basis for a novel treatment of epilepsy. Continuous radiotelemetric EEG monitoring demonstrated modest acute anticonvulsant effects but no long-term reductions in the probability of spontaneous seizures after transient partial blockade of NMDA receptors (NMDAR) during ictal and interictal activity in the kainate animal model of chronic epilepsy. In vitro, depotentiation was induced when NMDAR were partially blocked during epileptiform activity in hippocampal slices from control animals, but not in slices from chronically epileptic rats. However in slices from epileptic animals, depotentiation during epileptiform activity was induced by partial block of NMDAR using NR2B- but not NR2A-selective antagonists. These results suggest that chronic epileptic activity is associated with changes in NMDA receptor-mediated signaling that is reflected in the pharmacology of activity- and NMDA receptor-dependent depotentiation.


Delayed recognition and infection control for tuberculosis patients in the emergency department.
The recent increase in tuberculosis (TB) cases may have an important effect on emergency department infection-control measures. We describe infection-control interventions for TB patients admitted through the ED and hypothesize that ED suspicion of TB is associated with more rapid isolation and treatment. Retrospective chart review. The ED of a 400-bed urban, university-affiliated county hospital. Fifty-five patients with TB culture-positive and acid-fast bacillus stain-positive respiratory specimens who were evaluated in the ED during 1991 and 1992. We identified cases from the mycobacteriology log. Demographic and historical data and time elapsed before initiation of infection-control measures and TB therapy were recorded. We assessed the relationships of individual clinical findings and the ED presumptive diagnosis of TB (predictor variables) to time elapsed before isolation and therapy (outcome variables) with the log-rank test. The median time (interquartile range) from ED registration to isolation was 8 hours (range, 3 to 13 hours). An ED presumptive diagnosis of TB was made in 71% of cases and was significantly associated with shorter time elapsed before isolation (5 hours [range, 2 to 10 hours] versus 21 hours [range, 11 to 111 hours]; P < .001) and less time elapsed before therapy (12 hours [range, 9 to 22 hours] versus 128 hours [68 to 374 hours]; P < .001). We found TB exposure, radiographic changes typical of TB, absence of HIV risk factors, presence of cough, and sputum production to be associated with more rapid isolation. Among patients with active pulmonary TB in the ED, TB is often unsuspected and isolation measures are often not used. ED suspicion of TB is associated with more rapid isolation and treatment.


Impact of ketamine on neuronal network dynamics: translational modeling of schizophrenia-relevant deficits.
Subanesthetic doses of the psychomimetic, ketamine, have been used for many years to elicit behavioral effects reminiscent of schizophrenia in both healthy humans and in animal models of the disease. More recently, there has been a move toward the use of simple neurophysiological measures (event-related potentials, brain oscillations) to assay the functional integrity of neuronal circuits in schizophrenia as these measures can be assessed in patients, healthy controls, intact animals, and even in brain slices. Furthermore, alterations of these measures are correlated with basic information processing deficits that are now considered central to the disease. Thus, here we review recent studies that determine the effect of ketamine on these measures and discuss to what extent they recapitulate findings in patients with schizophrenia. In particular, we examine methodological differences between human and animal studies and compare in vivo and in vitro effects of ketamine. Ketamine acts on multiple cortical and subcortical sites, as well as on receptors other than the N-methyl-d-aspartate receptor. Acute ketamine models' changes correlated with psychotic states (e.g. increased baseline gamma-band oscillations), whereas chronic ketamine causes cortical circuit changes and neurophysiological deficits (e.g. impaired event-related gamma-band oscillations) correlated with cognitive impairments in schizophrenia.


Factors associated with conversion in laparoscopic surgery in a low-resource setting: a single-center prospective study.
Laparoscopy has a clear patient benefit related to postoperative morbidity but may not be as commonly performed in low-and middle-income countries. The decision to convert to laparotomy can be complex and involve factors related to the surgeon, patient, and procedure. The objective of this work is to analyze the factors associated with conversion in laparoscopic surgery in a low-resource setting. This is a single-center prospective study of patients who underwent laparoscopic surgery between May 1, 2018 and October 31, 2021. The parameters studied were age, sex, body mass index (BMI), intraoperative complication (e.g., accidental enterotomy, hemorrhage), equipment malfunction (e.g., technical failure of the equipment, break in CO2 supply line), operating time, and conversion rate. A total of 123 laparoscopic surgeries were performed. The average age of patients was 31.2 years (range 11-75). The procedures performed included appendix procedures (48%), followed by gynecological (18.7%), gallbladder (14.6%), digestive (10.56%), and abdominal procedures (4%). The average length of hospitalization was 3 days (range 1-16). Conversion to laparotomy was reported in 8.9% (n = 11) cases. Equipment malfunction was encountered in 9.8% (n = 12) cases. Surgical complications were noted in 11 cases (8.9%). Risk factors for conversion were shown to be BMI > 25 kg/m2 (OR 4.6; p = 0.034), intraoperative complications (OR 12.6; p = 0.028), and equipment malfunction (OR 9.4; p = 0.002). A better understanding of the underlying factors associated with high conversion rates, such as overweight/obesity, intraoperative complications, and equipment failure, is the first step toward surgical planning to reduce postoperative morbidity in low-resource settings.


Antioxidant cinnamaldehyde attenuates UVB-induced photoaging.
Ultraviolet (UV) irradiation disrupts skin through several deleterious actions, such as induction of reactive oxygen species (ROS), DNA damage, and collagen degradation. Cinnamaldehyde (CIN) is a major constituent of the cinnamon and it possesses potent antioxidative activity; however, it is unclear whether CIN is capable of inhibiting the adverse effects of UVB. To investigate protective effects of CIN against UVB-induced photodamage. HaCaT keratinocytes were pretreated with CIN, irradiated with UVB, and assessed for the ROS production by flow cytometry and for the DNA damage by ELISA. As in vivo mouse model, Hos:HR-1 hairless mice were treated with ointments containing DMSO or CIN and irradiated multiple times with UVB. After 10 weeks of irradiation, wrinkle formation, epidermal thickness, infiltrating cell number, malondialdehyde amount, collagen amount, MAP kinase signaling, and related gene expressions (Hmox1, Col1a1, Mmp1a, and Mmp13) were analyzed. CIN significantly reduced the ROS production and accelerated the repair of DNA damage pyrimidine(6-4)pyrimidone photoproducts in UVB-irradiated human keratinocytes in vitro. In the mouse model, topical application of CIN significantly inhibited wrinkle formation, epidermal hyperplasia, and dermal inflammatory cell infiltration. The antioxidative process was significantly promoted in the CIN-applied site, as evidenced by upregulation of the antioxidative enzyme Hmox1 as well as the reduced accumulation of malondialdehyde. In addition, topical application of CIN normalized the UVB-induced collagen/Col1a1 downregulation and the UVB-induced Mmp13 upregulation, implying the prevention of UVB-induced collagen degradation. CIN and CIN-containing herbal agents may exert potent protective effects against UVB exposure on skin.


Characteristics and Outcomes of Patients Who Underwent Coronary Atherectomy in Centers With and Without On-Site Cardiac Surgery.
We aimed to describe the clinical characteristics and outcomes of patients who underwent atherectomy at the time of percutaneous coronary intervention in centers with on-site surgical centers (SCs) versus nonsurgical centers (NSCs). Patients treated with coronary atherectomy between January 1, 2006, to December 31, 2019, from the British Cardiovascular Society Intervention (BCIS) registry were included. Primary outcomes were in-hospital all-cause mortality and major adverse cardiovascular and cerebrovascular events. A total of 20,833 patients were treated with coronary atherectomy, of which 7,983 (38%) were performed at NSC. The proportion of coronary atherectomies performed in NSC increased from 12.5% in 2006 to 42% in 2019. Compared with patients treated at SC, patients treated in NSC were older (mean age 75.1 ± SD years vs 74.2 ± SD, p <0.001), but had comparable prevalence of hypertension (NSC 73.9% vs SC 72.8%, p = 0.085), diabetes mellitus (NSC 32.2% vs SC 31.6%, p = 0.43) and renal disease (NSC 6.0% vs SC 6.0%, p = 0.99). Intracoronary imaging was used more often in NSC than SC (22.3% vs 19.4%, p <0.001). After adjustment, the odds of in-hospital mortality (odds ratios [OR] 0.76, 95% confidence intervals [CI] 0.50 to 1.16), major adverse cardiovascular and cerebrovascular events (OR 0.80, 95% CI 0.53 to 1.21), emergency coronary artery bypass graft (OR 0.49, 95% CI 0.15 to 1.57), major bleeding (OR 0.67, 95% CI 0.36 to 1.24) and coronary perforation (OR 1.07, 95% CI 0.97 to 1.43) in NSC were comparable with SC. In conclusion, coronary atherectomy in hospitals with off-site surgical cover has become more frequent, with no association with poorer outcomes, compared with hospitals with on-site surgical cover.


The basic properties of the electronic structure of the oxygen-evolving complex of photosystem II are not perturbed by Ca2+ removal.
Ca(2+) is an integral component of the Mn(4)O(5)Ca cluster of the oxygen-evolving complex in photosystem II (PS II). Its removal leads to the loss of the water oxidizing functionality. The S(2)' state of the Ca(2+)-depleted cluster from spinach is examined by X- and Q-band EPR and (55)Mn electron nuclear double resonance (ENDOR) spectroscopy. Spectral simulations demonstrate that upon Ca(2+) removal, its electronic structure remains essentially unaltered, i.e. that of a manganese tetramer. No redistribution of the manganese valence states and only minor perturbation of the exchange interactions between the manganese ions were found. Interestingly, the S(2)' state in spinach PS II is very similar to the native S(2) state of Thermosynechococcus elongatus in terms of spin state energies and insensitivity to methanol addition. These results assign the Ca(2+) a functional as opposed to a structural role in water splitting catalysis, such as (i) being essential for efficient proton-coupled electron transfer between Y(Z) and the manganese cluster and/or (ii) providing an initial binding site for substrate water. Additionally, a novel (55)Mn(2+) signal, detected by Q-band pulse EPR and ENDOR, was observed in Ca(2+)-depleted PS II. Mn(2+) titration, monitored by (55)Mn ENDOR, revealed a specific Mn(2+) binding site with a submicromolar K(D). Ca(2+) titration of Mn(2+)-loaded, Ca(2+)-depleted PS II demonstrated that the site is reversibly made accessible to Mn(2+) by Ca(2+) depletion and reconstitution. Mn(2+) is proposed to bind at one of the extrinsic subunits. This process is possibly relevant for the formation of the Mn(4)O(5)Ca cluster during photoassembly and/or D1 repair.


Pars interarticularis repair using pedicle screws and laminar hooks fixation technique in patients with symptomatic lumbar spondylolysis.
Prospective case series. To assess the outcomes of pars repair surgery using pedicle screws and laminar hooks. This study was conducted on 22 patients with symptomatic lumbar spondylolysis. Curettage of the fibrocartilage in the defect and drilling of the sclerotic bone ends were done, followed by impaction of cancellous bone graft. Pedicle screws were inserted bilaterally in the corresponding pedicles and connected to a laminar hook via rods (screw-rod-hook fixation). The intensity of back pain and the functional outcome were assessed using the visual analog scale (VAS) and the Oswestry disability index (ODI). Plain radiographs were performed immediately postoperatively and after 3 and 6 months. CT scan was done at the final follow-up to assess pars healing. The mean follow-up period was 27 months. The mean preoperative VAS and ODI were 7.4 ± 0.8 and 64.8 ± 6.7, which improved to 2.4 ± 0.8 and 20 ± 6 respectively at the final follow-up (P < 0.001). Healing of the defect was found in 19 patients at the final follow-up. Non-fusion with graft resorption was noticed in the remaining 3 cases (13.6%). However, postoperative VAS and ODI values improved even in the radiologically non-fused patients. Therapeutic study, Level IV. Pars repair using pedicle screws and laminar hooks is a relatively simple yet effective procedure.


Spatial modulation of nanopattern dimensions by combining interference lithography and grayscale-patterned secondary exposure.
Functional nanostructures are exploited for a variety of cutting-edge fields including plasmonics, metasurfaces, and biosensors, just to name a few. Some applications require nanostructures with uniform feature sizes while others rely on spatially varying morphologies. However, fine manipulation of the feature size over a large area remains a substantial challenge because mainstream approaches to precise nanopatterning are based on low-throughput pixel-by-pixel processing, such as those utilizing focused beams of photons, electrons, or ions. In this work, we provide a solution toward wafer-scale, arbitrary modulation of feature size distribution by introducing a lithographic portfolio combining interference lithography (IL) and grayscale-patterned secondary exposure (SE). Employed after the high-throughput IL, a SE with patterned intensity distribution spatially modulates the dimensions of photoresist nanostructures. Based on this approach, we successfully fabricated 4-inch wafer-scale nanogratings with uniform linewidths of <5% variation, using grayscale-patterned SE to compensate for the linewidth difference caused by the Gaussian distribution of the laser beams in the IL. Besides, we also demonstrated a wafer-scale structural color painting by spatially modulating the filling ratio to achieve gradient grayscale color using SE.


Remnant Lipoprotein Cholesterol and Mortality After Acute Myocardial Infarction: Further Evidence for a Hypercholesterolemia Paradox From the TRIUMPH Registry.
Remnants are partially hydrolyzed, triglyceride-rich lipoproteins that, like other apolipoprotein B-containing lipoproteins, are atherogenic. Prior observational studies suggest paradoxically better outcomes in hypercholesterolemic patients who sustain an acute myocardial infarction (AMI), one of several known recurrent risk paradoxes. To date, the association of directly measured remnant lipoprotein cholesterol (RLP-C) with survival after an AMI has not been examined. Higher RLP-C levels may be paradoxically associated with lower mortality. We examined 2465 AMI survivors in a prospective, 24-center US study of AMI outcomes. Lipoprotein cholesterol subfractions were directly measured by ultracentrifugation. RLP-C was defined as intermediate-density lipoprotein cholesterol (IDL-C) + very-low-density lipoprotein cholesterol subfraction 3 (VLDL3 -C). Given a linear relationship between RLP-C and mortality, we examined RLP-C by tertiles and continuously. Cox regression hazard ratios (HRs) were adjusted for the Global Registry of Acute Coronary Events (GRACE) score and 23 other covariates. Participants were age 58 ± 12 years (mean ± SD), and 68% were men. After 2 years of follow-up, 226 (9%) participants died. The mortality proportion was 12.4% in the lowest tertile of RLP-C (0-15 mg/dL), 8.5% in the middle tertile (16-23 mg/dL), and 6.8% in the highest tertile (24-120 mg/dL; P < 0.001). A 1-SD increase in RLP-C (11 mg/dL) predicted a 24% lower adjusted risk of 2-year mortality (HR: 0.76, 95% confidence interval [CI]: 0.64-0.91). Similar results were found for a 1-SD increase in IDL-C (HR per 8 mg/dL: 0.80, 95% CI: 0.67-0.96), VLDL3 -C (HR per 4 mg/dL: 0.74, 95% CI: 0.61-0.89), and very-low-density lipoprotein cholesterol (VLDL-C; HR per 8 mg/dL: 0.69, 95% CI: 0.55-0.85). Higher RLP-C levels were associated with lower mortality 2 years after AMI despite rigorous adjustment for known confounders. Unknown protective factors or a lead-time bias likely explains the paradox.


Life stress, social support, and self-esteem in an elderly population.
Findings in previous studies of the stress-buffering properties of social support have been erratic. This study suggests that at least part of the reason for those inconclusive findings may be that researchers are using oversimplified models of the stress process and limited statistical approaches to assess the effects. The findings in this study indicate that social support (a) helps to reduce the deleterious effects of stress on emotional disorder primarily by bolstering the self-esteem of older adults and (b) affects psychological well-being only indirectly through self-esteem. Two distinct approaches to the statistical estimation of stress-buffering effects are also examined.


Tie2 Receptor in Tumor-Infiltrating Macrophages Is Dispensable for Tumor Angiogenesis and Tumor Relapse after Chemotherapy.
Tumor relapse after chemotherapy relies on the reconstruction of damaged tumor vasculature. In this context, proangiogenic Tie2-expressing macrophages have been suggested to serve as crucial instructors of tumor revascularization by secreting angiogenic factors while being closely associated with the vessel wall. Although the proangiogenic nature of Tie2+ macrophages is well described, the functional contribution of macrophage Tie2 expression remains elusive. Here, we employed a Cre-loxP system to specifically delete Tie2 in macrophages. In multiple syngeneic solid tumor models and two distinct chemotherapeutic treatment regimens, macrophage-expressed Tie2 did not contribute to primary tumor growth, tumor revascularization after chemotherapy, tumor recurrence, or metastasis. Exposing cultured murine macrophage cell lines and bone marrow-derived macrophages to hypoxia or stimulating them with Ang2 did not induce expression of Tie2 at the RNA or protein level. Furthermore, a comprehensive meta-analysis of publicly available single cell RNA sequencing datasets of human and murine tumor-infiltrating CD11b+ myeloid cells did not reveal a transcriptionally distinct macrophage population marked by the expression of Tie2. Collectively, these data question the previously reported critical role of Tie2-expressing macrophages for tumor angiogenesis and tumor relapse after chemotherapy. Moreover, lack of Tie2 inducibility and absence of Tie2-positive macrophages in multiple recently published tumor studies refute a possible prognostic value of macrophage-expressed Tie2. Multiple preclinical tumor models, cell stimulation experiments, and meta-analysis of published tumor single cell RNA sequencing data challenge the reported role of Tie2-positive macrophages for tumor angiogenesis, metastasis, and relapse after chemotherapy. See related commentary by Zhang and Brekken, p. 1172.


alpha 2-Macroglobulin-proteinase complexes in cystic fibrosis serum. Analysis by monoclonal antibodies and receptor-mediated endocytosis by normal human fibroblasts.
alpha 2-Macroglobulin complexed to proteinases activated during clotting of cystic fibrosis and control sera was quantitated with the complex-specific monoclonal antibody F2B2 . Similar amounts of alpha 2-macroglobulin complexes (between 40 and 90 micrograms/ml) were generated in cystic fibrosis and control sera. Endocytosis of the complexes by normal human fibroblasts was compared to the amount of complexes detected by the F2B2 -radioimmunoassay. Normal uptake was observed with 13 out of 14 cystic fibrosis sera. One cystic fibrosis serum showed strongly reduced endocytosis of the complexes. Complexes isolated from this serum on immobilized F2B2 failed to inhibit binding of purified alpha 2-macroglobulin-trypsin to its receptor, demonstrating deficient receptor-binding of these complexes. The low uptake complexes could not be distinguished from complexes isolated from control or other cystic fibrosis sera by isoelectric focusing, rate electrophoresis or SDS-polyacrylamide gel electrophoresis.


To control or to be controlled? Dual roles of CDK2 in DNA damage and DNA damage response.
CDK2 (cyclin-dependent kinase 2), a member of the CDK family, has been shown to play a role in many cellular activities including cell cycle progression, apoptosis and senescence. Recently, accumulating evidence indicates that CDK2 is involved in DNA damage and DNA repair response (DDR). When DNA is damaged by internal or external genotoxic stresses, CDK2 activity is required for proper DNA repair in vivo and in vitro, whereas inactivation of CDK2 by siRNA techniques or by inhibitors could result in DNA damage and stimulate DDR. Hence, CDK2 seems to play dual roles in DNA damage and DDR. On one aspect, it is activated and stimulates DDR to repair DNA damage when DNA damage occurs; on the other hand, its inactivation directly leads to DNA damage and evokes DDR. Here, we describe the roles of CDK2 in DNA damage and DDR, and discuss the potential application of CDK2 inhibitors as anti-cancer agents.


Development and characterization of 20 new polymorphic microsatellite markers from Mangifera indica (Anacardiaceae).
Twenty microsatellite loci for mango (Mangifera indica), an important commercial fruit tree in East Asia, were developed to evaluate the genetic diversity and identification of cultivars. The 20 new microsatellite markers were isolated from mango using a magnetic bead enrichment method, and polymorphisms were identified in 22 mango cultivars. The number of alleles ranged from one to nine, with expected heterozygosity ranging from 0 to 0.826. The polymorphism information content ranged from 0 to 0.756 with a mean of 0.525. These new microsatellite loci should be useful and convenient for further studies of the genetic diversity and identification of cultivars in mango.


New Mouse Models of Roux-en Y Gastric Bypass and One Anastomosis Gastric Bypass for Type 2 Diabetes.
Current bariatric surgery models primarily utilize mice with obesity, overlooking those with type 2 diabetes (T2DM). These models have limitations in replicating clinical procedures accurately and achieving broad applicability. This study aimed to develop novel mouse models of Roux-en-Y gastric bypass (RYGB) and one anastomosis gastric bypass (OAGB) surgeries specifically designed for T2DM research, utilizing simplified surgical techniques closely resembling clinical procedures. Eight-week-old C57/Bl6 mice, except for the Blank-Control group, were induced with T2DM by combining a high-fat diet and streptozotocin injection. RYGB involved creating a 10% gastric pouch, a 4-cm biliopancreatic limb (BL), and a 4-cm Roux limb (RL). Similarly, OAGB maintained a 10% gastric pouch and a 4-cm BL. To assess the efficacy of these models, we measured the body weight and fasting blood glucose (FBG) and conducted intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), and liver B-ultrasound, as well as a histopathological analysis of multiple organs 12 weeks post-operation. The survival rates in the Blank-Control, T2DM-Sham, T2DM-RYGB, and T2DM-OAGB groups were 100% (6/6), 100% (6/6), 85.7% (6/7), and 100% (6/6), respectively. Both RYGB and OAGB surgeries similarly led to sustained weight loss, reduced the FBG levels, improved the IPGTT and ITT results, and alleviated the histopathological manifestations in multiple organs. The innovative mouse models of RYGB and OAGB surgeries effectively improve T2DM. Both surgeries demonstrate comparable efficacy in ameliorating T2DM, even when utilizing a gastric pouch of the same size and the same length of BL in OAGB.


Properties and biotechnological applications of natural and engineered haloalkane dehalogenases.
Haloalkane dehalogenases (HLDs) convert halogenated compounds to corresponding alcohols, halides, and protons. They belong to α/β-hydrolases, and their principal catalytic mechanism is SN2 nucleophilic substitution followed by the addition of water. Since HLDs generally have broad and different substrate specificities, they have various biotechnological applications. HLDs have previously been believed to be present only in bacterial strains that utilize xenobiotic halogenated compounds, and three archetypal HLDs, i.e., DhlA, DhaA, and LinB, have been intensively investigated by biochemical, structural, and computational analyses. Furthermore, by using the resulting data and target-selected random mutagenesis approaches, these HLDs have been successfully engineered to improve their substrate specificities and activities. In addition, important insights into protein evolution have been obtained by studying these HLDs. At the same time, the genome and metagenome information has revealed that HLD homologues are widely distributed in many bacterial strains, including ones that have not been reported to degrade halogenated compounds. Some of these cryptic HLD homologues have been experimentally confirmed to be "true" HLDs with unique substrate specificities and enantioselectivities. Although their biological functions and physiological roles remain mysterious, these potential HLDs are considered promising materials for the development of new biocatalysts.


Large 'small' groups: their place in higher education.
Small group teaching in higher education appears to be an ideal worth aiming for. The review of the literature in this paper shows that factural information about the effectiveness of such teaching is far from prolific. In addition, what may be the most common form of small group, viz. the 'seminar', has received far less attention than the 'lecture' or 'tutorial'. Special attention is drawn to the relevance of the studies for medical education but the overall finding is that need for well designed evaluative research is urgent, particularly with regard to 'seminar' learning groups.


The development of a culture specific screening questionnaire NSRQ-20 for use in psychiatric epidemiology: a preliminary report.
A list of ten culture-specific symptoms frequently volunteered by Nigerian patients with Minor Psychiatric Disorders was added to the twenty items of the SRQ-20. The resultant 30-item questionnaire (SRQ-30) discriminated very well between a sample of new non-psychotic psychiatric referrals and a sample of subjects with very low probability of caseness (relatives of the new psychiatric referrals). Elimination of items of the SRQ-30 which poorly discriminated between the sample of psychiatric referrals and a matched sample of general hospital patients (ten items) produced the Nigerian version of the SRQ-20 (NSRQ-20) whose sensitivity is shown to be higher than that of the SRQ-30. Further validation study and future research trends on the NSRQ-20 are suggested.


The genetic deletion of the Dual Specificity Phosphatase 3 (DUSP3) attenuates kidney damage and inflammation following ischaemia/reperfusion injury in mouse.
Dual Specificity Phosphatase 3 (DUSP3) regulates the innate immune response, with a putative role in angiogenesis. Modulating inflammation and perfusion contributes to renal conditioning against ischaemia/reperfusion (I/R). We postulate that the functional loss of DUSP3 is associated with kidney resistance to I/R. Ten C57BL/6 male WT and Dusp3-/- mice underwent right nephrectomy and left renal I/R (30 min/48 hours). Renal injury was assessed based on serum levels of urea (BUN) and Jablonski score. The expression of CD31 and VEGF vascular markers was quantified by RT-qPCR and immuno-staining. Renal resistivity index (RRI) was measured in vivo by Doppler ultrasound. Comparative phosphoproteomics was conducted using IMAC enrichment of phosphopeptides. Inflammatory markers were quantified at both mRNA and protein levels in ischaemic vs non-ischaemic kidneys in WT vs Dusp3-/- . At baseline, we located DUSP3 in renal glomeruli and endothelial cells. CD31-positive vascular network was significantly larger in Dusp3-/- kidneys compared to WT, with a lower RRI in Dusp3-/- mice. Following I/R, BUN and Jablonski score were significantly lower in Dusp3-/- vs WT mice. Phosphoproteomics highlighted a down-regulation of inflammatory pathways and up-regulation of phospho-sites involved in cell metabolism and VEGF-related angiogenesis in Dusp3-/- vs WT ischaemic kidneys. Dusp3-/- ischaemic kidneys showed decreased mRNA levels of CD11b, TNF-α, KIM-1, IL-6, IL-1β and caspase-3 compared to controls. The numbers of PCNA-, F4-80- and CD11b-positive cells were reduced in Dusp3-/- vs WT kidneys post-I/R. Genetic inactivation of Dusp3 is associated with kidney conditioning against I/R, possibly due to attenuated inflammation and improved perfusion.


Neurodevelopmental disease mechanisms, primary cilia, and endosomes converge on the BLOC-1 and BORC complexes.
The biogenesis of lysosome-related organelles complex-1 (BLOC-1) and the bloc-one-related complex (BORC) are the cytosolic protein complexes required for specialized membrane protein traffic along the endocytic route and the spatial distribution of endosome-derived compartments, respectively. BLOC-1 and BORC complex subunits and components of their interactomes have been associated with the risk and/or pathomechanisms of neurodevelopmental disorders. Thus, cellular processes requiring BLOC-1 and BORC interactomes have the potential to offer novel insight into mechanisms underlying behavioral defects. We focus on interactions between BLOC-1 or BORC subunits with the actin and microtubule cytoskeleton, membrane tethers, and SNAREs. These interactions highlight requirements for BLOC-1 and BORC in membrane movement by motors, control of actin polymerization, and targeting of membrane proteins to specialized cellular domains such as the nerve terminal and the primary cilium. We propose that the endosome-primary cilia pathway is an underappreciated hub in the genesis and mechanisms of neurodevelopmental disorders. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 311-330, 2018.


Biosynthesis of ZnO and TiO2 nanoparticles using Ipomoea carnea leaf extract and its effect on black carrot (Daucus carota L.) cv. Pusa Asita.
Nano fertilizers (NFs) are now becoming an important tool for plant nutrient management having capabilities to improve soil fertility, crop productivity and quality of agricultural products. Since, they are needed in very small amount, thus, reduces cost of crop production. Among different essential or beneficial plant nutrients, Zn and Ti are important micro nutrients having number of beneficial effect on crop growth, yield, quality and post harvest life. Present experiment was carried out to prepare ZnO and TiO2 nanoparticles (NPs) through green technology by using aqueous extract of Ipomoea carnea (morning glory) leaves. In order to investigate size, morphology, composition, and stability of selected NPs, the detailed characterization was carried out using UV-visible spectroscopy, FTIR, HRTEM, EDX, BET, X-ray diffraction, XPS and particle size distribution studies. Subsequently, the effect of foliar spray of ZnO and TiO2 NPs was evaluated in respect of vegetative growth, yield and quality of black carrot (Daucus carota L.) cv. Pusa Asita in presence of 50% Recommended dose of fertilizer (RDF) to assess their effect on fertilizer use efficiency also. There were 8 treatments viz. Control (no fertilizer), recommended dose of fertilizer (RDF), TiO2 (5, 10 and 15 ppm along with 50% RDF), ZnO (50, 75 and 100 ppm along with 50% RDF)] with 3 replications following Randomised Block Design having 24 plots (1 m × 1 m). The observations were taken for vegetative growth, edible root yield and root quality parameters. Although, the growth, yield and quality parameters were found superior (root yield 43.84 g/plant) under conventional system of recommended dose of fertilizers (RDF) of NPK, however, TiO2 NPs also showed very promising result close to RDF as compared to ZnO NPs. Among them, 5 ppm TiO2 foliar application along with 50% NPK was found to be the best in terms of vegetative growth, root yield (38.73 g/plant) and quality of black carrot. It was also found that higher concentration of TiO2 and ZnO NPs had adverse effect on the plant performance. Therefore, it can be concluded that 5 ppm TiO2 NPs along with 50% RDF was good for black carrot production.


Pharmacokinetic and electrophysiologic interactions of amiodarone and procainamide.
The effects of amiodarone on the pharmacokinetic and electrophysiologic properties of procainamide were examined in eight patients treated for recurrent ventricular arrhythmias who received intravenous procainamide, 6 to 15 mg/kg, at control and after 1 to 2 weeks of oral amiodarone treatment. Compared with control, procainamide plasma clearance decreased from 0.43 +/- 0.12 L/kg-hr to 0.33 +/- 0.12 L/kg-hr (P less than 0.01), plasma elimination half-life increased from 3.77 +/- 0.64 hours to 5.21 +/- 0.42 hours (P less than 0.01), and volume of distribution was unchanged from 2.31 +/- 0.74 L/kg to 2.47 +/- 0.90 L/kg during amiodarone treatment. As single agents, intravenous procainamide and oral amiodarone produced equivalent increases in QRS duration, rate-corrected QT interval, right ventricular effective refractory period, and cycle length of induced ventricular tachycardia. After the addition of intravenous procainamide to amiodarone the QRS duration, rate-corrected QT interval, and, in six of eight patients, ventricular tachycardia cycle length were significantly increased compared with control or either drug alone, suggesting additive electrophysiologic effect. However, acceleration of induced ventricular tachycardia occurred in one patient with combined treatment, suggesting a potential for adverse electrophysiologic interactions. These findings indicate that amiodarone has pharmacokinetic and electrophysiologic interactions with procainamide and suggest that the intravenous dose of procainamide be reduced by 20% to 30% during concurrent drug administration.


In vitro radioisotope precursor incorporation into ribonucleic acid and protein in dystrophic mouse gastrocnemius muscle (C57 BL/6J dy2J/dy2J).
An in vitro tissue slice technique has been developed and used to compare radioisotope precurosr incorporation into RNA and protein in normal and dystrophic mouse gastrophic muscle. Significant differences are observed with both RNA and protein when incorporation is measured on a fresh weight of muscle basis. Specific activity comparisons show significantly increased incorporation with protein but not with RNA. A comparison of the results with in vivo studies has been made. The in vitro system developed is applicable to the study of macromolecular metabolism in normal and diseased human muscle tissue.


Prognostic utility of serum CRP levels in combination with CURB-65 in patients with clinically suspected sepsis: a decision curve analysis.
The prognostic utility of serum C reactive protein (CRP) alone in sepsis is controversial. We used decision curve analysis (DCA) to evaluate the clinical usefulness of combining serum CRP levels with the CUBR-65 score in patients with suspected sepsis. Retrospective cohort study. Emergency department (ED) of an urban teaching hospital in Japan. Consecutive ED patients over 15 years of age who were admitted to the hospital after having a blood culture taken in the ED between 1 January 2010 and 31 December 2012. 30-day in-hospital mortality. Data from 1262 patients were analysed for score evaluation. The 30-day in-hospital mortality was 8.4%. Multivariable analysis showed that serum CRP ≥150 mg/L was an independent predictor of death (adjusted OR 2.0; 95% CI 1.3 to 3.1). We compared the predictive performance of CURB-65 with the performance of a modified CURB-65 with that included CRP (≥150 mg/L) to quantify the clinical usefulness of combining serum CRP with CURB-65. The areas under the receiver operating characteristics curves of CURB-65 and a modified CURB-65 were 0.76 (95% CI 0.72 to 0.80) and 0.77 (95% CI 0.72 to 0.81), respectively. Both models had good calibration for mortality and were useful among threshold probabilities from 0% to 30%. However, while incorporating CRP into CURB-65 yielded a significant category-free net reclassification improvement of 0.387 (95% CI 0.193 to 0.582) and integrated discrimination improvement of 0.015 (95% CI 0.004 to 0.027), DCA showed that CURB-65 and the modified CURB-65 score had comparable net benefits for prediction of mortality. Measurement of serum CRP added limited clinical usefulness to CURB-65 in predicting mortality in patients with clinically suspected sepsis, regardless of the source.


Giant vesicle formation through self-assembly of chitooligosaccharide-based graft copolymers.
A simple approach is described for the preparation of chitooligosaccharide-based giant vesicles with variable size by simply tuning the water content in the water-dioxane mixture, by which reactive vesicles with diameters in the range of 0.5-400 microm were easily prepared.


Bioelectrochemical approach for enhancing lignocellulose degradation and biofilm formation in Geobacillus strain WSUCF1.
Investigations on microbial electrocatalysis as a strategy for enhancing the rates of substrate utilization leading to enhanced yield of biomass and enhanced biofilm formation are reported. A thermophilic Geobacillus sp. strain WSUCF1 (60 °C), a potential lignocellulose degrading microorganism was used as the electrocatalyst. Glucose, cellulose, and corn stover were used as the feedstocks. The results of this investigation showed that applying the oxidation potential of -0.383 mV (vs PRE) increased the glucose utilization and COD removal by 25.5% and 29.7% respectively. The bioelectrocatalysis strategy also increased the biomass yield by 81.2, 42.1, and 49.5% in the case of systems fed with glucose, cellulose, and corn stover, respectively, when compared with the systems without applied oxidation potential. This is the first work reporting the effects of applied oxidation potential on increasing the rates of degradation of lignocellulosic biomass and enhanced biofilm formation.


Studies on bovine insulin with methyl vinyl ketone. Isolation of crystalline A1-3-oxobutyl derivative of bovine insulin.
Reaction of methyl vinyl ketone with bovine insulin affords, amongst others, a crystalline A1-(3-oxobutyl)insulin. This retains full biological activity in the mouse convulsion assay. The presence of zinc ions changes the course of the above reaction, and illustrates the use of zinc as a "blocking function".


Age at menopause and all-cause and cause-specific dementia: a prospective analysis of the UK Biobank cohort.
Are there associations between natural or surgical menopause and incident dementia by age at menopause? Compared to age at menopause of 46-50 years, earlier natural menopause (≤40 and 41-45 years) was related to higher risk of all-cause dementia, while a U-shape relationship was observed between age at surgical menopause and risk of dementia. Menopause marks the end of female reproductive period. Age at menopause reflects the length of exposure to endogenous estrogen. Evidence on the association between age at natural, surgical menopause, and risk of dementia has been inconsistent. A population-based cohort study involving 160 080 women who participated in the UK Biobank study. Women with no dementia at baseline, and had no missing data on key exposure variables and covariates were included. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs on the association of categorical menopause age with incident all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VD). Restricted cubic splines were used to model the non-linear relationship between continuous age at natural, surgical menopause, and risk of dementia. In addition, we analyzed the interaction effect of ever-used menopausal hormone therapy (MHT) at baseline, income level, leisure activities, and age at menopause on risk of dementia. Compared to women with age at menopause of 46-50 years, women with earlier natural menopause younger than 40 years (1.36, 1.01-1.83) and 41-45 years (1.19, 1.03-1.39) had a higher risk of all-cause dementia, while late natural menopause >55 years was linked to lower risk of dementia (0.83, 0.71-0.98). Compared to natural menopause, surgical menopause was associated with 10% higher risk of dementia (1.10, 0.98-1.24). A U-shape relationship was observed between surgical menopause and risk of dementia. Women with surgical menopause before age 40 years (1.94, 1.38-2.73) and after age 55 years (1.65, 1.21-2.24) were both linked to increased risk of all-cause dementia. Women with early natural menopause without ever taking MHT at baseline had an increased risk of AD. Also, in each categorized age at the menopause level, higher income level or higher number of leisure activities was linked to a lowers risk of dementia. Menopausal age was based on women's self-report, which might cause recall bias. Women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures to delay the development of dementia. This work was supported by the Start-up Foundation for Scientific Research in Shandong University (202099000066), Science Fund Program for Excellent Young Scholars of Shandong Provence (Overseas) (2022HWYQ-030), and the National Natural Science Foundation of China (82273702). There are no competing interests. N/A.


Usefulness of Serial 12-Lead Electrocardiograms in Predicting 30-Day Outcomes in Patients With Undifferentiated Chest Pain (the ASAP CATH Study).
An initial electrocardiogram (ECG) and serial troponin measurements are both independently and incrementally predictive of acute coronary syndrome in patients presenting with undifferentiated chest pain in the Emergency Department (ED). However, it is unclear if serial (ECGs) add significant to the contemporary diagnostic evaluation of this patient group. The ASAP CATH study was a single center, prospective study that enrolled patients presenting to an ED with undifferentiated chest pain. In addition to standard clinical evaluation, serial ECGs were performed at 90-minute intervals to evaluate whether serial changes suggestive of ischemia developed (Q waves, ST elevation or depression, or T-wave inversion). Total 365 subjects were enrolled from March 2014 to May 2015. Serial ECG changes developed in 6.6% (n = 24 of 365), the most common being the development of T-wave inversion (66.7%, n = 16 of 24). The sensitivity and positive predictive value of serial ECG changes were poor (<30%), with a less areas under the curve (0.55) compared with serial troponins alone (0.83). The addition of serial ECG changes to Thrombolysis In Myocardial Infarction risk scoring showed a decrease in the net reclassification index for major adverse cardiovascular events (-0.04, p <0.1) and was not significant for the prediction of major adverse cardiovascular events and/or acute coronary syndrome in 30 days (-0.003, p = 0.94). In conclusion, routine serial ECG evaluation for patients presenting with undifferentiated chest pain in the ED may not significantly improved diagnostic prognosis beyond current standard evaluation modalities.


Rectalepidural fistula complicating Crohn's enterocolitis.
A previously unreported complication of a patient with Crohn's enterocolitis and internal fistulation is presented. The patient presented with meningeal signs in the lumbosacral region, fever, and sepsis. Computerized axial tomography revealed air in the epidural space, and a presumptive diagnosis of rectalepidural fistula was made. Surgical management included a diverting end sigmoid colostomy and presacral drainage.


Distribution of EGFR Mutations in 10,607 Russian Patients with Lung Cancer.
This study was aimed to evaluate distribution of epidermal growth factor receptor (EGFR) mutations in a large series of Russian lung cancer (LC) patients. 10,607 LC samples were considered for EGFR analysis; EGFR status was successfully determined in 10,426 cases (98.3 %), indicating relatively low failure rate. EGFR mutations (ex19del and L858R) were detected in 1759/8716 (20.2 %) adenocarcinomas, 28/669 (4.2 %) squamous cell carcinomas (SCC) and 8/119 (6.7 %) large cell carcinomas. The occurrence of EGFR mutations in adenocarcinomas gradually increased with age, being attributed mainly to the increment of the L858R frequency in non-smokers (patients aged 18-30 years: 1/27 (3.7 %); 31-40 years: 5/98 (5.1 %); 41-50 years: 18/276 (6.5 %); 51-60 years: 102/944 (10.8 %); 61-70 years: 138/1011 (13.7 %); 71-80 years: 85/496 (17.1 %); 81-100 years: 5/27 (18.5 %); p < 0.0001). The EGFR mutation was detected in 804/2107 (38.2 %) non-smoking women versus 125/806 (15.5 %) non-smoking men (p < 0.0001), while the corresponding figures for smokers were 60/273 (22.0 %) versus 147/2214 (6.6 %) (p < 0.0001). The obtained gender-related data differ from the estimates obtained in Asian studies; they indicate that increased prevalence of EGFR mutations in white females may not be entirely attributed to the low prevalence of smoking, but is likely to be related to gender factors per se. Biological causes of distinct age- and gender-related distribution of EGFR mutations in LC deserve further investigation.


Immunization with anticardiolipin cofactor (beta-2-glycoprotein I) induces experimental antiphospholipid syndrome in naive mice.
Beta-2-GPI is a 50 kDa glycoprotein which is known to be a serum co-factor, with a role in determining the binding of pathogenic anticardiolipin antibodies to phospholipids. Immunization of naive mice with beta-2-GPI resulted in elevated levels of antibodies directed against negatively charged phospholipids (cardiolipin, phosphotidylserine, phosphatidylinositol). The presence of increased titres of antiphospholipid antibodies in the sera of the mice was later followed by prolonged activated partial thromboplastin time (APTT), thrombocytopenia, and when the mice were mated, by a high percentage of fetal resorptions in the uterus. These data point to the ability of beta-2-GPI to induce pathogenic anti-cardiolipin antibodies following active immunization.


Ursodeoxycholic acid and bezafibrate were useful for steroid-refractory, immune-related hepatitis: a case report.
Immune checkpoint inhibitors have shown clinically significant antitumor efficacy and have been approved for the treatment of various kinds of advanced malignancies. On the other hand, these immunotherapies show unique adverse events, termed "immune-related adverse events," which are distinctly associated with conventional cytotoxic chemotherapy. Hepatotoxicity is recognized as an immune-related adverse event; prompt treatment with corticosteroids is recommended. However, some cases are refractory to steroids. Here, we report the first case (to our knowledge) of steroid-refractory immune-related hepatitis that was successfully treated with ursodeoxycholic acid and bezafibrate. A 68-year-old Asian man, came to our hospital for the treatment of malignant melanoma involving the gingiva and presenting with multiple lymph node and bone metastases was administered nivolumab as a first-line treatment. Two months into treatment, the patient developed diarrhea as a result of immune-related colitis; the colitis was treated successfully with prednisolone 60 mg/ day, resulting in improvement in the patient's symptoms. However, when steroids were being tapered, acute elevation of liver enzymes was observed. Autoimmune hepatitis was suspected as an immune-related adverse event, and treatment with intravenous prednisolone 60 mg/ day was reinitiated. However, restoration of the steroid treatment failed to improve the patient's liver enzymes. On the basis of histological findings from liver biopsy and exclusion of other etiologies such as viral infection and other drug-induced hepatitis, steroid-refractory hepatic immune-related adverse event was deemed the most likely cause of the patient's acute hepatitis. In general, mycophenolate mofetil or tacrolimus is known to provide benefits in cases of steroid-refractory hepatitis. We therefore decided to add oral ursodeoxycholic acid and bezafibrate in consideration of the patient's background of repeated aspiration pneumonia. Administration of this regimen resulted in an improvement in liver function, which remained normal even after tapering of prednisolone. Ursodeoxycholic acid and bezafibrate may be useful for treatment of steroid-refractory immune-related adverse event hepatitis.


Awareness, perceptions and attitudes toward medication-related osteonecrosis of the jaw among physicians who treat osteoporosis.
Osteoporosis is the most common indication for antiresorptive drugs (ARDs). Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of ARDs. Multiple risk factors can increase the risk of MRONJ, one of which is the duration of ARD intake, which is usually prolonged for osteoporosis cases. Prevention of MRONJ relies on collaborative care between treating physicians and dental practitioners. Therefore, knowledge about MRONJ and its prevention strategies is crucial for both teams. This study aimed to assess the knowledge and attitudes of physicians toward MRONJ in osteoporosis patients. Another aim was to develop recommendations for the prevention of MRONJ. Through an online survey, basic information such as the practice location, training, knowledge, perceptions, and attitudes of physicians regarding ARDs and MRONJ in osteoporosis patients was collected. Statistical analysis was performed for all variables, and their correlations were explored. A total of 221 physicians participated in the survey: 34.8% were rheumatologists, 25.3% were endocrinologists, 8.6% were family medicine physicians, 5.9% were orthopedists, and 5.9% were internal medicine physicians. Of them, 58.0% reported more than 6 years of experience. Only 78.7% were aware of MRONJ and recognized that bisphosphonates (BPs) can contribute to MRONJ. In contrast, 56.0% recognized denosumab as a causative factor for MRONJ. Duration of ARD therapy and pre- and post-ARD dental care were known to influence the risk of MRONJ by 62% and 65.6% of the participants, respectively. Only 41.6% and 31.2% of participants informed patients about MRONJ prior to BP and denosumab therapy, respectively. Only 25.3% and 20.8% referred patients to dentists before BP and denosumab therapy, respectively. Overall, 65.6% of the participants had a negative attitude toward MRONJ, and 34.4% had a positive attitude. A positive attitude was mostly observed among rheumatologists (55.8%) compared to other specialists (p <0.001). More years of experience were associated with a higher level of knowledge and positive attitude. The findings of this study identified a notable gap in the awareness, knowledge and attitudes of physicians regarding MRONJ in osteoporosis patients. Continuing education programs about ARDs and MRONJ risk are highly recommended.


Dose-dependent changes in the rat cochlea following aminoglycoside intoxication. I. Physiological study.
The dose-dependent effects of amikacin on the rat cochlea were studied electrophysiologically using CAP audiograms, amplitude and latency-intensity curves, and CAP tuning curves using a forward masking procedure. The animals were given a daily subcutaneous injection of amikacin in doses ranging from 100 to 1000 mg/kg, for five consecutive days, and were tested one month after the end of the treatment. No functional evidence of ototoxicity was found in animals treated with 100 and 200 mg/kg per day doses of amikacin. The first electrophysiological changes were observed with doses of 300-600 mg/kg per day. They consisted of a broadening of the tip and a hypersensitivity of the tail of the CAP tuning curves, without a change in the CAP threshold sensitivity and latency. Animals treated with 700 mg of amikacin showed an elevation of the tip of the CAP tuning curves and an increase in CAP latency. The classical feature of antibiotic ototoxicity was observed in animals given 800 mg/kg per day of amikacin with an increase in CAP threshold sensitivity and latency, a disruption of the CAP amplitude-intensity function, and a clear hyposensitivity of the CAP tuning curves. These results are discussed in the light of anatomical findings described in a companion paper.


HLA-DR antibodies in transfusion-related acute lung injury (TRALI): a case report.
Transfusion-related acute lung injury (TRALI) is a serious adverse consequence of blood product transfusion. Cases of TRALI have gone unrecognized or misdiagnosed, since the symptoms can be confused with other transfusion-related events or with non-transfusion related comorbidities. Suspected cases of TRALI may be insufficiently investigated, and mild or moderate cases may not be investigated or reported at all. We report here the case of a 73-year man who developed TRALI following a transfusion of packed red blood cells (pRBCs) mediated by HLA class II antibodies (HLA-DR) detected by luminex technology. A very few cases of TRALI have been described being caused by HLA class II antibodies without the simultaneous presence of anti-HLA class I antibodies. Technology for antibody detection has increased the power and the specificity, especially with the use of flow cytometry with a better definition of the antigen/antibody pairs that have resulted in TRALI episodes. In this sense, HLA class II antibodies can exactly be detected with these methods and have surely been underestimated until now.


Malignant pancreatic oncocytoma. An unusual cause of organic hypoglycemia.
A case of malignant islet-cell tumor with oncocytic features occurring in a 54-year-old woman with symptoms of organic hypoglycemia is reported. The tumor was composed of ribbons of cells arranged in an endocrine pattern. The cytoplasm of these cells was eosinophilic and finely granular. Ultrastructurally, the cells contained numerous mitochondria and dense-core neurosecretory granules. Tumor cells were focally immunoreactive for neuron-specific enolase, insulin, glucagon and VIP. Capillaries invasion and metastases to lymph nodes argued in favor of malignancy but there was no subsequent malignant involvement during a 3-year follow-up after surgery. Such insulinomas with oncocytic features have not been previously described. Endocrine features in oncocytomas of the pancreas and of other locations are discussed.


Graphene oxide/alginate/silk fibroin composite as a novel bionanostructure with improved blood compatibility, less toxicity and enhanced mechanical properties.
For biomedical applications, the design and synthesis of biocompatible nanostructures, are considered as critical challenges. In this study, graphene oxide (GO) was covalently modified by natural sodium alginate (Alg) polymer. By adding silk fibroin (SF) to this nanostructure, a hybrid nanobiocomposite (GO/Alg/SF) was resulted and its unique features were determined using FT-IR, EDX, FE-SEM, XRD and TG analyses. Because of using less toxic and high biocompatible materials, specific biological results were achieved. The cell viability of this novel nanostructure was 89.2 % and its hemolytic effect was less than 6% while the highest concentration (1000 μg/mL) of this nanostructure was chosen for these purposes. Also, high mechanical properties including the compressive strength (0.87 ± 0.034 (MPa)) and the compressive modulus (2.25 ± 0.091 (MPa)) were exposed. This nanostructure can be considered as a scaffold for wound dressing applications due to the mentioned properties.


Secondary Metabolites Produced by an Endophytic Fungus Pestalotiopsis microspora.
An endophytic fungus Pestalotiopsis microspora isolated from the fruits of Manilkara zapota was cultured in potato dextrose broth media. Chromatographic separation of the EtOAc extract of the broth and mycelium led to the isolation of a new azaphilonoid named pitholide E (1), in addition to previously identified pitholide B (2), pitholide D (3), pestalotin (LL-P880α) (4), PC-2 (5), LL-P880β (6), tyrosol (7) and 4-oxo-4H-pyran-3-acetic acid (8). An endophytic fungus P. microspora from M. zapota and the isolation of compounds 1-5, 7 and 8 from P. microspora are reported here for the first time.


A puborectal sling in the management of anal incontinence and rectal prolapse.
A review is presented of 11 years experience in the use of a synthetic puborectal sling in the treatment of rectal prolapse and faecal incontinence. This perineal approach operation has been performed on 24 patients from 1973 to 1984. In over 60% of the patients rectal prolapse and anal incontinence were controlled.


Vibrational spectroscopic, molecular docking and density functional theory studies on 2-acetylamino-5-bromo-6-methylpyridine.
Conformational and molecular docking analysis of 2-acetylamino-5-bromo-6-methylpyridine molecule was carried out and the vibrational spectral analysis was also carried out using experimental and theoretical methods. The calculated and experimentally observed vibrational frequencies of the molecule were assigned and compared. The pyridine ring CH stretching and CH3 stretching vibrational modes were shifted towards higher wavenumber (blue shift). The C=O stretching vibrational frequency was shifted towards lower wavenumber (red shift). Ultraviolet-visible spectrum of the molecule simulated theoretically was further validated experimentally. Molecular reactivity and stability were investigated using the frontier molecular orbital analysis and the related quantum chemical molecular properties. Natural bond orbital analysis and the structure activity relations were also studied to confirm the bioactivity of the molecule. Anticancer activity was examined based on molecular docking analysis and it has been identified that the AABMP molecule can act as a good inhibitor against lung cancer.


Comprehensive analysis of the expression levels and prognostic values of PRDX family genes in glioma.
Gliomas are a histologically and molecularly heterogeneous group of neoplasms accounting for 80% of malignant primary brain tumors. Growing evidence suggests that production of reactive oxygen species (ROS) is linked to glioma pathogenesis, although it is still unclear whether it is a cause or an effect of this process. Peroxiredoxins (PRDXs), a family of six antioxidant proteins, may promote or inhibit carcinogenesis, depending on the tumor type and stage. The current knowledge on their expression, regulation and functions in glioma is scarce. In this study, a comprehensive analysis of PRDXs expression in distinct glioma subtypes and non-tumor brain tissues was conducted using gene expression data from The Cancer Genome Atlas (TCGA), REpository for Molecular BRAin NeoplasiaDaTa (REMBRANDT), The Chinese Glioma Atlas (CGGA) and Gene Expression Omnibus (GEO) datasets. The association between gene expression and patient survival was investigated. DNA methylation, mutations, copy number alterations of deregulated PRDXs as well as the correlation between gene expression and tumor-infiltrating immune cells were assessed. The analysis revealed overexpression of PRDX1, PRDX4, and PRDX6 in most histological glioma types compared to the non-tumor tissues, while PRDX2, PRDX3 and PRDX5 expression remained unaltered. The expression of PRDX4 and PRDX6 was higher in mesenchymal than proneural and classical glioma subtypes. Moreover, lower expression of PRDX1, PRDX4 and PRDX6 was observed in tumors with a glioma CpG island methylator phenotype (G-CIMP) compared to non-G-CIMP tumors, as well as in isocitrate dehydrogenase (IDH) mutant and 1p/19q co-deleted gliomas compared to the wild-type counterparts. High expression of PRDX1, PRDX4 or PRDX6 correlated with poor survival of glioma patients. PRDX1 and PRDX6 displayed a positive correlation with different immune cell population in low grade gliomas and, to a lesser extent, in glioblastoma. PRDX1 expression exhibited negative correlation with DNA methylation. These results indicate that high expression of PRDX1, PRDX4 and PRDX6 is associated with poor outcome in gliomas.


Effects of the nitrification inhibitor nitrapyrin and mulch on N2O emission and fertilizer use efficiency using 15N tracing techniques.
Nitrous oxide (N2O), is a potent greenhouse gas (GHG) that shares 7% of global warming around the world. Among different sources, agricultural systems account for approx. 60% of global anthropogenic N2O emissions. These N2O emissions are associated with the activity of nitrifiers and denitrifiers that contribute to >4 Tg (teragrams) N2O-N emission per year. Application of nitrogen (N) fertilizers and manures in agricultural fields plays an imperative role in this regard. On the other hand nitrification inhibitors are an effective approach to minimize N2O-N emissions from agricultural fields. Here we examined the effects of applying urea with a nitrification inhibitor (Ni) nitrapyrin and mulch (Mu) on urea transformation, nitrous oxide (N2O) emissions, grain yield and nitrogen (N) uptake efficiency. The treatments include a control (zero N), urea (U) applied at 200 kg N ha-1, U + Ni (Ni applied at 700 g ha-1), U+ Mu (Mu applied at 4 t ha-1) and U + Ni + Mu. The N2O emission factor (EF) was 66% and 75% when U and Mu were applied, respectively. Yield-scaled N2O emissions were lower in U and Mu by 45% and 55%, respectively. The Ni coupled with Mu enhanced urea-15N recovery by 58% and wheat grain yield by 23% and total N uptake by 30% compared with U alone. In conclusion, Ni usage is an effective strategy to mitigate N2O emissions under field conditions.


Evolution of Tembusu Virus in Ducks, Chickens, Geese, Sparrows, and Mosquitoes in Northern China.
Tembusu virus (TMUV) is a contagious pathogen from fowl that mainly infects ducks and geese, causing symptoms of high fever, loss of appetite, retarded growth, neurological symptoms, severe duck-drop syndrome, and even death. During an epidemiological investigation of TMUV in Northern China, we isolated 11 TMUV strains from ducks, chickens, geese, sparrows, and mosquitoes (2011⁻2017). Phylogenetic analysis of the open-reading frames of genes revealed that these strains clustered into Chinese strains II. The nucleotide and amino acid homologies of NS1 of the strains ranged between 85.8⁻99.8% and 92.5⁻99.68%, respectively, which were lower than those of E (86.7⁻99.9% and 96.5⁻99.9%, respectively), NS3 (87.6⁻99.9% and 98.2⁻99.8%, respectively), and NS5 (86.5⁻99.9% and 97.8⁻99.9%, respectively). Predictions of the tertiary structure of the viral proteins indicated that NS1 in 4 of 11 strains had a protein structure mutation at 180TAV182 that changed a random crimp into an alpha helix. The protein of 6 of 11 strains had a glycosylation site mutation from NTTD to NITD. Furthermore, epidemiological data suggested that TMUV has been circulating in half of China's provinces (17 of 34). Our findings, for the first time, have identified the NS1 protein as a potential hypervariable region for genetic evolution. Additionally, the territorial scope of the virus has expanded, requiring strict bio-security measures or a multivalent vaccine to control its spread.


A framework for P-cycle assessment in wastewater treatment plants.
Phosphorus (P) in wastewater has a variety of negative effects and is usually permanently lost as a non-renewable resource. To mitigate future P shortage, P must be recovered from wastewater, preferably by bio-based technologies to avoid toxic side streams. A standardized procedure for the determination of P types and P concentrations in all liquid and solid process stages was established, which is applicable to all full-scale wastewater treatment plants (WWTPs). Based on this, an equally universal calculation framework for P-cycle assessment based on volume flow and mass load rates was designed to identify the most promising process streams for biological P recovery. As an example, in 16 process streams of a typical WWTP, concentrations of free, bound and total P were calculated and microbial communities were analyzed by flow cytometry over 748 days. The most promising process streams for the recovery of free P were anaerobic digester sludge, centrate and the water-extracts of the biosolids with 0.510 kg P m-3, 0.075 kg P m-3 and 1.023 kg P m-3, while the best process streams for the recovery of bound P were return sludge, excess sludge, anaerobic digester sludge, and the solids of the biosolids with 0.300 kg P m-3, 0.268 kg P m-3, 0.213 kg P m-3 and 1.336 kg P m-3, respectively. Microorganisms capable of P accumulation were active in all process stages and it was observed that chemical P precipitation antagonizes biological P removal. The framework for P-cycle assessment was able to identify process streams that are economically viable to make future in-stream technologies for biological P removal feasible.


Clinical implications of ctDNA for EGFR-TKIs as first-line treatment in NSCLC.
This study aimed to explore the clinical implications of ctDNA for epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as the first-line treatment in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) in real-world settings. A total of 122 patients with NSCLC who underwent tissue and liquid next generation sequencing (NGS) tests were included. 66 patients with detected EGFR mutation in both tumor-tissue and plasma were included into the EGFRt+, p+ group, and 56 patients with EGFR mutation detected only in tumor-tissue were included into the EGFRt+, p- group. The differences in clinical characteristics, concomitant mutations and prognosis between the two groups were compared. The detection rate of the EGFRt+, p+ group was 54.1% (66/122). EGFRt+, p+ in the NGS test was particularly relevant to the size of tumors, liver metastasis, bone metastasis and TP53 mutation. In patients with TP53 mutation in ctDNA, the detection rate of EGFR mutation in ctDNA was up to 91.3%. EGFRt+, p+ could be an independent prognostic factor for first-line EGFR-TKIs treatment. Combination therapy seems to be a promising approach to improve the outcome for EGFRt+, p+ (P = 0.017, HR 0.509 [95% CI 0.288-0.897]). Moreover, the combination of TP53 mutated status and EGFRm status in plasma showed a better completion of risk stratification for PFS (Log-rank P < 0.001). Co-detection of EGFR mutation in tumor tissue and plasma is an independent prognostic factor for first-line EGFR-TKIs treatment. Moreover, combination therapy could be a promising approach to improve the outcome for these patients.


Quantitative Assessment of the in vivo Dissolution Rate to Establish a Modified IVIVC for Isosorbide Mononitrate Tablets.
A modified in vitro-in vivo correlation (IVIVC) of the oral solid dosage forms has been proposed as a linear correlation between in vitro and in vivo dissolution. Nevertheless, the analysis of in vivo dissolution is limited by the lack of available methods. In this proof-of-concept study, a novel pharmacokinetic (PK) model containing the in vivo dissolution process and its quantification was presented to directly estimate the in vivo dissolution rate constant (kd). The new model was validated with a hypothetical oral solution (kd → +∞). The accuracy of the new method was clarified by comparing with the relatively true value of kd from the literature. Isosorbide mononitrate (ISMN) was used as a model drug to explore the practicability of the novel method. The dissolution capacities of ISMN reference and test tablets were discriminated by an improved in vitro dissolution method. Following the human PK studies, the kd values and corresponding in vivo dissolution profiles of two formulations were obtained using the novel method. Finally, a modified level A IVIVC between in vitro and in vivo dissolution of ISMN tablets was established, which is expected to guide the optimization of the tablet formulation containing ISMN.


Poly N-acetyllactosamine substitutions on N- and not O-oligosaccharides or Thomsen-Friedenreich antigen facilitate lung specific metastasis of melanoma cells via galectin-3.
Galectin-3 on vascular endothelium has been shown to facilitate lung specific metastasis. Metastatic variants of B16 melanoma were chosen to identify specific ligands that mediate lung colonization via galectin-3. Flow cytometry showed that, galectin-3 binding to cells correlates with surface expression of poly N-acetyllactosamine (polylacNAc) but not with other reported ligands, e.g. Thomsen-Friedenreich (T/Tn) antigen. Immobilized galectin-3 promoted adhesion of melanoma cells in a metastasis dependent manner. Moreover, adhesion and galectin-3 binding to cells were specifically inhibited with lactose. These properties together with lung metastasis were inhibited with N-glycosylation inhibitor Swainsonine (SW), whereas, O-glycosylation inhibitor Benzyl-alpha-N-acetylgalactosamine (BG) had no effect. BG treatment significantly increased expression of T/Tn antigen on low metastatic cells; however, had no effect on their metastatic potential. The studies very comprehensively demonstrate the importance of polylacNAc substitutions on N-oligosaccharides in galectin-3 mediated lung metastasis.


Spin regulation for efficient electrocatalytic N2 reduction over diatomic Fe-Mo catalyst.
Electrocatalytic nitrogen reduction reaction (eNRR) is a promising method for the sustainable production of ammonia as an alternative to the traditional energy-intensive Haber-Bosch process. In this work, an efficient strategy by atomic spin regulation to promote NRR through Fe-transition metal (TM) hybrid heteronuclear dual-atom catalysts has been studied. By means of DFT computations, the stability, activity, and selectivity of 30 kinds of Fe-based dual-atoms anchored on N-doped porous graphene are systematically investigated to evaluate their catalytic performance. Fe/MoNC is screened as an excellent NRR catalyst with the limiting potentials of 0.63 V, and also suppresses HER. In the Fe/MoNC, the neighboring Fe atom regulates the spin state of the Mo center in MoN4 from high-spin state (2.63 μB) to medium-spin state (0.74 μB), which can effectively relieve the strong overlapping between Mo 4d orbital with the NxHy intermediates, promote the desorption of reaction product, and eventually achieve a lower limiting potential. Interestingly, the archetype of the active center of nitrogenase is also a FeMo-cofactor, which is consistent with our screening results. The work may provide new insight into the mechanism of nitrogenase, and promote the rational design of efficient NRR catalysts by atomic spin regulation.


Carboxymethylated cyclosophoraose as a novel chiral additive for the stereoisomeric separation of some flavonoids by capillary electrophoresis.
A carboxymethylated cyclosophoraose (CM-Cys) was synthesized by the chemical modification of neutral Cys, which was isolated from Rhizobium trifolii TA-1. CM-Cys was successfully applied as a novel chiral selector for the separation of some flavonoids including catechin, 3,5,7,3',4'-pentahydroxyflavanone, hesperidin, hesperetin, isosakuranetin, naringenin, naringin, and eriodictyol. The effects of pH, chiral additive concentration, and temperature on resolution and migration time were also studied.


Diminished neutralization responses towards SARS-CoV-2 Omicron VoC after mRNA or vector-based COVID-19 vaccinations.
SARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection against infection. The novel variant of concern (VoC) Omicron BA.1 and its sub-lineages have the largest number of amino acid alterations in its Spike protein to date. Thus, they may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals in particular in those who have only received a primary immunization scheme. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron sub-lineages BA.1, BA.2, BA.2.12.1, BA.3, BA.4/5, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (96-100%) towards the SARS-CoV-2 B.1 isolate, and minor to moderate reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant and its sub-lineages had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron BA.1 and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination, vector-based AZD1222 and Ad26.CoV2.S performed less well with peak responder rates of 48%, 56% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argue for booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based primary immunization scheme.


Does insulin-like growth factor 1 receptor (IGF-1R) targeting provide new treatment options for chordomas? A retrospective clinical and immunohistochemical study.
The overall prognosis of chordoma is poor, and current treatment options are limited. The insulin-like growth factor 1 receptor (IGF-1R) pathway is important for cell signalling, and attractive for selective inhibition. We investigated the expression of IGF-1R and its ligands, IGF-1 and IGF-2, in a series of 50 chordomas, in order to assess whether IGF-1R-signalling could be a potential target for specific inhibition in chordomas. Fifty chordomas (34 primary tumours, 16 recurrences) from 44 patients were evaluated immunohistochemically for the expression of IGF-1R, IGF-1 and IGF-2. Thirty-eight chordomas (76%) expressed IGF-1R, 46 (92%) expressed IGF-1 and 25 (50%) expressed IGF-2. Semi-quantitative analyses revealed a moderate to strong staining intensity in ≥ 50% of tumour cells for IGF-1R, IGF-1 and IGF-2 in 18 (36%), 32 (64%) and eight (16%) chordomas, respectively. Tumour volume correlated significantly with IGF-1R-staining intensity in primary chordomas (P = 0.042). IGF-1R and IGF-1 are expressed in the majority of chordomas. IGF-1 expression is much stronger than IGF-2 expression. Patients whose chordomas show a moderate to strong staining intensity in ≥ 50% of tumour cells for IGF-1R (36%) might benefit most from IGF-1R targeting, particularly if they suffer from large and surgically non-resectable chordomas.


Collagen-gelatin scaffold impregnated with bFGF accelerates palatal wound healing of palatal mucosa in dogs.
We have developed a collagen-gelatin sponge (CGS) as a scaffold capable of the sustained release of bFGF to improve the healing process of the existing collagen scaffold. The aim of this study was to evaluate the efficacy of CGS impregnated with basic fibroblast growth factor (bFGF) in palatal wound healing in beagles. Four standardized 6 mm diameter full-thickness wounds were made in the palate of each dog and covered with CGS impregnated with normal saline or bFGF at concentrations of 1 μg/cm2, 7 μg/cm2 and 14 μg/cm2. One and 2 wk after surgery, the wound area, neoepithelium length, thickness, area of regenerated submucosal tissue, and the number and total area of neoformed capillaries were evaluated. Two weeks after implantation, wounds treated with bFGF 7 μg/cm2 and 14 μg/cm2 were completely epithelized, while the length of the neoformed epithelium was significantly longer in the 7 μg/cm2 group. Groups impregnated with bFGF 7 μg/cm2 and 14 μg/cm2 showed promoted regeneration of submucosal tissue 2 wk later. The number and area of neoformed capillaries were significantly higher in the bFGF 7 μg/cm2 group than in other groups. We conclude that palatal wound healing in the bFGF 7 μg/cm2 group was promoted with good neovascularization and showed less contracture than other groups. Our new collagen-gelatin scaffold, CGS, impregnated with bFGF, could be a promising treatment to accelerate the regeneration of palatal mucosa.


Yes SIR! On the structure-inactivity relationships in drug discovery.
In analogy with structure-activity relationships (SARs), which are at the core of medicinal chemistry, studying structure-inactivity relationships (SIRs) is essential to understanding and predicting biological activity. Current computational methods should predict or distinguish 'activity' and 'inactivity' with the same confidence because both concepts are complementary. However, the lack of inactivity data, in particular in the public domain, limits the development of predictive models and its broad application. In this review, we encourage the scientific community to disclose and analyze high-confidence activity data considering both the labeled 'active' and 'inactive' compounds.


A review of emergency equipment carried and procedures performed by UK front line paramedics.
To assess which items of resuscitation equipment are carried on United Kingdom (UK) front line ambulances and what procedures paramedics are able to perform. To compare these findings with those of a previous survey in 1997. Postal survey to the chief executives of all the UK ambulance services and direct comparison with the data from 1997. Nasopharyngeal airway usage (NPA) has increased (21-55%) and the laryngeal mask airway (LMA) (from 10 to 26%). No services employ the Combitube. 94% of services use a Hudson type trauma mask (increase of 17%). One service no longer allows its paramedics to deliver 12-15 l of oxygen. 68% of trust paramedics can perform needle thoracocentesis (increase of 35%). No paramedics perform chest drain insertion. All services have 14G intravenous cannulae available and 45% carry the intraosseous needle (increase of 30%). No services employ the MAST suit. There is an increase by 29% in the use of crystalloids and a decrease in the use of colloids of 22%. 23% of fluid resuscitation protocols are based upon the principles of hypotensive resuscitation. Spinal boards and extrication devices are used by 97% of services. The use of inflatable splints has decreased (38-23%). There has been a minor increase in the use of traction splints to 74% of services. The use of Entonox is universal. Nalbuphine (Nubain) is the most widely used opioid. The use of morphine/diamorphine has doubled to 10% with a further 26% to introduce their use. 29% of services have equipped some vehicles with automatic external defibrillators. The equipment available to UK paramedics and procedures that they may perform continues to expand. There are still variations in the basic management of airway, breathing and circulation care and only some services are keeping up to date with current medical thinking, for example the increasing use of crystalloids and hypotensive resuscitation. It remains to be seen whether the widespread use of Nalbuphine as a first line analgesic may decrease as the use of natural strong opiates becomes more widespread.


Cerebellar nuclear topography of simple and synergistic movements in the alert baboon (Papio papio).
Movements elicited by the stimulation of the cerebellar nuclei were studied in alert baboons chronically prepared. The motor responses were filmed and recorded in eight muscles through chronically implanted electrodes. Two types of motor effects were observed: (1) Simple movements that concerned the unidirectional displacement of a limb segment. (2) Complex movements that involved distinct and frequently noncontiguous muscles were stereotyped and could not be dissociated. These movements are defined as motor synergies. Electromyographic study allowed us to investigate the motor response latencies and the modality of cerebellar control on musculature. Simple movements were due to the activation of muscles within the involved segment in addition to the co-contraction of muscles of a nearby segment. Thus they could be due to a cerebellar control over muscular synergies. Complex movements would correspond to the simultaneous activation of distinct muscular groups and could also be the outcome of a cerebellar control on motor synergies. Thus the effects of the interposed nucleus concern preferably flexor muscles whereas the effects of the dentate nucleus appear to be equally distributed among flexor and extensor muscles. Somatotopic motor localization were evidenced both in the interposed and dentate nuclei: there are somatotopic relations between every region of the interposed nucleus and musculature. As regards the dentate nucleus, two subdivisions were distinguished according to the complexity of elicited motor effects: (A) an antero-medial region from which motor synergies can be elicited. (B) a postero-lateral region giving rise to simple movements, mainly hand movements.


Evaluating automated endmember extraction for classifying hyperspectral data and deriving spectral parameters for monitoring forest vegetation health.
The hyperspectral remote sensing datasets possess high capability in differentiating the spectrally similar features, and thus, they are immensely important in various forestry activities, especially vegetation classifications. But extracting endmembers for data training is a challenging task. The present study is focused on the use of automated endmember extraction technique for deriving endmembers during the unavailability of ground spectra. We used the Sequential Maximum Angle Convex Cone (SMACC) method on EO-1 Hyperion data for endmember extraction in the Barkot forest range of Dehradun district, Uttarakhand which were used for classification of the study area using support vector machine (SVM). Further, we estimated the vegetation health of the region by assigning the threshold weights for various derived environmental variables such as NDVI (Normalised Difference Vegetation Index), CRI (Carotenoid Reflectance Index), Anthocyanin Reflectance Index (ARI), Modified Simple Ratio (MSR), Modified Chlorophyll Absorption Ratio Index (MCARI) and WBI (Water Band Index). Then, to further validate the health of the forest types, we correlated it with the Land Surface Temperature (LST) from LANDSAT 5 ETM + data. The results showed a high classification accuracy of 89.13%. The healthy vegetation area coverage of the area was about 78.6% with most healthy class as Tectona grandis and Shorea robusta and its correlation with LST showed lower temperature range in healthy vegetation areas and vice versa. The study was useful in determining the superiority of SMACC automated endmember extraction and estimating the vegetation health.


Long-term efficacy of brief psychological treatments for common mental disorders in Myanmar refugees in Malaysia: 12-month follow-up of a randomized, active-controlled trial of integrative adapt therapy v. cognitive behavioral therapy.
Long-term efficacy of brief psychotherapies for refugees in low-resource settings is insufficiently understood. Integrative adapt therapy (IAT) is a scalable treatment addressing refugee-specific psychosocial challenges. We report 12-month post-treatment data from a single-blind, active-controlled trial (October 2017-August 2019) where 327 Myanmar refugees in Malaysia were assigned to either six sessions of IAT (n = 164) or cognitive behavioral treatment (CBT) (n = 163). Primary outcomes were posttraumatic stress disorder (PTSD), depression, anxiety, and persistent complex bereavement disorder (PCBD) symptom scores at treatment end and 12-month post-treatment. Secondary outcome was functional impairment. 282 (86.2%) participants were retained at 12-month follow-up. For both groups, large treatment effects for common mental disorders (CMD) symptoms were maintained at 12-month post-treatment compared to baseline (d = 0.75-1.13). Although participants in IAT had greater symptom reductions and larger effect sizes than CBT participants for all CMDs at treatment end, there were no significant differences between treatment arms at 12-month post-treatment for PTSD [mean difference: -0.9, 95% CI (-2.5 to 0.6), p = 0.25], depression [mean difference: 0.1, 95% CI (-0.6 to 0.7), p = 0.89), anxiety [mean difference: -0.4, 95% CI (-1.4 to 0.6), p = 0.46], and PCBD [mean difference: -0.6, 95% CI (-3.1 to 1.9), p = 0.65]. CBT participants showed greater improvement in functioning than IAT participants at 12-month post-treatment [mean difference: -2.5, 95% CI (-4.7 to -0.3], p = 0.03]. No adverse effects were recorded for either therapy. Both IAT and CBT showed sustained treatment gains for CMD symptoms amongst refugees over the 12-month period.


Access to special care dentistry, part 9. Special care dentistry services for older people.
This article looks at three common neurological conditions associated with later years: stroke, Parkinson's disease and dementia. All of them impact on oral health, access to dental services and delivery of dental care, and treatment goals need to be adapted to take into account patients' changing needs, medical status, pattern of recovery or the stage of dementia that they have reached. The article concludes by considering the topic of elder abuse. The dental team may have a role both in identifying abuse and ensuring appropriate action is taken.


Prostaglandin content in human middle ear effusions.
The concentrations of prostaglandins (PGs) were measured by a radioimmunoassay in human middle ear effusions (MEEs) obtained from patients with otitis media with effusions. Each sample of MEE was divided into two groups: serous effusions and mucoid ones. The main PG in both the serous and mucoid effusions was TXB2 (375 and 857 pg/ml, respectively), followed by PGE2 (173 and 459 pg/ml, respectively). Smaller quantities of PGD2 (35 and 64 pg/ml, respectively), PGF2 alpha (139 and 183 pg/ml, respectively), and 6ketoPGF1 alpha (129 and 201 pg/ml, respectively) were also found in the MEEs. The amounts of each PG in the mucoid effusions were 2 or 3 times higher than those found in the serous effusions, while protein concentrations and the profile of these PGs in the MEEs were almost the same in the mucoid and serous groups. These results suggest that PGs may play an important role as a mediator of the inflammatory responses in the pathogenesis of MEEs.


Construction of a DNA Library on Microbeads Using Whole Genome Amplification.
A polymerase chain reaction (PCR) in water droplets with water-in-oil emulsion (emulsion PCR) facilitates parallel amplification of a single-molecule template. The amplified DNA can be immobilized onto microbeads bound to primer DNA. The product, termed a "bead library", has various applications such as next-generation sequencing (NGS) and the directed evolution of various functional biomolecules. Here, we describe a method for genomic library construction on microbeads using emulsion PCR.


Patient Perceptions of Using Clinical Decision Support for Cancer Screening and Prevention: "I wouldn't have thought about getting screened without it."
We sought to gain an understanding of cancer prevention and screening perspectives among patients exposed to a clinical decision support (CDS) tool because they were due or overdue for certain cancer screenings or prevention. Semi-structured qualitative interviews were conducted with 37 adult patients due or overdue for cancer prevention services in 10 primary care clinics within the same health system. Data were thematically segmented and coded using qualitative content analysis. We identified three themes: 1) The CDS tool had more strengths than weaknesses, with areas for improvement; 2) Many facilitators and barriers to cancer prevention and screening exist; and 3) Discussions and decision-making varied by type of cancer prevention and screening. Almost all participants made positive comments regarding the CDS. Some participants learned new information, reporting the CDS helped them make a decision they otherwise would not have made. Participants who used the tool with their provider had higher self-reported rates of deciding to be screened than those who did not. Learning about patients' perceptions of a CDS tool may increase understanding of how patient-tailored CDS impacts cancer screening and prevention rates. Participants found a personalized CDS tool for cancer screening and prevention in primary care useful and a welcome addition to their visit. However, many providers were not using the tool with eligible patients.