Australian student radiographers' experiences and perspectives in general paediatric medical imaging examinations.
Paediatric patients differ from adult patients with respect to anatomy, examination factors, behaviour, and intellectual development, requiring dedicated specialised knowledge and expertise. In the absence of a formal dedicated paediatric medical imaging subspecialty, this study undertook to understand student radiographers' experiences and perspectives on paediatric medical imaging. The study entailed a descriptive cross-sectional survey design entailed a 51-item closed and open-ended response questionnaire using a total sampling method. Data were collected from both under- and postgraduate student radiographers who undertook clinical placement. Data interpretation and analysis involved statistical analysis of close-ended questions and thematic analysis of open-ended questions. The overall response rate was 70%. Most participants acknowledged the importance of dedicated paediatric content as well as the theory content covered. The shortcoming in pre-placement practical component was overcome through varied approaches like observations and attempting through supervision whilst experiencing uncertainty, anxiety and felt unfair to risk the patient. As reported in literature like their qualified counterparts expressed similar challenges in technique adaptation, styles of interactions in gaining cooperation from both the children and parents. They also felt paediatric content and the practicals should be embedded throughout the course offering to not compromise the day-to-day service delivery. The study findings iterate the importance paediatric imaging in the service delivery context. The importance of undertaking these examinations reliant on experiential learning is insufficient to bridge the gap of preparation prior to placement. Collaborative academic and clinical radiography education will ensure that radiography students' dedicated specialised paediatric imaging knowledge and experience are enhanced.


Identification of new candidate genes for spina bifida through exome sequencing.
Neural tube defects are a group of birth defects caused by failure of neural tube closure during development. The etiology of NTD, requiring a complex interaction between environmental and genetic factors, is not well understood. We performed whole-exome sequencing (WES) in six trios, with a single affected proband with spina bifida, to identify rare/novel variants as potential causes of the NTD. Our analysis identified four de novo and ten X-linked recessive variants in four of the six probands, all of them in genes previously never implicated in NTD. Among the 14 variants, we ruled out six of them, based on different criteria and pursued the evaluation of eight potential candidates in the following genes: RXRγ, DTX1, COL15A1, ARHGAP36, TKTL1, AMOT, GPR50, and NKRF. The de novo variants where located in the RXRγ, DTX1, and COL15A1 genes while ARHGAP36, TKTL1, AMOT, GPR50, and NKRF carry X-linked recessive variants. This analysis also revealed that four patients presented multiple variants, while we were unable to identify any significant variant in two patients. Our preliminary conclusion support a major role for the de novo variants with respect to the X-linked recessive variants where the X-linked could represent a contribution to the phenotype in an oligogenic model.


Multiple endocrine neoplasia type 1 presenting as insulinoma, gastrinoma, and postbulbar duodenal ulcers: report of a case.
We report herein the unusual case of a 55-year-old man with multiple endocrine neoplasia type 1 presenting as hyperparathyroidism, hyperpituitarism, insulinoma, and gastrinoma with postbulbar duodenal ulcers. The patient was referred to our hospital for further investigations of nephrolithiasis, acromegaly, and hematemesis. Laboratory studies showed high serum levels of calcium, parathyroid hormone, growth hormone, insulin, gastrin, and prolactin. Computed tomography of the cranial cavity demonstrated an enlargement of the serra turcica and swelling of two parathyroid glands in the neck. Computed tomography and angiography of the abdomen also showed a mass in the head of the pancreas. Endoscopy demonstrated reflux esophagitis, erosive gastritis, and multiple postbulbar duodenal ulcers. We diagnosed this patient as having multiple endocrine neoplasia type 1, with concomitant lesions of the pituitary gland, parathyroid glands, and islet cells of the pancreas. Following excision of the two enlarged parathyroid glands, his serum calcium and parathyroid hormone levels fell to within the normal range. Thereafter, a total gastrectomy was performed to alleviate the frequent bleeding from the upper gastrointestinal tract. However, resection of the pancreatic mass could not be performed owing to severe inflammation around the duodenum, probably induced by the postbulbar duodenal ulcers.


Asthma does not influence the severity of COVID-19: a meta-analysis.
Previous studies have reported a correlation between coronavirus disease-2019 (COVID-19) and asthma. However, data on whether asthma constitutes a risk factor for COVID-19 and the prevalence of asthma in COVID-19 cases still remain scant. Here, we interrogated and analyzed the association between COVID-19 and asthma. In this study, we systematically searched PubMed, Embase, and Web of Science databases for studies published between January 1 and August 28, 2020. We included studies that reported the epidemiological and clinical features of COVID-19 and its prevalence in asthma patients. We excluded reviews, animal trials, single case reports, small case series and studies evaluating other coronavirus-related illnesses. Raw data from the studies were pooled into a meta-analysis. We analyzed findings from 18 studies, including asthma patients with COVID-19. The pooled prevalence of asthma in COVID-19 cases was 0.08 (95% CI, 0.06-0.11), with an overall I2 of 99.07%, p < 0.005. The data indicated that asthma did not increase the risk of developing severe COVID-19 (odds ratio [OR] 1.04 (95% CI, 0.75-1.46) p = 0.28; I2=20%). In addition, there was no significant difference in the incidence of asthma with age in COVID-19 infections [OR] 0.77(95% CI, 0.59-1.00) p = 0.24; I2=29%). Taken together, our data suggested that asthma is not a significant risk factor for the development of severe COVID-19.


Development of the cerebellum with particular reference to cellular differentiation in the external granular layer.
Immunocytochemical evidence of differentiation in developing human cerebellum is presented in this study. Antibodies to neuron specific enolase, neurofilament protein, glial fibrillary acidic protein, vimentin, cytokeratin, epithelial membrane antigen and lymphoid markers, DLC and Leu 7 were used. The external granular layer showed positivity with neuronal markers between 27 weeks gestation and 4 months postnatal, but was negative for all other markers including glial fibrillary acidic protein. Characteristic staining reactions were noted in the other cerebellar layers. Monoclonal antibodies, UJ13A (pan-neuroectodermal marker) and G10 (localising microtubule-associated protein MAP1x) were also used in a limited number of cryostat sections and were positive and negative, respectively, in the external granular layer. The results of this study are discussed in relation to the theory that the external granular layer may be one source of medulloblastomas.


Measuring dental drift and orthodontic tooth movement in response to various initial forces in adult rats.
A method for the quantification of orthodontic tooth movement in the rat is presented. Reliability, sensitivity, and validity were assessed and tooth movement kinetics were determined for initial forces of 20, 40, and 60 gm. The appliance consisted of a 9 mm length of closed coil spring suspended between a cleat and bonded to the occlusal surface of the maxillary first molars and the maxillary incisors. Initial tipping forces were placed by suspending known weights from the anterior end of these coils before fixation to the incisors. Tooth movement was quantified from enlarged cephalograms by measuring the position of a reproducible landmark on the molar cleat with respect to either zygomatic amalgam implants or a barbed broach placed submucosally on the palate. All measurements were made along the molar-incisor vector by projecting at 90 degrees to this line. Validity and sensitivity were assessed by quantifying molar distal drift and comparing these results with reports of bone turnover rates adjacent to distally drifting adult rat molars. Reliability was obtained by estimating the error of a single measurement in a longitudinal study of 12 adult male Sprague-Dawley rats (180 to 200 days) receiving both amalgam and broach implants and a cross-sectional study of 72 animals divided equally into six groups to be killed at 1, 3, 5, 7, 10, and 14 days. No orthodontic forces were used in this portion of the study. Implant stability within the craniofacial complex was assessed by measuring bilateral broaches as a function of time with respect to each other. There were no systematic errors between replicate films for either the amalgam or the broach method. The 95% confidence limit for a single determination of molar position was 62 microns using the amalgams and 47 microns for the broach (p less than 0.001). The latter could be reduced to 23 microns when the average of four independent determinations was used. Homologous implants did not differ with respect to each other in the sagittal plane but did in the transverse plane (p less than 0.01), migrating laterally 9 microns/day. Linear regression analysis of molar distal movement over time predicted 7.7 microns/day distal drift (p less than 0.01), which compared favorably with reports of 6.7 microns/day of alveolar bone turnover during this drifting process. Characteristic three-part cumulative tooth movement kinetics were obtained for the 40 and 60 gm initial force groups. No individual time point at 60 gm differed from its counterpart at 40 gm.(ABSTRACT TRUNCATED AT 400 WORDS)


A study on Candida carriage and cytological evaluation of oral mucosa in human immunodeficiency virus (HIV) patients.
This study was undertaken for identification and prevalence of various oral manifestations seen in the oral cavity of HIV infected patients. A quantitative evaluation of candida was done by counting the colony forming units from the oral cavity of HIV infected and non infected individuals. Further, cytopathological changes were evaluated in the oral mucosa of HIV infected patients. Study group consisted of 30 enzyme linked immunosorbent assay (ELISA) confirmed HIV seropositive patients, while the control group consisted of 10 subjects who were HIV negative (by ELISA).


Usefulness of a small scale indirect 125I-labelled protein A binding assay for detection of monoclonal antibodies against hematopoietic cell surface antigens.
We describe a small-scale solid-phase indirect 125iodine protein A binding assay (IPA) and discuss its usefulness for detection of hematopoietic cell surface antigens and for screening hybridoma clones producing monoclonal antibodies (McAbs) against K562 cell surface antigens correlated with differentiation induced by 12-O-tetradecanoyl phorbol-13-acetate (TPA). This assay was performed in polystyrene Terasaki microtest plates instead of 96-well microtiter plates, using hematopoietic cells attached to the wells by air drying. This method facilitates washing procedures and reduces the radioactive waste. The specificity of this IPA method is as high as those of RIAs and ELISAs generally used. Titration curves of a McAb, My7, specific for CD13 on HL60 and TPA-treated HL60 (HL60-TPA) cells, were linear between the 10(-1) and 10(-4) dilutions. A difference in the CD13 expression between HL60 and HL60-TPA cells could be detected by both IPA and flow cytometry using My7 at 10(-1)-10(-3) dilutions. At the 10(-3) dilution, however, CD13 expressed on HL60 cells was detected by the IPA method but not by flow cytometry. These results show that the sensitivity of IPA is superior to that of flow cytometry. By screening hybridoma clones with this IPA method, we succeeded in producing three interesting and useful McAbs (21H73, 37G7 and 49C12) against K562 cell surface antigens whose expression was altered after the differentiation induced by TPA. We also demonstrated that the IPA method is suitable for cell surface marker analysis of leukemia cells freshly isolated from patients.


Removal of Z-lines and alpha-actinin from isolated myofibrils by a calcium-activated neutral protease.
A calcium-activated factor (CaAF) has been isolated and partially purified from the post-myofibrillar supernatant fraction of rabbit skeletal muscle. The 200-fold purified CaAF hydrolyzed denatured casein, [3-H]acetyl hemoglobin, and N-ethyl[3-H]maleimide-labeled alpha-actinin. The proteolytic activity has a pH optimum at 6.9 and is dependent on the presence of Ca2+ (optimum concentration, 10 mM). Digestion of isolated myofibrils with CaAF results in removal of Z-lines and in a parallel loss of a 90, 000-dalton protein that has a mobility identical with that of alpha-actinin as determined by polyacrylamide gel electrophoresis. A protein with the properties of alpha-actinin (identical electrophoretic mobility, and ability to accelerate the Mg2+-activated ATPase of reconstituted actomyosin) was isolated from the supernatant of CaAF-treated myofibrils. The release of alpha-actinin from myofibrils by the calcium-activated neutral protease occurs in the absence of detectable change in the electrophoretic profiles of the other myofibrillar proteins, or in the ethylene glycol bis(beta-aminoethyl ether)-N, N' tetraacetic acid (EGTA) sensitivity of Mg2+-activated ATPase. In contrast to the specific removal of Z-lines and of alpha-actinin by CaAF, trypsin treatment of myofibrils results in extensive degradation of myosin heavy chains and of the inhibitory component of troponin (TN-I), and in loss of EGTA sensitivity of myofibrillar ATPase. The degradation of TN-I and loss of EGTA sensitivity occur before the Z-line disappearance.


Reliability and validity of the Chinese version of the Copenhagen Multi-Centre Psychosocial Infertility-Fertility Problem Stress Scales.
The aim of this study is to introduce the Copenhagen Multi-Centre Psychosocial Infertility (COMPI)-Fertility Problem Stress Scales (COMPI-FPSS) into China and test its applicability in Chinese infertile population. Infertility-related stress not only influences patients' psychological well-being but is also strongly associated with reduced pregnancy rates and poorer assisted conception outcomes, thus warranting focussed attention. The design used in this study is a cross-sectional survey. A total of 418 participants were recruited by convenience sampling from March to July 2022. The data were randomly divided into two parts: one for item analysis and exploratory factor analysis and the other for confirmatory factor analysis and reliability test. The critical ratio and homogeneity test were used to verify the differentiation and homogeneity of the COMPI-FPSS; the construct validity was determined by explanatory and confirmatory factor analyses; Cronbach's α coefficient and Spearman-Brown coefficient were used to assess the reliability; and criterion validity was expressed using correlation coefficients for the Perceived Stress Scale and the Negative Affect Scale as the validity criteria. The revised Chinese version of COMPI-FPSS has 11 items and 2 dimensions (i.e., personal stress domain and social stress domain). Exploratory factor analysis showed that the cumulative variance contribution rate of the two factors was 68.6%, and confirmatory factor analysis indicated that the model fitted well. The score of the COMPI-FPSS was significantly and positively associated with perceived stress and negative affect. The Cronbach's α coefficient of the total scale was 0.905, and the Spearman-Brown coefficient was 0.836, explaining excellent reliability. The revised Chinese version of COMPI-FPSS shows good reliability and validity, and it can be used to evaluate the infertility-related stress of infertile patients in China.


Impact of Routines and Rituals on Burden of Treatment, Patient Training, Cognitive Load, and Anxiety in Self-Injected Biologic Therapy.
Self-injection of biologics is a mainstay of chronic disease treatment, yet the process of self-injection often causes persistent apprehension and anxiety, distinct from needle phobia. While literature alludes to the role that routines and rituals play in self-injection, there is no comprehensive study on the routines and rituals self-injectors employ, nor of the process by which they are discovered and ingrained. We conducted a mixed-method, observational pilot ethnography study of 27 patients with plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis with and without prior biologic self-injection experience. Patients submitted self-made videos, photos, and projective exercises of an actual biologic self-injection and completed validated instruments to assess burden of treatment. Videos and photos containing routine and ritual elements were thematically categorized based on functional and emotional benefit, and analyzed for differences based on current biologic, dosing frequency, time on current biologic, and burden of treatment measures. During patients' initial at-home injections, training gaps became apparent, leading to a process of experimentation aimed at reducing pain/anxiety, increasing confidence, and building a consistent injection process. Routines were present in 27/27 (100%) patients and anchored the time, place, and process for injection, and incorporated approved use steps for the injection device. Ritual elements served as emotional coping strategies for patients and were present in 21/27 (77.8%) of patients. Our findings suggest that providing patients device training using adult learning principles, teaching routines and rituals concurrently, and providing at-home opportunities for practice with a device trainer may be useful strategies to reduce anxiety, avoid unnecessary experimentation, and improve adherence to injection therapy. While further studies are needed to generalize our findings, we posit that routine and ritual elements can be incorporated into existing patient-clinician interactions or novel digital interventions through mobile medical applications, smart training devices, and connected injection ecosystems.


Celastrol inhibits necroptosis by attenuating the RIPK1/RIPK3/MLKL pathway and confers protection against acute pancreatitis in mice.
Necroptosis is a necrotic form of regulated cell death, which is primarily mediated by the receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) pathway in a caspase-independent manner. Necroptosis has been found to occur in virtually all tissues and diseases evaluated, including pancreatitis. Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium wilfordii (thunder god vine), possesses potent anti-inflammatory and anti-oxidative activities. Yet, it is unclear whether celastrol has any effects on necroptosis and necroptotic-related diseases. Here we showed that celastrol significantly suppressed necroptosis induced by lipopolysaccharide (LPS) plus pan-caspase inhibitor (IDN-6556) or by tumor-necrosis factor-α in combination with LCL-161 (Smac mimetic) and IDN-6556 (TSI). In these in vitro cellular models, celastrol inhibited the phosphorylation of RIPK1, RIPK3, and MLKL and the formation of necrosome during necroptotic induction, suggesting its possible action on upstream signaling of the necroptotic pathway. Consistent with the known role of mitochondrial dysfunction in necroptosis, we found that celastrol significantly rescued TSI-induced loss of mitochondrial membrane potential. TSI-induced intracellular and mitochondrial reactive oxygen species (mtROS), which are involved in the autophosphorylation of RIPK1 and recruitment of RIPK3, were significantly attenuated by celastrol. Moreover, in a mouse model of acute pancreatitis that is associated with necroptosis, celastrol administration significantly reduced the severity of caerulein-induced acute pancreatitis accompanied by decreased phosphorylation of MLKL in pancreatic tissues. Collectively, celastrol can attenuate the activation of RIPK1/RIPK3/MLKL signaling likely by attenuating mtROS production, thereby inhibiting necroptosis and conferring protection against caerulein-induced pancreatitis in mice.


Sarcolemma: transmitter of active tension in frog skeletal muscle.
Maximumn tetanic tension developed by frog muscle fibers was measured before and after they had been injured at one end so as to break myoplasmic continuity but to leave the sarcolemma-tube connection to the tendon. The lateral mechanical coupling between myoplasm and sarcolemma is adequate to bear and transmit the maximum active tension developed during stimulation.


Detection of Helicobacter pylori in the stools of newborn infants.
To investigate the transmission route of Helicobacter pylori, stool specimens of 50 infants 3 days old were studied by a stool antigen immunoassay and polymerase chain reaction (PCR). By PCR, H. pylori DNA was detected in 15 neonates (30%). The stool antigen test was positive in only 1 neonate with a positive PCR. The detection rate of H. pylori DNA in neonates was significantly higher for those with mothers having urines positive for anti-H. pylori IgG antibody (60%) than for those mothers with negative urines (17%) (P < 0.01). A follow-up study was done 24 months later on 8 of the 15 infants with positive PCR results, including the infant with a positive stool antigen test. All infants were negative by both PCR and stool antigen test.


Entropic uncertainty relations for Markovian and non-Markovian processes under a structured bosonic reservoir.
The uncertainty relation is a fundamental limit in quantum mechanics and is of great importance to quantum information processing as it relates to quantum precision measurement. Due to interactions with the surrounding environment, a quantum system will unavoidably suffer from decoherence. Here, we investigate the dynamic behaviors of the entropic uncertainty relation of an atom-cavity interacting system under a bosonic reservoir during the crossover between Markovian and non-Markovian regimes. Specifically, we explore the dynamic behavior of the entropic uncertainty relation for a pair of incompatible observables under the reservoir-induced atomic decay effect both with and without quantum memory. We find that the uncertainty dramatically depends on both the atom-cavity and the cavity-reservoir interactions, as well as the correlation time, τ, of the structured reservoir. Furthermore, we verify that the uncertainty is anti-correlated with the purity of the state of the observed qubit-system. We also propose a remarkably simple and efficient way to reduce the uncertainty by utilizing quantum weak measurement reversal. Therefore our work offers a new insight into the uncertainty dynamics for multi-component measurements within an open system, and is thus important for quantum precision measurements.


Enhanced mitotic activity induced by irradiation is abolished by PGI2 pretreatment.
It is well known that irradiation may induce pronounced vascular lesions. Experimental studies revealed that irradiation induces an increased mitotic activity. As PGI2 has been claimed to be an antilesional agent, we wondered whether a pretreatment with PGI2 might abolish some of the effects induced by irradiation. 2 Groups of 24 rabbits were studied. 8 Rabbits each were irradiated with either 5 or 10 Gy on an abdominal aortic segment; 8 animals were sham treated. In each of the 3 groups half of the animals (n = 4) received PGI2 and half the buffer vehicle only. It is demonstrated that PGI2 is able to depress the enhanced mitotic activity induced by irradiation. In comparison to the controls, vascular thromboxane formation is decreased, the temporary increase in PGI2-formation by the vessel wall is less pronounced, whereas the conversion of exogenous arachidonic acid is unchanged. It is hypothetized that stable PGI2-analogues given during irradiation may probably prevent at least in part radiation-induced vascular changes and finally radiation-induced vasculopathy; this claim has to be proven in human.


Kinetics of repeat propagation in the microgene polymerization reaction.
Repetitive DNA is a periodic copolymer with the intrinsic property of exponential propagation to longer repeats. Microgene polymerization reaction (MPR) is a model system in which a short nonrepetitive homo-duplex DNA evolves to multiple repetitive products during heat-cool cycles. The mechanism underlying this process involves staggered annealing of complementary DNA strands of variable lengths and polymerase-mediated filling-in of the generated overhangs. MPR is considered here as a process sharing common features with two polymerization types, chain-growth and step-growth, and significant distinctions from both types were highlighted. The involved reaction stages were formulated and a kinetic model was derived and tested experimentally. The model can quantitatively explain MPR propagation and be used as a good approximation for this phenomenon.


Trans and gender diverse people's experiences and evaluations with general and trans-specific healthcare services: a cross-sectional survey.
Research into access to and experiences with healthcare services of gender-diverse and trans individuals remains scarce. In this paper, self-reported experiences with general and trans-specific healthcare services were analyzed for differences between gender-diverse people, trans men, and trans women, using data from a five-country survey. More than half of all respondents indicated they had delayed general healthcare services at least once because of their gender identity, mostly out of fear of being treated badly. Almost one in four participants felt personally discriminated against in general healthcare services within the previous year. Gender-diverse people had significantly less experiences with seeking trans-specific healthcare. Additional effects were found for different socio-demographic variables (age; sex assigned at birth; educational level; socioeconomic status; and belonging to an ethnic, sexual, and/or disability minority). Gender-diverse people gave significantly worse evaluations of trans-specific healthcare services (in general as well as for specific types of trans-specific healthcare). The findings highlight the need for healthcare providers in creating inclusive healthcare settings, with attention for gender-diverse clients and those belonging to precarious minority groups due to their level of education or sexual, disability, and/or ethnic background.


Carbon nitride quantum dots-modified cobalt phosphate for enhanced photocatalytic H2 evolution.
In the present work, carbon nitride quantum dots (CNQDs)-modified cobalt phosphate (CoPi) composites CNQDs/CoPi-x (x = 1, 2, 3) were prepared at room temperature and characterized by FTIR, XRD, UV-Vis DRS, EIS, SEM, TEM/HR-TEM, XPS, and N2 gas adsorption. The morphologies and surface areas of CNQDs/CoPi-x have no remarkable change after modification of CNQDs, compared with pure CoPi. The obtained CNQDs/CoPi-x shows enhanced activity and stability of photocatalytic H2 evolution compared to pure CoPi using Eosin Y (EY) as a sensitizer and triethanolamine as an electron donor. The CNQDs/CoPi-2 possesses the highest hydrogen evolution rate, 234.5 μmol h-1 g-1 , upon visible light, which outshines that of CoPi by 2.4 times. It was believed that the enhanced photocatalytic performances of the CNQDs/CoPi-2 could result from the boosted electron transfer from radical EY·- to CNQDs/CoPi-2 by the employment of CNQDs; in addition, the visible-light activity of CNQDs contributes to hydrogen evolution. The mechanism of photocatalytic hydrogen production was discussed. This study may contribute toward the development of production of "green hydrogen" using solar.


Regeneration of the human corneal endothelium.
The ability of the human corneal endothelium to regenerate is studied with the scanning electron microscope through examples of corneal diseases and penetrating keratoplasties. This study does not lead to final conclusions on the possibilities of regeneration of the human corneal endothelium but allows us to say that: --regeneration occurs through size increasing and deformation of the remaining cells. --the increase in number and size of surface microvilli may simply indicate a state of cell activation. --the presence of two nuclei in one cell is probably obtained by amitotic division but no complete mitosis has been seen. --Displacement of endothelial cells is a real progression and the cell is able to overcome obstacles. --the fibroblastic transformation of the endothelial cells is present in man but this may simply represent the migrating form of the cells.


Point-of-care ultrasound to confirm endotracheal tube cuff position in relationship to the cricoid in the pediatric population.
Anatomically, the subglottic area and the cricoid ring are the narrowest portions of the larynx. To limit the potential for damage related to mucosal pressure injuries from the presence of an endotracheal tube, the cuff should be placed below the cricoid in children. Previously, no clinical or imaging method has been used in real time to determine the exact location of the endotracheal tube cuff after endotracheal intubation. Point-of-care ultrasound may provide an option as a safe and rapid means of visualizing the endotracheal tube cuff and its relationship to the cricoid ring thereby achieving ideal endotracheal tube cuff positioning-below the cricoid. In this prospective, nonrandomized trial, point-of-care ultrasound was used following endotracheal intubation in children to evaluate the position of the endotracheal tube cuff in relationship to the cricoid and tracheal rings. After anesthesia was induced and the trachea was intubated, the endotracheal tube cuff and its position in relation to the cricoid and tracheal rings were identified in the longitudinal plane using point-of-care ultrasound. With the patient's neck in a neutral position, the level of the proximal (cephalad) margin of the saline-filled cuff of the endotracheal tube was identified and recorded in relationship to the cricoid and tracheal rings. The ideal position is defined as the cephalad margin of the endotracheal tube cuff below the level of the cricoid. The study cohort included 80 patients, ranging in age from 1 to 78 months. In all patients, the cuff of the ETT, cricoid, and tracheal rings were identified. The cephalad end of the endotracheal tube cuff was found at the level of the cricoid in 16.3% of patients, at the first tracheal ring in 27.5% of patients, at the second tracheal ring in 23.8% of patients, at the third tracheal ring in 17.5% of patients, and at below the fourth tracheal ring in 15% of patients. Initial endotracheal tube cuff position had no significant association with age, height, weight, endotracheal tube size, and endotracheal tube type. Point-of-care ultrasound provides a rapid and effective means of identifying the position of the endotracheal tube cuff in relationship to the cricoid ring. The technique may have applications in the perioperative arena, emergency departments, and intensive care units.


Cystadenolymphoma: an immunohistochemical study with special reference to Ig E and mastcells.
Cystadenolymphomas (adenolymphomas) were analysed by immunohistochemical studies for the presence of immunoglobulin A, E, G and M. The distribution pattern was examined by a quantitative analysis. The relative ratio of immunoglobulins was 31.8% (Ig A), 26.6% (Ig E), 28.6% (Ig G) and 13% (Ig M). The different compartments of the lymphoid stroma were analysed separately (subepithelial area, parafollicular area, follicular area). The distribution of mast cells was studied in a parallel approach by the toluidine blue technique. These cells were found in the stroma, but also in the epithelial parts. Our results show that the subepithelial zone in cystadenolymphomas is a region of special cellular reaction (plasma cells, mast cells). The Ig E producing plasma cells and the mastcells seem to play a special role in these tumors.


Construction of a high-density linkage map and fine mapping of QTLs for growth and gonad related traits in blunt snout bream.
High-density genetic maps based on SNPs are essential for fine mapping loci controlling specific traits for fish species. Using restriction-site associated DNA tag sequencing (RAD-Seq) technology, we identified 42,784 SNPs evenly distributed across the Megalobrama amblycephala genome. Based on 2 parents and 187 intra-specific hybridization progenies, a total of 14,648 high-confidence SNPs were assigned to 24 consensus linkage groups (LGs) of maternal and paternal map. The total length of the integrated map was 3,258.38 cM with an average distance of 0.57 cM among 5676 effective loci, thereby representing the first high-density genetic map reported for M. amblycephala. A total of eight positive quantitative trait loci (QTLs) were detected in QTL analysis. Of that, five QTL explained ≥35% of phenotypic variation for growth traits and three QTL explained ≥16% phenotypic variation for gonad related traits. A total of 176 mapped markers had significant hits in the zebrafish genome and almost all of the 24 putative-chromosomes of M. amblycephala were in relatively conserved synteny with chromosomes of zebrafish. Almost all M. amblycephala and zebrafish chromosomes had a 1:1 correspondence except for putative-chromosome 4, which mapped to two chromosomes of zebrafish caused by the difference in chromosome numbers between two species.


Temperature Dependence of the Krokinobacter rhodopsin 2 Kinetics.
We investigated the temperature-dependent kinetics of the light-driven Na+ pump Krokinobacter rhodopsin 2 (KR2) at Na+-pumping conditions. The recorded microsecond flash photolysis data were subjected to detailed global target analysis, employing Eyring constraints and spectral decomposition. The analysis resulted in the kinetic rates, the composition of the different photocycle equilibria, and the spectra of the involved photointermediates. Our results show that with the temperature increase (from 10 to 40°C), the overall photocycle duration is accelerated by a factor of 6, with the L-to-M transition exhibiting an impressive 40-fold increase. It follows from the analysis that in KR2 the chromophore and the protein scaffold are more kinetically decoupled than in other microbial rhodopsins. We link this effect to the rigidity of the retinal protein environment. This kinetic decoupling should be considered in future studies and could potentially be exploited for fine-tuning biotechnological applications.


[Effect of Mitochondrial Dysfunction on Coronary Artery Disease - Part 2].
Organelles whose functions change as a result of molecular processes are involved in the pathogenesis of atherosclerosis, which is the main cause of coronary artery disease, in addition to molecular processes. Recently, the role of mitochondria in the pathogenesis of coronary artery disease has attracted the attention of researchers. Mitochondria is a cell organelle with its own genome that plays a regulatory role in aerobic respiration, energy production, and cell metabolism. The number of mitochondria in cells changes dynamically, and there are di���erent numbers of mitochondria in every tissue and every cell, depending on their function and energy needs. Oxidative stress causes mitochondrial dysfunction by leading to alterations in the mitochondrial genome and mitochondrial biogenesis. The dysfunctional mitochondria population in the cardiovascular system is closely related to the coronary artery disease process and cell death mechanisms. It is thought that the altered mitochondria (dys)function accompanying the molecular changes in the atherosclerosis process will be among the new therapeutic targets of coronary artery disease in the near future.


Complications following ex-press glaucoma shunt implantation.
To report post-operative course and complications in patients who underwent Ex-Press glaucoma shunt placement. Small case series. Four patients were referred for management following Ex-Press shunt implantation. Patients underwent complete ophthalmologic evaluation and were appropriately managed. Of the four patients, two had inadequate control of intraocular pressure related to bleb failure caused by subconjunctival scar tissue formation. One patient experienced suprachoroidal hemorrhage 5 days after shunt placement followed a year later with conjunctival erosion and shunt rim exposure. Endophthalmitis from conjunctival erosion over the Ex-Press shunt rim was observed in one patient. Patients with subconjunctival implantation of the Ex-Press shunt should be monitored closely for possible conjunctival erosion that can lead to endophthalmitis and failure from fibrosis.


Completeness and utility of interview data from proxy respondents in prenatal care research in rural China.
In household surveys, the use of data provided by relatives can increase response rates and generalisability of research findings. This study assessed the quality of data from relatives and the impact of the data source on the association between the use of prenatal care and pregnancy outcomes. Data for 3,673 new mothers and 293 proxy respondents were available from a house-hold survey in 2008-2009 in rural China. Analyses were performed using chi-square test, ANOVA, Kruskal-Wallis test, and logistic regression models. Differences in the studied variables were small, but proxy respondents were slightly more likely to have missing data than the new mothers. Differences and missing data were more common for the use of prenatal care and outcome variables (mode of delivery, place of delivery, birth weight, use of postnatal care, and gestational age at birth) than for the background characteristics of the participants. Husbands' reports were closer to the index reports than that of the other proxies. The associations between the exposures and outcomes were mostly similar between the proxy and index respondents. Relatives can be interviewed instead of women to study prenatal care without a substantial negative impact on study results. Studies using proxy respondents should stratify the analysis by type of respondents.


Rapid onset of severe ocular injury after exposure to a button battery.
Button batteries are commonly used in many household electronic items and are a potential health hazard, especially in children. We present the case of a 2-year-old girl presented with swelling and redness of her right eye of 3 hours' duration. Examination revealed a button battery that had became lodged in the superior fornix of her right eye. After the intact battery was removed, the patient was found to have suffered an alkali burn to the underlying conjunctiva and sclera. The burn healed with symblepharon formation.


Class distribution of immunoglobulin-containing plasma cells in the stroma of medullary carcinoma of breast.
A class distribution of plasma cells associated with the stroma in twenty-eight cases of medullary carcinoma of the breast was investigated by an unlabeled immunoperoxidase method. The stroma of the medullary carcinomas tested was found to contain predominantly IgG plasma cells except in two cases. Stroma of the other types of breast carcinoma, including ten cases of papillo-tubular carcinoma, five cases of scirrhous carcinoma, and six cases of medullary tubular carcinoma, contained predominantly IgG plasma cells, although few plasma cells were associated with carcinoma tissues in the latter group. Plasma cells associated with control specimens, including normal breast, fibroadenoma, cystic disease, and intraductal papilloma, were found to be predominantly of IgA type. Few carcinomatous epithelial cells contained secretory components in the cytoplasm, while a number of cells positive for secretory components were observed in acinar and ductular epithelia of normal breast tissues and in benign proliferative lesions of the breast. It is suggested that the lymphoid cells infiltrating the stroma of medullary carcinoma represent a sign of host immune response against the carcinoma cells which is related to the well-known favorable prognosis associated with this tumor.


[Critical points in the storage and expiry of drugs. Improvements implemented by healthcare units in the accreditation process].
Measures for controlling the expiry date and storage conditions of the drugs is a standard used in the accreditation program. The present paper has two principal aims: to identify the critical points in the clinical units evaluated, and to find out the different actions for improvement introduced in these areas. A descriptive-retrospective study was used. For analysing the critical points, the units that did not achieve the referred standard (n=64) during the accreditation process were selected. All the information analysed on the units (n=48) that had introduced improvements was obtained from the computer application that supports the accreditation processes. The critical points (drug expiry date and storage conditions, were found in 32.98% of the units evaluated. These were mainly due to associated with lack of responsibility, absence of refrigeration control records and standard procedures. The 241 improvement actions made in the 48 units analysed were recorded in the computer program. The deficiencies were resolved, which enabled them to achieve accreditation. The actions introduced to resolve the critical points regarding drug storage and expiry in clinical units, can be easily implemented by other healthcare units in order to achieve accreditation.


Ruptured abdominal aortic aneurysms: who should be offered surgery?
Operation for ruptured abdominal aortic aneurysm is generally still associated with a high mortality rate. A review of our experience over a 9-year period was undertaken to identify factors present on admission associated with 30-day operative mortality. A retrospective analysis of 154 patients with ruptured abdominal aortic aneurysm submitted for operation in a university teaching hospital between January 1985 and December 1993 was undertaken. The hospital mortality rate was 39%. Logistic regression identified a set of five independent preoperative factors associated with mortality: age (> 76 years), creatinine level (> 0.19 mmol/L), loss of consciousness after arrival, Hb (< 9 g%), and electrocardiographic ischemia. In the 52 patients with a single risk factor present, the mortality rate was 37%, with two factors (32 patients) it was 72%, with three or more factors (8 patients), it was 100%, and no patient had all five risk factors. A 16% mortality rate was found in the 62 patients with no risk factors. These risk factors can be easily determined on admission and may be used to help improve patient selection for surgical intervention. The current operative mortality rate for ruptured abdominal aortic aneurysm remains high, and in some cases health care resources are used in a nonproductive fashion. Restricted patient selection and allocation of scarce resources will bring advantages to both the patient and the community.


Tumor-host interface in oral squamous cell carcinoma: Impact on nodal metastasis and prognosis.
To evaluate tumor-host interface in oral squamous cell carcinoma (OSCC) by the Brandwein-Gensler histological risk score (BG risk score); to assess its association with clinicopathological features and impact on survival outcomes in a contemporary cohort staged as per AJCC 8th edition pTNM classification. This retrospective cohort study at a tertiary care centre included 178 cases of OSCC treated by primary surgical resection from 2013 to 2016. Pathological lymph node status, disease-free survival (DFS), overall survival (OS) were assessed. BG risk score assessment categorized 25 (14%) cases as low-risk, 93 (52%) as intermediate-risk, and 60 (34%) as high-risk. BG risk score category progression from low to intermediate to high risk was associated with an incremental risk of worsening pN status, DFS, and OS. BG risk score categories significantly demarcated 2-year DFS (96% in low-risk, 51.6% in intermediate-risk, 15% in high-risk; p < 0.001) and OS (96% in low-risk, 66.7% in intermediate-risk, 31.3% in high-risk; p < 0.001). On stratified analysis, BG risk score could further demarcate prognosis in early (I/II) and late (III/IV) stage subgroups (p < 0.001). Multivariate analysis indicated the prognostic impact of BG risk score categories to be additional to, and of equal magnitude to, impact of pTNM stage. BG risk score is a powerful prognostic tool in OSCC additional to pTNM staging. It can enable risk stratification and inform decisions regarding post-surgical adjuvant treatment. It is undertaken with routine histopathological evaluation, with no increased expense or turnaround time. A case is made for its inclusion in OSCC reporting guidelines.


Scotland, Malawi and medicine: Livingstone's legacy, I presume? An historical perspective.
In this personal short historical perspective I reflect on aspects of the medical history of Malawi, formerly Nyasaland, highlighting the role of Scotland and its people in the development of the Malawi medical services in both the colonial as well as the postcolonial period which began in 1964. The paper, after discussing the history of medical training in Malawi and current constraints and challenges, goes on to make some suggestions - based on historical lessons - about future role of Scottish involvement in Malawi's medical development. It would be unfortunate if, in a rush to 'help or do something' the mistakes of the past are repeated.


Look-up and look-down neurons in the mouse visual thalamus during freely moving exploration.
Visual information reaches cortex via the thalamic dorsal lateral geniculate nucleus (dLGN). dLGN activity is modulated by global sleep/wake states and arousal, indicating that it is not simply a passive relay station. However, its potential for more specific visuomotor integration is largely unexplored. We addressed this question by developing robust 3D video reconstruction of mouse head and body during spontaneous exploration paired with simultaneous neuronal recordings from dLGN. Unbiased evaluation of a wide range of postures and movements revealed a widespread coupling between neuronal activity and few behavioral parameters. In particular, postures associated with the animal looking up/down correlated with activity in >50% neurons, and the extent of this effect was comparable with that induced by full-body movements (typically locomotion). By contrast, thalamic activity was minimally correlated with other postures or movements (e.g., left/right head and body torsions). Importantly, up/down postures and full-body movements were largely independent and jointly coupled to neuronal activity. Thus, although most units were excited during full-body movements, some expressed highest firing when the animal was looking up ("look-up" neurons), whereas others expressed highest firing when the animal was looking down ("look-down" neurons). These results were observed in the dark, thus representing a genuine behavioral modulation, and were amplified in a lit arena. Our results demonstrate that the primary visual thalamus, beyond global modulations by sleep/awake states, is potentially involved in specific visuomotor integration and reveal two distinct couplings between up/down postures and neuronal activity.


Preparing for the Artificial Intelligence Revolution in Nuclear Cardiology.
A major opportunity in nuclear cardiology is the many significant artificial intelligence (AI) applications that have recently been reported. These developments include using deep learning (DL) for reducing the needed injected dose and acquisition time in perfusion acquisitions also due to DL improvements in image reconstruction and filtering, SPECT attenuation correction using DL without need for transmission images, DL and machine learning (ML) use for feature extraction to define myocardial left ventricular (LV) borders for functional measurements and improved detection of the LV valve plane and AI, ML, and DL implementations for MPI diagnosis, prognosis, and structured reporting. Although some have, most of these applications have yet to make it to widespread commercial distribution due to the recency of their developments, most reported in 2020. We must be prepared both technically and socio-economically to fully benefit from these and a tsunami of other AI applications that are coming.


30 years of large river restoration: How long do restored floodplain channels remain suitable for targeted rheophilic fishes in the lower river Rhine?
The ecological efficacy of river restoration projects may change over time, resulting in the loss of their ecological function for targeted species. The goal of this study was to evaluate the rheophilic nursery function of restored floodplain channels over time, by analysing 30 years of monitoring data from 12 restoration projects in the lower river Rhine. We hypothesised that the nursery function would change over time, caused by the combined effects of decreasing flow conditions and succession processes affecting habitat heterogeneity. We found that nursery area suitability for rheophilic fish was almost 4 times higher in two-sided connected channels than in one-sided connected channels, although the response trends of rheophilic fish were similar for both water body types. These response curves showed clear optima with channel age, for rheophilic fish abundance at 13 to 14 years post-restoration, indicating optimal nursery conditions. On the other hand, rheophilic species richness showed a steadily decreasing trend with channel age, suggesting aging channels became less suitable as nursery areas for most rheophilic fish species. The presence of permanent flow was found to be the main driving factor in explaining both rheophilic fish community trends and habitat succession in individual restored channels. We did not observe an effect of habitat heterogeneity on nursery function for rheophilic fish. To create and maintain optimal nursery conditions in restored floodplain channels of strongly anthropogenically influenced rivers such as the river Rhine, we propose a management strategy involving cyclic rejuvenation through human intervention, focusing on restoring permanent flow, with a frequency of on average every 15 years, depending on the rate of aggradation and targeted rheophilic species. We also propose a thorough investigation of the relationship between habitat heterogeneity and nursery success in floodplain channels, as a next step in the identification of suitable nursery areas for rheophilic fishes.


Photoengineering of neural tissue repair processes in peripheral nerves and the spinal cord: research development with clinical applications.
The purpose of the present paper is to provide our data on the effects of phototherapy on peripheral nerve recovery. The aim is to call attention to an issue that still requires much research to elucidate the biological mechanisms through which phototherapy exerts its effects on nerve tissue, and to provide clinicians with the basis for planning clinical trials on the use of phototherapy for enhancing post-traumatic nerve regeneration.


[Pancreatic duct occlusion with fibrin (glue) to protect the pancreatico-digestive anastomosis after resection of the head of the pancreas in oncologic surgery].
The PDO with FS represents a technically simple, quick and efficient method for the protection of pancreatic-jejunal anastomosis, which is endangered by dehiscences. We could prove--first, in an animal experimental, then in a clinical study of 93 patients--that neither subsequent dehiscence nor a pancreatic fistula occurred. Also, the loss of exo- and endocrine functions is low and can rather be considered as an expression of the extended resection of the pancreatic parenchyma in the scope of the oncological intervention.


Angiographic predictors of unplanned rotational atherectomy in complex calcified coronary artery disease: a pooled analysis from the randomised ROTAXUS and PREPARE-CALC trials.
Calcified coronary lesions present therapeutic challenges for the interventional cardiologist, often requiring rotational atherectomy (RA). This study aimed to develop an angiographic scoring tool to predict the need for a priori RA. A pooled analysis of the randomised ROTAXUS and PREPARE-CALC studies was carried out, (N=220 patients, N=313 lesions), by virtue of the fact that both studies made provision for crossover to RA (from balloon dilatation or modified balloon dilatation, respectively). Logistical regression techniques were employed to assess for the presence of patient- or lesion-specific factors leading to a necessity for RA. External validation was performed though retrospective calculation of the score for 192 patients who underwent bail-out RA in a single centre. Lesion length (odds ratio [OR] 1.02, 95% confidence interval [CI]: 1.00-1.04 per mm, p=0.04), bifurcation lesion (OR 2.60, 95% CI: 1.27-5.30, p=0.009), vessel tortuosity >45° (OR 3.49, 95% CI: 1.73-7.03, p<0.001) and severe vessel calcification (OR 11.60, 95% CI: 3.40-39.64, p<0.001) were predictive of the need for RA in multivariate analysis. Based on the regression coefficients, a scoring system was devised. The greater the score, the more likely a lesion required RA. The scoring system performed well in the external validation cohort, with 78% of patients crossing over having a score of greater than the proposed cut-off of 3. We provide an angiographic scoring tool to support the expeditious use of time and resources, allowing assessment of the likelihood of success of a balloon-based strategy, or the necessity for RA.


Bidirectional pigment granule movements of melanophores are regulated by protein phosphorylation and dephosphorylation.
Studies were conducted to investigate the molecular basis for bidirectional pigment granule transport in digitonin-lysed melanophores. Pigment granule dispersion, but not aggregation, required cAMP and resulted in the phosphorylation of a 57 kd polypeptide. cAMP-dependent protein kinase inhibitor prevented this phosphorylation as well as pigment dispersal. In contrast, both pigment aggregation and the concomitant dephosphorylation of the 57 kd polypeptide were blocked by phosphatase inhibitors. These data support a model in which pigment dispersion and aggregation require protein phosphorylation and dephosphorylation, respectively. Furthermore, studies using the ATP analog, ATP gamma S, suggest either that protein phosphorylation alone is sufficient for dispersion or that transport is mediated by a unique force-generating ATPase that can use ATP gamma S for hydrolyzable energy.


Marginal gap and fracture resistance of implant-supported 3D-printed definitive composite crowns: An in vitro study.
To compare the marginal gap and fracture resistance of implant-supported 3-dimensional (3D) printed definitive composite crowns with those fabricated by using 3 different millable materials. A prefabricated abutment was digitized by using a laboratory scanner (E4 Lab Scanner) and a complete-coverage maxillary first premolar crown was designed (Dental Designer). Forty crowns were fabricated either by 3D printing (Saremco Print Crowntec, SP) or milling (Brilliant Crios, BC; Vita Enamic, VE; Cerasmart 270, CS) (n = 10). Baseline marginal gap values were evaluated by measuring 60 predetermined points on an abutment (15 points for each side) with a stereomicroscope at ×40 magnification. Marginal gap values were reevaluated after adhesive cementation. Load-to-fracture test was performed by using a universal testing machine. Two-way analysis of variance (ANOVA) was used to evaluate the effect of material type and cementation on marginal gap values. While Tukey HSD tests were used to compare the materials' marginal gap values before and after cementation, the effect of cementation on marginal gap values within each material was analyzed by using paired samples t-tests. Fracture resistance data were analyzed by using 1-way ANOVA (α=0.05). Material type and cementation significantly affected marginal gap values (P < .001). Regardless of cementation, SP had the lowest marginal gap values (P < .001), while the differences among milled crowns were nonsignificant (P ≥ .14). Cementation significantly increased the marginal gap values (P < .001). Material type did not affect fracture resistance values (F = 1.589, P = .209). Implant-supported 3D-printed composite crowns showed higher marginal adaptation compared with the milled crowns before and after cementation. In addition, all crowns endured similar forces before fracture.


Comparison of the microbial community and flavor compounds in fermented mandarin fish (Siniperca chuatsi): Three typical types of Chinese fermented mandarin fish products.
Fermented mandarin fish have been receiving attention from consumers due to their nutritional value and specific flavor. Microbial diversity in fermented mandarin fish has an important impact on their flavor and quality. However, little is known about the microbiome and the differences among different products. In this study, the bacterial profiles and flavor compounds in three typical fermented mandarin fish products were investigated and compared, and a correlation network was used to explore the potential relationship between microorganisms and flavor. Bacterial community analysis demonstrated clear differences in microbiota among the HF-, MF-, and OF-fermented mandarin fish products. Psychrilyobacter, Fusobacterium, and Vibrio were the most dominant in the HF-, MF-, and OF-fermented products, respectively. In addition, 14, 12, and 4 flavor substances (relative odor activity value, ROAV ≥ 1) were detected in the muscles from the central dorsal and ventral sides of the three samples, respectively. Several bacteria correlated with the production of important flavor compounds, and three genera (Arcobacter, Psychrilyobacter, and Shewanella) were the primary microorganisms contributing to more than six characteristic flavor compounds in fermented mandarin fish products. Therefore, the study's systematic method allows identificating important microbes and characteristic volatile flavor compounds in fermented mandarin fish and provides new insights into the relationship between microorganisms and flavor.


Clinical significance of STING expression and methylation in lung adenocarcinoma based on bioinformatics analysis.
The role of stimulator of interferon genes [STING, also known as transmembrane protein 173 (TMEM173)] in various human cancers has begun to emerge. However, the clinical value of STING in lung adenocarcinoma (LUAD) remains elusive. This study aims to elucidate the clinical significance of STING expression and methylation in LUAD. Here, through analyzing data from public resources, we found that both the mRNA and protein expression of STING were reduced in lung cancer. Moreover, lower expression of STING was associated with a worse prognosis in LUAD, but not lung squamous cell carcinoma (LUSC). Of note, higher methylation of STING was found in LUAD and had the potential to distinguish LUAD tissues from adjacent non-tumor lung tissues and correlated with unfavorable outcomes. Furthermore, the methylation of STING could serve as an independent prognostic indicator for both the overall survival (OS) and disease-free survival (DFS) of LUAD patients. Additionally, the constructed nomogram exhibited a favorable predictive accuracy in predicting the probability of 1- and 2-year OS. Our findings suggest that the mRNA expression, and especially the DNA methylation of STING, have the potential to be prognostic indicators for LUAD patients.


Is Long-Term Survival in Metastases from Neuroendocrine Neoplasms Improved by Liver Resection?
Background and Objectives: Although many of the neuroendocrine neoplasms (NEN) have a typically prolonged natural history compared with other gastrointestinal tract cancers, at least 40% of patients develop liver metastases. This study aims to identify whether liver resection improves the overall survival of patients with liver metastases from NEN. Materials and Methods: We conducted a retrospective study at "Fundeni" Clinical Institute over a time period of 15 years; we thereby identified a series of 93 patients treated for NEN with liver metastases, which we further divided into 2 groups as follows: A (45 patients) had been subjected to liver resection complemented by systemic therapies, and B (48 patients) underwent systemic therapy alone. To reduce the patient selection bias we performed at first a propensity score matching. This was followed by a bootstrapping selection with Jackknife error correction, with the purpose of getting a statistically illustrative sample. Results: The overall survival of the matched virtual cohort under study was 41 months (95% CI 37-45). Group A virtual matched patients showed a higher survival rate (52 mo., 95% CI: 45-59) than B (31 mo., 95% CI: 27-35), (p < 0.001, Log-Rank test). Upon multivariate analysis, seven independent factors were identified to have an influence on survival: location (midgut) and primary tumor grading (G3), absence of concomitant LM, number (2-4), location (unilobar), grading (G3) of LM, and 25-50% hepatic involvement at the time of the metastatic disease diagnosis. Conclusions: Hepatic resection is nowadays the main treatment providing potential cure and prolonged survival, for patients with NEN when integrated in a multimodal strategy based on systemic therapy.


Thrombotic Risk and Cardiovascular Events in Patients With Revascularization Deferral After Fractional Flow Reserve Assessment.
The aim of this study was to evaluate the impact of thrombotic risk on the occurrence of cardiovascular events in patients with coronary artery disease with deferred revascularization after fractional flow reserve (FFR) measurements. Deferral of revascularization on the basis of FFR is generally considered to be safe, but after deferral, some patients have cardiovascular events over time. From J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), 1,263 patients with deferral of revascularization on the basis of FFR were evaluated. The association between thrombotic risk as assessed by CREDO-Kyoto (Coronary Revascularization Demonstrating Outcome Study in Kyoto) thrombotic score and 5-year target vessel failure (TVF) and major adverse cardiac and cerebrovascular events (MACCE) was investigated. FFR and high thrombotic risk (HTR) were associated with increased risk for 5-year TVF (FFR per 0.01-unit decrease: HR: 1.08; 95% CI: 1.05-1.11; P < 0.001; HTR: HR: 2.16; 95% CI: 1.37-3.39; P < 0.001) and MACCE (FFR per 0.01-unit decrease: HR: 1.05; 95% CI: 1.02-1.06; P < 0.001; HTR: HR: 2.11; 95% CI: 1.56-2.84; P = 0.001). Patients with HTR had higher risk for 5-year TVF (HR: 2.30; 95% CI: 1.45-3.66; P < 0.001) and MACCE (HR: 2.34; 95% CI: 1.75-3.13; P < 0.001) than those without HTR, even when they had negative FFR. Assessment of thrombotic risk provides additional prognostic value to FFR in predicting 5-year TVF and MACCE in patients with deferral of revascularization after FFR measurements. (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry; UMIN000014473).


Genetic interaction networks mediate individual statin drug response in Saccharomyces cerevisiae.
Eukaryotic genetic interaction networks (GINs) are extensively described in the Saccharomyces cerevisiae S288C model using deletion libraries, yet being limited to this one genetic background, not informative to individual drug response. Here we created deletion libraries in three additional genetic backgrounds. Statin response was probed with five queries against four genetic backgrounds. The 20 resultant GINs representing drug-gene and gene-gene interactions were not conserved by functional enrichment, hierarchical clustering, and topology-based community partitioning. An unfolded protein response (UPR) community exhibited genetic background variation including different betweenness genes that were network bottlenecks, and we experimentally validated this UPR community via measurements of the UPR that were differentially activated and regulated in statin-resistant strains relative to the statin-sensitive S288C background. These network analyses by topology and function provide insight into the complexity of drug response influenced by genetic background.


Choice of surgical lesion set: answers from the data.
Surgical ablation of atrial fibrillation has gained widespread acceptance, particularly in patients having concomitant cardiac surgery. Today, surgeons can choose from a variety of ablation technologies to facilitate operations intended to treat atrial fibrillation. Evidence suggests that virtually all of the available energy sources are effective at creating lines of conduction block on the arrested heart. However, there is controversy surrounding the choice of lesion set when these new devices are used. The purpose of this review is to address the critical question of lesion set by detailed consideration of contemporary data focusing on the (1) pathogenesis of atrial fibrillation, (2) results of catheter ablation, and (3) results of surgical ablation.


Features of a syndrome with congenital cataract and hypertrophic cardiomyopathy.
We studied 12 patients from six unrelated families with a syndrome that has an autosomal recessive pattern of inheritance and can be diagnosed from clinical, histologic, and biochemical characteristics. The four major symptoms are congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy of voluntary muscles, and exercise-related lactic acidosis. The patients had bilateral and total cataract in the first weeks of life, underwent cataract surgery, and developed nystagmus and strabismus. Corrected visual acuity was lower than 20/40 in aphakic eyes. Patients were mentally normal, and at school age they visited a school for blind and visually impaired children. The majority of the patients developed axial myopia with myopic fundus changes; aphakic refraction usually was lower than 10.0 diopters after the first decade. The cardiac myopathy was progressive and the cause of premature death. Three of the 12 patients died in the neonatal period and six patients died in early adulthood.


Efficacy of cyclosporin A for idiopathic pulmonary fibrosis.
In an 11-year-old girl with severe dyspnoea and cyanosis, idiopathic pulmonary fibrosis (IPF) was diagnosed. The PaO2 of blood could be maintained between 50 mm Hg and 70 mm Hg with a high dose pulse corticosteroid therapy, although this dose could not be reduced. Azathioprine in addition to prednisolone provoked deterioration. Twelve weeks after admission, cyclosporin A (Cs A), a known immunosuppressant, was started together with prednisolone. The PaO2 reverted to normal within 1 month and prednisolone could be tapered off within 6 months. Two years after admission, the patient is free of symptoms on continuous Cs A therapy. This case seems to be the first case successfully treated with Cs A.


Risk HLA Variants Affect the T-Cell Repertoire in Multiple Sclerosis.
The major histocompatibility complex (MHC) locus has a predominant role in the genetic predisposition to multiple sclerosis (MS), with 32 associations found to be involved. We aimed to investigate the impact of MHC MS-risk alleles on T-cell repertoire in patients with MS. We studied 161 untreated patients with relapsing-remitting MS for whom Class I and II human leukocyte antigen (HLA) alleles were inferred from whole-genome genotyping data, and T-cell receptor (TCR) CDR3 sequences were obtained through next-generation sequencing. T-cell repertoire features including diversity, public clones, and architecture were evaluated. We identified 5 MS-risk loci associated with TCR diversity: HLA-DRB1*15:01 (7.65 × 10-3), rs9271366 (1.96 × 10-3), rs766848979 A (1.89 × 10-2), rs9277626 (2.95 × 10-2), and rs11751659 (1.92 × 10-2), with evidence of expanded clonotypes in carriers of risk alleles. Moreover, HLA-DRB1*15:01 (4.99 × 10-3), rs9271366 (6.54 × 10-3), rs1049079 C (4.37 × 10-2), AA DQΒ1 position -5 L (1.05 × 10-3), and AA DQΒ1 position 221 Q (9.39 × 10-4) showed an association with the CDR3 aminoacidic sequence architecture, suggesting an impact on the antigen recognition breadth as well. Evaluating the sharing of clones across MS-risk allele carrier individuals revealed the presence of highly shared clonotypes predicted to target viral antigens, including Epstein-Barr virus. Our study supports the association between MHC-risk alleles and macrofeatures of the T-cell repertoire in the context of MS. Further studies are needed to understand the underlying molecular mechanisms.


Structure of Transmembrane Helix 8 and Possible Membrane Defects in CFTR.
The cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that regulates the flow of anions across epithelia. Mutations in CFTR cause cystic fibrosis. CFTR belongs to the ATP-binding cassette transporter superfamily, and gating is controlled by phosphorylation and ATP binding and hydrolysis. Recently obtained ATP-free and ATP-bound structures of zebrafish CFTR revealed an unwound segment of transmembrane helix (TM) 8, which appears to be a unique feature of CFTR not present in other ATP-binding cassette transporter structures. Here, using μs-long molecular dynamics simulations, we investigate the interactions formed by this TM8 segment with nearby helices in both ATP-free and ATP-bound states. We highlight ATP-dependent interactions as well as the structural role of TM8 in maintaining the functional architecture of the pore via interactions common to both the ATP-bound and ATP-free state. The results of the molecular dynamics simulations are discussed in the context of the gating mechanism of CFTR.


The impact of environmental factors on the transport and survival of pathogens in agricultural soils from karst areas of Yunnan province, China: Laboratory column simulated leaching experiments.
Groundwater is considered the best candidate for drinking water supply in the karst area. The groundwater water resources, however, are vulnerable to pathogenic microorganism contamination because of the typically thin soil layers overlying aquifers and the high permeability of the aquifer host rock, resulting in short residence times and low natural attenuation capacities. Until now, little attention has been paid to the critical environmental factors affecting the pathogenic microorganism contamination in soil-groundwater systems in the karst area. In the study, orthogonality column experiments with controlling ambient temperatures, pH values of inlet water, and soil porosities were carried out to investigate the transport and lifespan of pathogenic microorganisms in the leachate of agricultural soils in the karst area of Yunnan province, China. The pathogenic indicators, i.e., total bacteria count (TBC) and total coliforms count (TCC), and hydrochemical parameters, i.e., pH and permanganate index (CODMn) in the leaching water, were systematically monitored. The results showed that bacteria including coliforms can survive for prolonged periods of time in karst soils. The soils overlying the karst rocks were unable to impede the bacteria from seeping into the groundwater. The soils, in turn, likely served as both reservoirs and incubators for pathogenic bacteria. The ambient temperature was the most predominant influential factor affecting both TBC and TCC. The bacteria concentrations were proportional to the temperature in the leachate. Therefore, more attention should be paid to temperature variations in protecting the water supply, particularly in the high-temperature period, such as during the summer months.


First report of F1534C kdr mutation in deltamethrin resistant Aedes albopictus from northern part of West Bengal, India.
Dengue is the most rapidly spreading vector-borne disease with an estimated 100-400 million cases each year. Control of Dengue vectors largely depends upon synthetic pyrethroids. Development of insecticide resistance in Aedes mosquitoes however, poses severe threat to insecticide-based vector management programme. Mutations in the Voltage Gated Sodium Channel gene (vgsc) serve as the primary machinery behind this resistance development. In Aedes albopictus, at least four such kdr (knock down resistance) mutations had already been documented. Here, we describe the occurrence of F1534C kdr mutation in wild population of Ae. albopictus from northern part of West Bengal, India including a novel T1520I mutation. Four populations of Ae. albopictus from the studied region were found resistant against DDT and synthetic pyrethroids, among them only one population possessed F1534C kdr mutation. A total of 200 successful amplification followed by partial sequencing of vgsc gene further revealed the presence of F1534C kdr mutation in both phenotypically susceptible and resistant mosquito specimen. Studied populations were found 81% homozygote susceptible (1534F/F), 12.5% heterozygote (1534F/C) and 6% homozygote resistant (1534C/C) for F1534C kdr mutation. The findings of the current study will help to uncover the mechanisms underlying insecticide resistance and hence to reduce errors in vector control measurements.


Analysis of four methods of measuring three-dimensional pelvic tilt in the lateral decubitus position.
Proper alignment of acetabular implantation is necessary for good patient outcomes and preventing complications or additional surgeries in total hip arthroplasty (THA). Rotation of the pelvis in lateral decubitus (LD) is typically not accounted for as surgeons use the surgery table as a reference plane to align implants. This study compared four techniques to measure 3D pelvic rotations in LD position using computer models. CT scans of 19 subjects in LD position were used to create 3D pelvis models. Pelvic rotations were measured by three users using four techniques: landmark (LM), defined plane (DP), anterior pelvic plane (APP), and plane of best symmetry (POBS) methods. Measurements were analysed for intra-user reliability and relationships between methods were assessed using intraclass correlation coefficient, standard error of measurement, and coefficient of determination. The POBS method exhibited the highest inter-observer reliability and is recommended as a new measurement technique to measure pelvic rotations before THA surgery. The LM method exhibited low reliability but may be suitable for expert users familiar with pelvic landmarks. The APP method should only be used when the patients' APP planes are known in neutral standing and side-lying postures. The DP method is not recommended due to substantial individual variability. Graphical abstract.


A 3-dimensional airway analysis of an obstructive sleep apnea surgical correction with cone beam computed tomography.
The purpose of this case report is to present cephalometric changes in the craniofacial region and volumetric changes in the oropharyngeal region of a patient diagnosed with obstructive sleep apnea syndrome after maxillomandibular advancement and genial tubercle advancement surgeries. Cone beam computed tomographic images were used to evaluate cephalometric changes in the craniofacial region and linear changes in the oropharyngeal region of the patient. A patient with obstructive sleep apnea was treated successfully with maxillomandibular advancement and genial tubercle advancement surgery. Airway analysis showed a significant increase in the volume of the patient's oropharynx after surgery. Cone beam computed tomographic images are recommended for 3-dimensional airway evaluation in the treatment of obstructive sleep apnea syndrome.


Conditioned suppression of an operant response using d-amphetamine as the conditioned stimulus.
The use of a drug state as a conditioned stimulus (CS) in a classical conditioning paradigm was investigated. Suppression of a single-lever food-reinforced response (variable-interval 60 s) served as an index of a classically conditioned response (conditioned suppression). d-Amphetamine (0.8 mg/kg) injections were paired with a series of inescapable shocks. Following drug-shock pairing, the effects of d-amphetamine on operant response totals was compared to effects obtained in control subjects which had received unpaired d-amphetamine and shock exposures. d-Amphetamine administered during daily operant sessions unaccompanied by shock was an effective CS for conditioned suppression of the operant response. Administration of cocaine hydrochloride (7.5 mg/kg) also produced a decrease in total responses, suggesting stimulus generalization from the shock-paired drug to a novel drug.


Ocular immunopathology of Behçet's disease.
A patient developed progressive, severe, recurrent bilateral iridocyclitis, retinal vasculitis, and hemorrhagic infarction of the retina that led to blindness despite immunosuppressive therapy. Histopathology of an enucleated blind and painful eye revealed marked nongranulomatous uveitis with a predominantly CD4+ T-lymphocytic infiltration, as well as B-cell and plasma cell aggregation. Extensive expression of adhesion molecules on vascular endothelial cells were found. This finding suggests that adhesion molecules play an important role in the vasculitic process, the trademark of Behçet's disease. The ocular pathology and the therapeutic approach to Behçet's disease are briefly reviewed.


Effect of Arterial Stiffness and Carotid Intima-Media Thickness Progression on the Risk of Dysglycemia, Insulin Resistance, and Dyslipidemia: a Temporal Causal Longitudinal Study.
We investigated the temporal causal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, and carotid intima-media thickness (cIMT) progression with the risk of dysglycemia, insulin resistance, and dyslipidemia. We included 3862, 17.7-year-old, participants from the Avon Longitudinal Study of Parents and Children, followed up for 7 years. cfPWV, cIMT, and fasting plasma samples were repeatedly measured. We computed homeostatic model assessment (HOMA) of insulin resistance and percent pancreatic beta-cell function. Data were analyzed using logistic regression, linear mixed-effect, and cross-lagged structural equation models. A higher cfPWV at 17.7 years was associated with higher insulin at age 24.5 years (odds ratio, 1.25 [CI, 1.08-1.44]; P=0.003), which slightly attenuated after covariates adjustment. Higher cIMT at 17.7 years was associated with lower insulin (odds ratio, 0.06 [0.01-0.95]; P=0.046) at 24.5 years, after covariate adjustments. In mixed-effect models, the 7-year progression in cfPWV (predictor) was directly associated with the increase in triglyceride (outcome). cIMT progression was associated with the 7-year increase in LDL (low-density lipoprotein), triglyceride, and glucose. In cross-lagged models, higher cfPWV at 17.7 years was associated with higher insulin (β=0.06, SE, 0.12, P=0.014), HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 24.5 years. However, insulin, HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 17.7 years were not associated with cfPWV at 24.5 years. Higher cIMT at 17.7 years was associated with reduced insulin, HOMA of insulin resistance, and HOMA-percent pancreatic beta-cell function at 24.5 years, but not vice versa. Higher glucose at 17.7 years was associated with higher cfPWV and cIMT at 24.5 years only. Arterial stiffness in adolescence may be a causal risk factor for hyperinsulinemia and insulin resistance in young adulthood.


Chromatography in the downstream processing of biotechnological products.
Chromatography techniques are essential for the isolation and purification of most of the high value products of modern biotechnology. The economically sensible and technically satisfactory downstream processing of a therapeutic protein, usually involves a number of chromatographic steps. Its development and optimization require considerable knowledge of the various physico-chemical and engineering aspects of biochemical chromatography. This review addresses the various modes of chromatography and the design of chromatographic separation processes from a biotechnologist's point of view. Strategies for optimizing the structure of the downstream process are outlined and scaling up consideration are discussed. The importance of the different chromatographic methods in research and development is estimated in an analysis of protein purification schemes recently published in the literature. Finally, examples of the application of chromatographic procedures for process scale product purification in the biotechnological industry are given.


Evidence-based guidance for use of intrathecal morphine as an alternative to diamorphine for Caesarean delivery analgesia.
Intrathecal morphine in combination with fentanyl is an effective and safe alternative to diamorphine for Caesarean delivery analgesia. Evidence suggests minimal differences in clinical efficacy and side-effects between intrathecal morphine and diamorphine. Recommended intrathecal morphine doses for Caesarean delivery analgesia are 100-150 ug.


Development of a sensitive high-performance liquid chromatographic method for detection of aflatoxins in pistachio nuts.
A very sensitive method is described for the detection of aflatoxins in pistachio nuts. The method employs the extraction procedure used in the BF method (described in the Association of Official Analytical Chemists' Book of Methods) followed by an acid alumina column clean-up to remove sample components which would otherwise interfere in the final determinative step. The quantitation of the aflatoxins is carried out by high-performance liquid chromatography on a C18 reversed-phase column after conversion of aflatoxins B1 and G1 to their more fluorescent derivatives, B2a and G2a. The limit of detection was found to be 0.5 microgram/kg. The chromatograms were found to be free of interfering peaks and multiple injections showed excellent reproducibility.


Treatment of unexplained infertility with danazol.
In order to investigate the possible stimulatory effect of danazol on fertility, a randomized clinical trial was performed on 40 women with unexplained infertility. Twenty-one women received 200 mg danazol daily for 100 days and 19 women received a placebo for the same period. No pregnancies occurred in the placebo group during a 6 month follow-up period. In the danazol group, 5 pregnancies occurred of which 1 were ectopic and 3 went to term.


Measurement of the hysteretic thermal properties of W-doped and undoped nanocrystalline powders of VO2.
Hysteresis loops exhibited by the thermal properties of undoped and 0.8 at.% W-doped nanocrystalline powders of VO2 synthesized by means of the solution combustion method and compacted in pellets, are experimentally measured by photothermal radiometry. It is shown that: (i) the W doping reduces both the hysteresis loops of VO2 and its transition temperature up to 15 °C. (ii) The thermal diffusivity decreases (increases) until (after) the metallic domains become dominant in the VO2 insulating matrix, such that its variation across the metal-insulation transition is enhanced by 23.5% with W-0.8 at.% doping. By contrast, thermal conductivity (thermal effusivity) increases up to 45% (40%) as the metallic phase emerges in the VO2 structure due to the insulator-to-metal transition, and it enhances up to 11% (25%) in the insulator state when the local rutile phase is induced by the tungsten doping. (iii) The characteristic peak of the VO2 specific heat capacity is observed in both heating and cooling processes, such that the phase transition of the 0.8 at.% W-doped sample requires about 24% less thermal energy than the undoped one. (iv) The impact of the W doping on the four above-mentioned thermal properties of VO2 mainly shows up in its insulator phase, as a result of the distortion of the local lattice induced by the electrons of tungsten. W doping at 0.8 at.% thus enhances the VO2 capability to transport heat but diminishes its thermal switching efficiency.


Use of three-dimensional-three-dimensional digital subtraction angiography spin fusion protocol for complex aortoiliac endovascular interventions.
Complex endovascular aortic interventions in patients with excessive tortuosity or difficult gantry angles can be challenging. Although fusion imaging can help navigate these issues, it is based on preoperative imaging studies, which becomes skewed after introduction of stiff wires and large devices into the aorta. The subtraction spin protocol performs two cone-beam computed tomography scans to create a subtracted image of the contrast-filled vessels after wire and device placement to accommodate vessel distortion. We have reported a complex fenestrated endovascular aneurysm repair case with a highly angulated neck to highlight the advantages of the subtraction spin protocol in anatomically hostile endovascular repairs.


Riok3 inhibits the antiviral immune response by facilitating TRIM40-mediated RIG-I and MDA5 degradation.
The type I interferon (IFN) pathway is a key component of innate immune response upon invasion of foreign pathogens. It is also under precise control to prevent excessive upregulation and undesired inflammation cascade. In the present study, we report that Riok3, an atypical kinase, negatively regulates retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) sensing-induced type I IFN signaling. Riok3 deficiency selectively inhibits RNA viral replication in vitro, resulting from an upregulated type I IFN pathway. Mice with myeloid-specific Riok3 knockout also show a more robust induction of type I IFN upon RNA virus infection and are more resistant to RNA virus-induced pathogenesis. Mechanistically, Riok3 recruits and interacts with the E3 ubiquitin ligase TRIM40, leading to the degradation of RIG-I and melanoma differentiation-associated gene-5 (MDA5) via K48- and K27-linked ubiquitination. Collectively, our data reveal the mechanism that Riok3 employs to be a negative regulator of antiviral innate immunity.


Marginal Fit Evaluation of CAD/CAM All Ceramic Crowns Obtained by Two Digital Workflows: An In Vitro Study Using Micro-CT Technology.
To evaluate the marginal fit of CAD/CAM all ceramic crowns made from lithium disilicate and zirconia using two different fabrication protocols (model and model-less). Forty anterior all ceramic restorations (20 lithium disilicate, 20 zirconia) were fabricated from digital impressions using a CEREC Bluecam scanner. Two different digital workflows were used: a fully digital model-less approach and a printed model digital approach. The crowns were cemented on the respective prepared typodont teeth and marginal gap was evaluated using Micro-CT. Each specimen was analyzed in sagittal and trans-axial orientations, allowing evaluation of the marginal fit (vertical and horizontal) on each surface. Logarithmic transformation was used with a significance of 0.05. After that a reliability analysis was performed by re-measuring four randomized selected images for each specimen and performing intraclass correlations to determine any systematic bias in the measurements. Vertical measurements in the lingual, distal and mesial views had an estimated marginal gap ranging from 101.9 to 133.9 µm for lithium disilicate crowns and 126.4 to 165.4 µm for zirconia. No significant differences were found between model and model-less techniques. Both workflows are valid protocols for the fabrication of monolithic ceramic restorations. The use of a printed model did not improve the marginal fit of lithium disilicate or zirconia crowns. Both materials are also clinically acceptable, no matter which workflow was used to obtain the restoration.


Immunotherapy and Hepatocellular Cancer: Where Are We Now?
Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as "adjuvants" to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner.


Effect of intravenous, perioperative-administered lidocaine on serum levels of endocannabinoids and related N-acylethanolamines in children.
Endocannabinoids and N-acylethanolamines (NAEs) are compounds that play a significant role in nociception. The promising therapeutic opportunities in postoperative pain management are connected with intra-venous (i.v.) lidocaine administration as a part of multimodal analgesia. Therefore, we analyzed the influence of perioperative, i.v. lidocaine infusion in children on postoperative serum concentrations of endocannabinoids and NAEs. Forty-four children undergoing extensive spinal surgery were divided into two groups: the lidocaine group (LG; N.=23), anesthetized generally with lidocaine as a co-analgesic, and the non-lidocaine group (NLG; N.=21), anesthetized generally without lidocaine. We also recruited 23 healthy age- and gender-matched children to the control group. Blood samples were collected before surgery, immediately after surgery, at six hours, and following morning after surgery, while in healthy children we collected blood samples only once. The serum concentrations of endocannabinoids (anandamide [AEA] and 2-arachidonyl glycerol [2-AG]) and NAEs (palmitoylethanolamide [PEA] and oleoylethanolamide [OEA]) were quantified by ultra-high-performance liquid chromatography-mass spectrometry. The concentrations of measured compounds were comparable in controls and in patients before surgery (all P>0.05). During the postoperative period, we found significantly higher AEA and lower 2-AG concentrations in the LG when compared to the NLG. The highest concentration of PEA was observed in LG patients six hours after the operation and, at that time it was significantly elevated when compared to the NLG (P=0.0003). Perioperative, i.v. lidocaine administration influences postoperative serum concentrations of endocannabinoids and NAEs in children.


Preparation of a bioflocculant by using acetonitrile as sole nitrogen source and its application in heavy metals removal.
A novel bioflocculant, A-GS408, produced by Klebsiella oxytoca GS-4-08 cultured in acetonitrile (ACN) as sole nitrogen source was investigated in this study. A complete degradation of 1 g l-1 of ACN was achieved in 350 h, and 4.6 g of crude A-GS408 can be obtained in one litter of synthetic medium. The as-prepared bioflocculant exhibits good flocculation efficiency (over 90%) toward Kaolin solution with the aid of Fe3+. Chemical analysis showed that the bioflocculant was mainly composed of polysaccharides (46.3%) and proteins (20.6%). FTIR and XPS results indicated the abundant carboxyl, amine and hydroxyl groups in A-GS408 s, which play an important role on Pd2+ and Cu2+ adsorption. The adsorption of heavy metals can be well stimulated by Freundlich isotherm equation, and the Kf was up to 439.2 mg1-1/n l1/n g-1 and 112.2 mg1-1/n l1/n g-1 for Pb2+ and Cu2+, respectively. The kinetic fitting results proved that the adsorption of heavy metals by A-GS408 was chemisorption. This study may provide a new method for preparation of bioflocculant, which can not only degrade toxic compound i.e., acetonitrile, but also can reuse considerable nitrogen source from nitrile-containing wastewater.


Immune checkpoint inhibitors in people living with HIV: what about anti-HIV effects?
: Immune checkpoint inhibitors (ICPi) have shown major therapeutic successes when used in various cancers. In the HIV field a double benefit of such ICPi should result from their dual ability to restore in-vitro HIV-specific CD8 T-cell functions and to enhance HIV production from reservoir cells, thus fulfilling the goals of the 'shock and kill' concept proposed as an HIV cure therapeutic strategy. We conducted a systematic review to identify studies reporting the tolerance profile of ICPi and their effects on HIV plasma loads (pVL), CD4 cell count, HIV reservoirs (cell-associated HIV-DNA) and/or HIV-specific CD8 T cells in PLWH. Thirty-one articles were included for a total 176 participants. Twelve percent of the participants experienced severe adverse events and 49% nonsevere adverse events. pVL remained stable in 91.9% participant, showed increases in 5.8% participant, and decreases in 2.3%. CD4 cell count remained stable in 60.7% participants, showed increases in 24.6%, and decreases in 14.7%. Regarding ICPi effects on HIV-DNA and HIV-specific immunity, we identified three distinct profiles: profile I, transient pVL increases followed by a boost in HIV-specific CD8 T cells concomitant to a decrease in HIV-DNA, reported in one participant. Profile II: increase in HIV-specific CD8 T cells without changes in pVL or HIV-DNA, reported in three participants. III: no effect, reported in five participants. In conclusion, the clinical, virological and immunological safety profiles of ICPi reported in about 200 PLWH appear to be favorable but there are still modest results in terms of HIV cure strategy.


AAGL 2021 Endometriosis Classification: An Anatomy-based Surgical Complexity Score.
To develop a new endometriosis classification system for scoring intraoperative surgical complexity and to examine its correlation with patient-reported pain and infertility. Multicenter study of patients treated at 3 recognized endometriosis centers. Three specialized endometriosis surgical centers in São Paulo, Brazil and Barcelona, Spain. Patients aged 15 to 45 years with histologically proven endometriosis and no history of pelvic malignancy underwent laparoscopic treatment of endometriosis. Demographic data and clinical history, including dysmenorrhea, noncyclic pelvic pain, dyspareunia, dysuria and dyschezia, were prospectively recorded. All patients were staged surgically according to the new 2021 American Association of Gynecologic Laparoscopists (AAGL) and revised American Society of Reproductive Medicine (ASRM) classification systems. The staging for each system was compared against a 4-level surgical complexity scale defined by the most complex procedure performed. A total of 1224 patients undergoing surgery met inclusion criteria. The AAGL score discriminated between 4 stages of surgical complexity with high reproducibility (κ = 0.621), whereas the ASRM score discriminated between the complexity stages with poor reproducibility (κ = 0.317). The AAGL staging system correlated with dysmenorrhea, dyspareunia, dyschezia, total pain score, and infertility comparably with the ASRM staging system. The AAGL 2021 Endometriosis Classification allows for identifying objective intraoperative findings that reliably discriminate surgical complexity levels better than the ASRM staging system. The AAGL severity stage correlates comparably with pain and infertility symptoms with the ASRM stage.


Bis(2-amino-4-methyl-pyridinium) bis-(pyridine-2,6-dicarboxyl-ato)cuprate(II).
The asymmetric unit of the title compound, (C(6)H(9)N(2))(2)[Cu(C(7)H(3)NO(4))(2)], contains half of a [Cu(pydc)(2)](2-) (pydcH(2) is pyridine-2,6-dicarb-oxy-lic acid) anion and one protonated 2-amino-4-methyl-pyridine (2a4mpH)(+) counter-ion. The anion is a six-coordinated complex with a distorted CuN(2)O(4) octa-hedral geometry around the Cu(II) ion. N-H⋯O and C-H⋯O hydrogen bonds along with π-π contacts between the pyridine rings of the (2a4mpH)(+) cations [centroid-centroid distance = 3.573 (2) Å] stabilize the crystal structure.


Trends of Blood Cadmium Concentration Among Workers and Non-Workers in the United States (NHANES 2003 to 2012).
We aimed to explore the trends of blood cadmium (bCd) concentrations among workers and non-workers in the United States. We used serial cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) (2003 to 2012), including 23,243 subjects aged 20 and above. We used linear regression to analyze the trends of bCd levels adjusting for demographic variables and smoking status, stratified by occupations. The geometric mean of bCd levels was 0.362 μg/L. Only 0.21% had elevated bCd concentrations (≥5 μg/L). Women, older age, ethnic minorities, people of lower socio economic status (SES), current smokers, blue-collars, and non-workers tended to have higher bCd levels. The bCd concentrations were stable through years in workers (n = 12,787), but had a decline from 0.532 to 0.476 μg/L (P-trend = 0.006) in non-workers (n = 10,456). Cd exposure in the United States has been controlled to a safe level. Special protective measures should be taken for the lower SES group and blue-collars.