Further treatment with MPTP does not produce parkinsonism in marmosets showing behavioural recovery from motor deficits induced by an earlier exposure to the toxin.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or 0.9% saline, was administered to a group of common marmosets initially treated with the toxin 12-18 months previously. Initial treatment had consisted of a cumulative dose of 6-22 mg/kg (i.p.) which caused marked parkinsonism. Subsequently, the animals gradually recovered normal motor function. Further treatment consisted of a cumulative dose of MPTP of 78-83 mg/kg (i.p.) but this produced only modest akinesia. At 12-18 months after the initial treatment with MPTP, the content of dopamine, HVA and DOPAC in the caudate and putamen was markedly reduced. However, levels of dopamine, HVA and DOPAC in the nucleus accumbens were normal. Three months after the second treatment with MPTP there was no further decrease in the content of dopamine in the caudate-putamen. However, in the nucleus accumbens the content of dopamine, HVA and DOPAC was now reduced. The initial treatment with MPTP substantially decreased the binding of [3H]mazindol in the caudate-putamen but less so in the nucleus accumbens. Only a small additional decrease occurred upon further treatment with MPTP. The density of tyrosine hydroxylase (TH) immunoreactive cells in substantia nigra was reduced after the initial treatment with MPTP. However, the cell loss was far less marked than the decrease in terminal density, assessed by the binding of [3H]mazindol. Subsequent treatment with MPTP caused a small further loss of tyrosine hydroxylase-positive cells. Initial treatment with MPTP may kill the majority of MPTP-sensitive dopamine cells in the nigra. Compensation by the remaining nigrostriatal neurones may account for the behavioural recovery observed.(ABSTRACT TRUNCATED AT 250 WORDS)


The effects of beraprost sodium on renal function and cardiometabolic profile in patients with diabetes mellitus: a systematic review and meta-analysis of clinical trials.
This systematic review and meta-analysis aimed to assess renal function and cardiometabolic biomarkers after treatment with beraprost sodium in patients with diabetes mellitus. We systemically searched PubMed, Embase, Scopus, Web of Science, and Cochrane Library up to August 2020. Statistical heterogeneities were computed using Cochrane's Q test and I2 test. A fixed- or random-effects model was used to calculate the weighted mean difference (WMD) and corresponding 95% confidence intervals (CI). From 341citations, seven trials were included into our meta-analysis. Our findings demonstrated that beraprost sodium intake significantly decreased blood urea nitrogen (BUN) (WMD = -5.62, 95% CI [-8.49, -2.74], P < 0.001) and cystatin C (WMD = -0.57, 95% CI [-0.68, -0.46], P < 0.001). Beraprost sodium intake had no significant effect on fasting blood sugar (FBS), hemoglobin A1c (HbA1c), cholesterol (TC), triglycerides (TG), HDL-C, LDL-C, systolic blood pressure (SBP), diastolic blood pressure (DBP), and creatinine (Cr) in patients with diabetes receiving beraprost sodium in comparison with the controls. Our meta-analysis revealed that beraprost sodium administration significantly decreased BUN and cystatin C levels in patients with diabetes. However, no significant effect was observed on the cardiometabolic profile.


The effect of site and technique of splenic tissue reimplantation on pneumococcal clearance from the blood.
The technique and site of reimplantation of splenic tissue influences survival of laboratory animals following intravenous injection of pneumococci. Splenic tissue was prepared by slicing, mincing, or grating the spleen. The tissue was placed subcutaneously, intraperitoneally, retroperitoneally, or in an omental pouch. This study was designed to determine the rate of pneumococcal clearance from the blood stream 16 weeks following splenic reimplantation by four different methods. All animals were challenged with an intravenous 1 mL bolus containing 10(7) bacteria. The New Zealand white rabbits were divided into six groups: intact spleen; splenectomized; spleen slices in an omental pouch; minced spleen in an omental pouch; splenic tissue implanted subcutaneously; and bits of spleen dropped into the peritoneal cavity. Animals with an intact spleen and those with spleen slices implanted into an omental pouch cleared bacteria during the first hour and all bacteria had disappeared at three hours. Bacteremia persisted longer than three hours in the other groups. Splenic tissue had regenerated in all animals with omental pouch implants, in four of six with minced spleen dropped into the peritoneal cavity but in only one with a subcutaneous implant. Reimplanted splenic tissue clears pneumococci from the blood stream best when thin slices of spleen are placed in an omental pouch. This technique also assures successful regeneration of splenic tissue.


Mutation hotspots and spatiotemporal distribution of SARS-CoV-2 lineages in Brazil, February 2020-2021.
The COVID-19 pandemic has already reached more than 110 million people and is associated with 2.5 million deaths worldwide. Brazil is the third worst-hit country, with approximately 10.2 million cases and 250 thousand deaths. International efforts have been established to share information about Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemiology and evolution to support the development of effective strategies for public health and disease management. We aimed to analyze the high-quality genome sequences from Brazil from February 2020-2021 to identify mutation hotspots, geographical and temporal distribution of SARS-CoV-2 lineages by using phylogenetics and phylodynamics analyses. We describe heterogeneous sequencing efforts, the progression of the different lineages along time, evaluating mutational spectra and frequency oscillations derived from the prevalence of specific lineages across different Brazilian regions. We found at least seven major (1-7) and two minor clades related to the six most prevalent lineages in the country and described its spatial distribution and dynamics. The emergence and recent frequency shift of lineages (P.1 and P.2) carrying mutations of concern in the spike protein (e. g., E484K, N501Y) draws attention due to their association with immune evasion and enhanced receptor binding affinity. Improvements in genomic surveillance are of paramount importance and should be extended in Brazil to better inform policy makers about better decisions to fight the COVID-19 pandemic.


The efficacy of immune checkpoint inhibitors in elderly patients: a meta-analysis and meta-regression.
Immune checkpoint inhibitor (ICI) therapy has improved patient survival in advanced cancers; however, the efficacy of ICIs in elderly patients is still elusive. This study assessed the efficacy of ICIs in elderly patients with advanced cancer in terms of overall survival (OS) and progression-free survival (PFS). We carried out a systematic review and identified 30 head-to-head phase II/III randomized controlled trials that compared immunotherapy with the standard of care in advanced solid tumor patients. The data on patients younger or over 65 years of age were indexed from PubMed-Medline, Embase, and Scopus and obtained for meta-analysis. The subgroup analyses were stratified by primary tumor type, line of treatment, or type of immunotherapy, and a meta-regression analysis was carried out after adjusting for all other variables. The study included 17 476 patients, comprising 58% (10 119) younger (<65 years old) and 42% (7357) elderly (≥65 years old) patients. The hazard ratio (HR) for OS was 0.77 [95% confidence interval (CI) 0.70-0.85] and 0.77 (95% CI 0.70-0.85) in the younger and elderly groups, respectively, suggesting similar efficacies of ICIs in these two age groups. The subgroup analyses revealed no significant relationship between age and treatment outcomes, except for the PFS benefit in younger patients with melanoma than in elderly patients (HR 0.44 in younger patients versus 0.65 in elderly patients, P = 0.04). These results were further supported by meta-regression analysis, which showed no statistically significant difference in OS (P = 0.954) and PFS (P = 0.555) between the two age groups. The findings suggest that age-associated impairments of the immune system did not affect the efficacy of ICIs in elderly patients compared to younger patients. Therefore, the choice of ICIs for elderly patients can be considered, regardless of chronological age.


Interphase cytogenetics of the ICF syndrome.
Interphase behaviour of centromeric heterochromatin of chromosomes 1 and 16 has been investigated in lymphocytes and fibroblasts of patients with ICF syndrome and of normal subjects with non-isotopic in situ hybridization, using the satellite II-related probe pHuR 195. We found evidence for interphase somatic pairing in ICF lymphocytes with a frequency higher than that found in normal cells. Lymphocytes of ICF patients showed nuclear protrusions and micronuclei and these nuclear abnormalities consistently involved a hybridization signal. Somatic pairing was also present in fibroblasts, but with frequencies similar in normal and ICF subjects. The fibroblasts do not have the major chromosomal abnormalities found in lymphocytes. The degree of heterochromatin condensation in fibroblasts was lower than that in lymphocytes and we postulate that the more decondensed state of chromocentres in the fibroblasts could be the reason for the absence of the major chromosomal abnormalities.


Fluvoxamine-a new serotonin re-uptake inhibitor: first clinical and psychometric experiences in depressed patients.
The clinical efficacy of fluvoxamine (DU 23000)--the first selective serotonin re-uptake inhibitor of the new class of 2-aminoethyloximethers of aralkylketones was investigated in endormorphous depressed patients during 5 weeks treatment with mean daily dosages of approximately 150 mg DU 23000. A marked and statistically significant improvement of the overall and detailed psychopathology was noted by means of the Global Clinical Impression and Hamilton Rating Scale as early as in the first week of drug administration. Bipolar patients tended to improve more than unipolar ones, retarded depressions more than agitated ones. An additional anxiolytic medication was occasionally required. The drug was well tolerated. Psychometric and laboratory findings did not show any significant changes. The findings are discussed in the light of the indolamine hypothesis of depression.


Functional analysis of novel alpha-1 antitrypsin variants G320R and V321F.
Alpha-1 antitrypsin (AAT) gene is highly polymorphic, with a large number of rare variants whose phenotypic consequences often remain inconclusive. Studies addressing functional characteristics of AAT variants are of significant biomedical importance since deficiency and dysfunctionality of AAT are associated with liver and lung diseases. We report the results of the functional analysis of two naturally occurring AAT variants, G320R and V321F, previously identified in patients with lung disease. Neither of variants has been fully functionally characterized. In order to perform their functional analysis both variants were expressed in prokaryotic and eukaryotic systems and their intracellular localization, activity, stability, and polymerization were determined. The results of this study demonstrated that variants G320R and V321F have neither impaired activity against porcine pancreatic elastase nor propensity to form polymers. However, both variants had altered electrophoretic mobility and reduced thermostability when compared to M variant of the protein, indicating a slightly impaired secondary or tertiary structure.


Frog tectal efferent axons fail to regenerate within the CNS but grow within peripheral nerve implants.
Tectal efferent axons, located adjacent to the optic tract, fail to regenerate past diencephalic lesions in Rana pipiens even though optic axons regenerate after the same injury (M. J. Lyon and D. J. Stelzner, J. Comp. Neurol. 255: 511-525). We tested the possibility that tectal efferent axons can regenerate within peripheral nerve implants. A 6- to 8-mm segment of autologous sciatic nerve was implanted into the anterolateral (N = 23) or centrolateral (N = 22) portion of the dorsal surface of the tectum. Frogs survived for 6 (N = 16) or 12 weeks (N = 29) before the free end of the nerve was recut and HRP applied. A control group had the nerve crushed prior to the HRP application. Neurons within the tectum, near and medial to the implant site, were retrogradely labeled from the nerve graft in most experimental operates but no neurons were labeled in controls. In addition, neurons were also labeled in nuclei which projected to the tectum in a number of cases. Three times as many neurons were labeled in 12-week operates (42 +/- 46) as in 6-week operates (15 +/- 12). The morphology and location of labeled neurons in the tectum was similar to tectal efferent neurons except that the somal area of neurons labeled from the graft was significantly larger (41%) than normal tectal efferent neurons. The basic finding is similar to experiments using the same paradigm in the mammalian central nervous system (CNS). One difference is the minimal glial reaction at the graft insertion site.(ABSTRACT TRUNCATED AT 250 WORDS)


The association of food security with psychological distress in New Zealand and any gender differences.
Food security (access to safe, nutritious, affordable food) is intrinsically linked to feelings of stress or distress and it is strongly associated with socioeconomic factors. However, the impact of food insecurity on mental health, independent of confounding socioeconomic factors, is not clear. We investigated the association of food insecurity with psychological distress in New Zealand, controlling for socioeconomic factors. Secondarily, we examined the association in males and females. We used data from the Survey of Families, Income and Employment (SoFIE) (N = 18,955). Respondents were classified as food insecure if, in the last 12 months, they: used special food grants/banks, had to buy cheaper food to pay for other things, or went without fresh fruit and vegetables often. Psychological distress was measured using the Kessler-10 scale dichotomised at low (10-15) and moderate to high (16+). Logistic regression analyses were used to investigate the association of food insecurity with psychological distress using a staged modelling approach. Interaction models included an interaction between food security and gender, as well as interactions between gender and all other covariates (significant at p-value < 0.1). Models were repeated, stratified by gender. A strong relationship between food insecurity and psychological distress was found (crude odds ratio OR 3.4). Whilst substantially reduced, the association remained after adjusting for confounding demographic and socioeconomic variables (adjusted OR 1.8). In stratified models, food insecure females had slightly higher odds for psychological distress (fully adjusted OR 2.0) than males (fully adjusted OR 1.5). As such, an independent association of food insecurity with psychological distress was found in both males and females--slightly more so in females. However, we cannot rule out residual confounding as an explanation for the independent association and any apparent gender interaction.


Methyl jasmonate conditions parsley suspension cells for increased elicitation of phenylpropanoid defense responses.
Pre-incubation of suspension-cultured parsley cells with methyl jasmonate greatly enhances their ability to respond to fungal elicitors by secretion of coumarin derivatives. The effect is most pronounced at relatively low elicitor concentration and also observed for the incorporation of esterified hydroxycinnamic acids and of "lignin-like" polymers into the cell wall. These three responses correspond to defense reactions induced locally when a fungal pathogen attacks plant cells. In contrast, the conditioning of parsley cells by the signal substance methyl jasmonate is reminiscent of the developmental nature of systemic acquired resistance and renders the cells more effective for the elicitor-induced local defense reactions.


Netrin1 is required for neural and glial precursor migrations into the olfactory bulb.
Netrin1 (NTN1) deficiency in mouse brain causes defects in axon guidance and cell migration during embryonic development. Here we show that NTN1 is required for olfactory bulb (OB) development at late embryogenesis and at early postnatal stages to facilitate the accumulation of proper numbers of granular and glomerular neuron subtypes and oligodendrocytes into the OB. In addition to the analysis of Ntn1-/- mice we made tissue and neurosphere cultures to clarify the role of NTN1 in the anterior forebrain. We propose that a subset of neural progenitors/precursors requires NTN1 to efficiently enter the rostral migratory stream to migrate into the OB. The analysis of postnatal Ntn1-/- OBs revealed a reduction of specific types of interneurons which have been shown to originate from particular subregions of the lateral ventricle walls. Based on Ntn1 expression in ventral parts of the ventricle walls, we observed a decrease in the mainly ventrally derived type II interneurons that express calcium-binding proteins calretinin and calbindin. Instead, no change in the numbers of dorsally derived tyrosine hydroxylase expressing interneurons was detected. In addition to the specific reduction of type II interneurons, our results indicate that NTN1 is required for oligodendroglial migration into the OB. Furthermore, we characterised the Ntn1 expressing subpopulation of neurosphere-forming cells from embryonic and adult brain as multipotent and self-renewing. However, NTN1 is dispensable for the proliferation of neurosphere forming progenitor cells and for their differentiation.


Deletion of the short arm of chromosome 3 in breast tumors.
Deletions in the short arm of chromosome 3 have long been known to be common in many tumor types, including carcinomas of the lung and kidney. Small interstitial deletions of the proximal-central region of 3p, with band 3p14 as a minimal common deleted segment, have recently been shown to occur in as many as 10% of carcinomas of the breast, often as the only chromosomal change. Seemingly identical deletions may also be found in the epithelial cells of mixed-lineage benign tumors of the breast and even in diffuse proliferative breast disease, a disorder that would not normally be accepted as neoplastic, but never in completely normal breast tissue. The cytogenetic evidence therefore indicates that the putative tumor suppressor gene deleted from 3p14 influences cellular proliferation; evidently, its loss is often not sufficient for a fully malignant phenotype to emerge. The first information about FHIT, a candidate suppressor gene recently identified in the FRA3B fragile site in 3p14 and found to be abnormal or lost in a high percentage of carcinomas of various organs, including breast, is compatible with such a general proliferation-regulating role.


Maternal psychological functioning, family processes, and child adjustment in rural, single-parent, African American families.
A family process model was tested, linking adequacy of family financial resources to academic and psychosocial adjustment among 156 African American 6- to 9-year-old children with single mothers who lived in the rural South. Seventy five percent of the sample lived in poverty. Lack of adequate financial resources was associated with more depressive symptoms and lower self-esteem among mothers. Self-esteem was linked with family routines and mother-child relationship quality. The paths from mother-child relationship quality and family routines to child academic and psychosocial adjustment were mediated by the development of child self-regulation. An alternative partially mediated model improved the fit of the data for families with boys.


On the death of Kentuckian Charles Floyd, August 20, 1804--the only casualty of the Lewis and Clark expedition: a solution to a 200-year-old medical mystery.
As a member of the Lewis and Clark Expedition, Charles Floyd was the first United States soldier to die west of the Mississippi River. He was among his companions and developed the sudden onset of abdominal pain and was dead the next day. The most common medical opinion for cause of death has been acute appendicitis. However a new edition of his journal reveals signs and symptoms previously overlooked suggesting a genetically determined metabolic etiology, which is explored in this report to the conclusion that he died from acute intermittent porphyria.


Increasing the expression level of ChR2 enhances the optogenetic excitability of cochlear neurons.
Optogenetics comprise a promising alternative to electrical stimulation for characterization of neural circuits and for the next generation of neural prostheses. Optogenetic stimulation relies on expression of photosensitive microbial proteins in animal cells to initiate a flow of ions into the cells in response to visible light. Here, we generated a novel transgenic mouse model in which we studied the optogenetic activation of spiral ganglion neurons, the primary afferent neurons of the auditory system, and showed a strong optogenetic response, with a similar amplitude as the acoustically evoked response. A twofold increase in the level of channelrhodopsin expression significantly increased the photosensitivity at both the single cell and organismal levels but also partially compromised the native electrophysiological properties of the neurons. The importance of channelrhodopsin expression level to optogenetic stimulation, revealed by these quantitative measurements, will be significant for the characterization of neural circuitry and for the use of optogenetics in neural prostheses.NEW & NOTEWORTHY This study reveals a dose-response relationship between channelrhodopsin expression and optogenetic excitation. Both single cell and organismal responses depend on the expression level of the heterologous protein. Expression level of the opsin is thus an important variable in determining the outcome of an optogenetic experiment. These results are key to the implementation of neural prostheses based on optogenetics, such as next generation cochlear implants, which would use light to elicit a neural response to sound.


Relationship of vitamin D status with advanced liver fibrosis and response to hepatitis C virus therapy: a meta-analysis.
There is growing evidence that vitamin D is related to chronic hepatitis C (CHC) pathogenicity. We analyzed the relationship of vitamin D status with advanced liver fibrosis (ALF) in CHC treatment-naïve patients and sustained virologic response (SVR) in CHC patients on pegylated interferon alpha plus ribavirin (pegIFNα/ribavirin) therapy. We performed a meta-analysis of all eligible studies published to date (April, 2014) in PubMed, SCOPUS, LILACS, and the Cochrane Library, assessing plasma/serum vitamin D levels related to ALF and/or SVR. Pooled odds ratios (ORs) were estimated by either fixed or random effects models. Fourteen studies were selected from the literature search, seven for ALF (1,083 patients) and 11 for SVR (2,672 patients). For liver fibrosis, low vitamin D status was related to a diagnosis of ALF, with the cutoffs of 10 ng/mL (OR=2.37, 95% confidence interval [CI]=1.20, 4.72) and 30 ng/mL (OR=2.22, 95% CI=1.24, 3.97) being significant, and a near-significance for 20 ng/mL (OR=1.44, 95% CI=0.99, 2.12). Regarding SVR, a significant heterogeneity among studies was found (P<0.001), and we only found a significant association with SVR for a vitamin D cutoff of 20 ng/mL (OR=0.53, 95% CI=0.31, 0.91). When meta-analysis was performed excluding the outliers, significant pooled ORs were found for all patients (10 ng/mL [OR=0.48, 95% CI=0.34, 0.67] and 20 ng/mL [OR=0.58, 95% CI=0.45, 0.76]) and GT1/4 patients (10 ng/mL [OR=0.53, 95% CI=0.34, 0.81] and 20 ng/mL [OR=0.54, 95% CI=0.39, 0.74]). Low vitamin D status in CHC patients is associated with a higher likelihood of having ALF and lower odds of achieving SVR following pegIFNα/ribavirin therapy.


Quantification of orelabrutinib in human plasma and cerebrospinal fluid by liquid chromatography tandem mass spectrometry.
A sensitive and simple method was developed to determine orelabrutinib in human plasma and cerebrospinal fluid by liquid chromatography tandem mass spectrometry (LC-MS/MS). The samples were prepared by simple protein precipitation with by 0.1% formic acid acetonitrile solution and efficient separations were performed on the Thermo Hypersll GOLD C18 column (2.1 mm × 150 mm, 5 μm) under a gradient program in a total run time of 9 min. The orelabrutinib was detected by electrospray ionization in positive ion mode with selective reaction monitoring (SRM) and mass spectrometric conditions were optimized in order to increase selectivity and sensitivity. The developed method was validated in terms of its accuracy, precision, selectivity, linearity, recovery, matrix effect, stability, and limits of quantification (LOQ). The lower limit of quantification is 0.50 ng/mL, the intraday and interday precision RSD are both less than 15%, and the recovery rate is 85.7%-92.9%. Finally, the method was successfully applied for the quantitation of orelabrutinib in human plasma and cerebrospinal fluid of clinical patients treated with orelabrutinib.


Methodology minute: An overview of the case-case study design and its applications in infection prevention.
The case-case study design is a potentially useful tool for infection preventionists during outbreak or cluster investigations. This column clarifies terminology related to case-case, case-control, and case-case-control study designs. Examples of practical applications of the case-case study design include determining risk factors for health care-onset versus community-onset infections, or antibiotic-resistant versus antibiotic-susceptible infections.


Vitamin D deficiency and connective tissue disease.
Recently, the evidence linking vitamin D status as a potential environmental factor affecting autoimmune disease prevalence continues to accumulate. Beyond that the traditional known metabolic activities, vitamin D has been shown to modulate the immune system and has anti-inflammatory properties. The immune-regulatory role of vitamin D affects both the innate and adaptive immune responses contributing to the immune-tolerance of self-structures. Vitamin D deficiency skews the immunologic response towards loss of tolerance. Serum levels of vitamin D have been found to be significantly lower in several autoimmune or immune-mediated diseases than in the healthy population. Experimental animal models and clinical studies show that 1,25-dihydroxyvitamin D3 or vitamin D receptor (VDR) agonists can either prevent or suppress symptoms of type 1 diabetes, experimental autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erthyematosus and inflammatory bowel disease. The heading aims at reviewing the complex immune-regulatory role of vitamin D from the cellular and humoral level through animal models of autoimmune rheumatic diseases and representing the known contribution of vitamin D in the pathogenesis of connective tissue diseases. Increased vitamin D intakes might reduce the incidence and severity of autoimmune disorders besides reducing the rate of osteoporotic bone fracture.


Effects of Mind-Body Interventions on Adolescents' Cooperativeness and Emotional Symptoms.
Mind-body interventions may support the development of adolescents' self-regulation and provide a protective effect against maladaptive outcomes, e.g., internalizing and externalizing problems. The present study aimed at evaluating the effects of mindfulness-oriented meditation training (MOM) and autogenic training (AT) on a group of healthy Italian adolescents' character dimensions, emotional and behavioral difficulties. 72 adolescents were randomly assigned to MOM/AT conditions and tested before and after the 8-week trainings through self-report measures (Temperament and Character Inventory 125, TCI; Strengths and Difficulties Questionnaire for Adolescents, SDQ-A). Main analyses involved robust and repeated measures ANOVAs, carried out separately for character TCI and SDQ-A scales. After trainings, we found increased levels of cooperativeness and reduced emotional symptoms. Changes in these dimensions were negatively correlated: the more participants increased in their cooperativeness the greater decrease they showed in emotional symptoms. Both MOM and AT enhanced a cooperative attitude in adolescents and helped reducing their emotional problems. Therefore, it may be useful to apply these mind-body interventions in school settings as they can have a protective effect on the well-being and psychosocial adjustment of youths, through fostering their character maturity and helping them to better regulate their emotions.


Obesity-induced upregulation of miR-361-5p promotes hepatosteatosis through targeting Sirt1.
Obesity is associated with an increased risk of many metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms remain poorly understood. Recent studies have demonstrated that MicroRNA-mediated gene silencing plays an important role in hepatic triglyceride (TG) metabolism. In the present study, we aimed to investigate the pathological function of miR-361-5p in the development of NAFLD. Expression levels of miR-361-5p was determined by quantitative real-time PCR in livers of obese mice and NAFLD patients. Liver tissues from mice with miR-361-5p overexpression or inhibition were collected and analyzed by TG contents, gene expression profile. Expression of miR-361-5p was increased in the livers of two obese mouse models and NAFLD subjects. Overexpression of miR-361-5p in C57BL/6 mice led to hepatosteatosis, whereas inhibition of miR-361-5p expression in db/db mice improved TG accumulation and insulin sensitivity. Mechanistically, we identified Sirt1 as a direct target gene of miR-361-5p and re-introduction of Sirt1 largely abolished the metabolic action of miR-361-5p. Our results demonstrated the role of miR-361-5p in the regulation of hepatic TG homeostasis, which may provide potential therapeutic target for hepatosteatosis.


Reconfiguration of dynamic large-scale brain network functional connectivity in generalized tonic-clonic seizures.
An increasing number of studies in patients with generalized tonic-clonic seizures (GTCS) have reported the alteration of functional connectivity (FC) in many brain networks. However, little is known about the underlying temporal variability of FC in large-scale brain functional networks in patients. Recently, dynamic FC could provide novel insight into the physiological mechanisms in the brain. Here, we recruited 63 GTCS and 65 age- and sex-matched healthy controls. Dynamic FC approaches were used to evaluate alterations in the temporal variability of FC in patients at the region- and network-levels. In addition, two kinds of brain templates (>102 and > 103 regions) and two kinds of temporal variability FC approaches were adopted to verify the stability of the results. Patients showed increased FC variability in regions of the default mode network (DMN), ventral attention network (VAN) and motor-related areas. The DAN, VAN, and DMN illustrated enhanced FC variability at the within-network level. In addition, increased FC variabilities between networks were found between the DMN and cognition-related networks, including the VAN, dorsal attention network and frontal-parietal network in GTCS. Meanwhile, the alterations in FC variability were relatively consistent across different methods and templates. Therefore, the consistent alteration of FC variability would reflect a dynamic restructuring of the large-scale brain networks in patients with GTCS. Overly frequent information communication among cognition-related networks, especially in the DMN, might play a role in the epileptic activity and/or cognitive dysfunction in patients.


The role of co-occurring insomnia and mental distress in the association between lumbar disc degeneration and low back pain related disability.
Lumbar disc degeneration (LDD) is associated with low back pain (LBP). Although both insomnia and mental distress appear to influence the pain experience, their role in the association between LDD and LBP is uncertain. Our objective was to investigate the role of co-occurring insomnia and mental distress in the association between LDD and LBP-related disability. A total of 1080 individuals who had experienced LBP during the previous year underwent 1.5-T lumbar magnetic resonance imaging, responded to questionnaires, and participated in a clinical examination at the age of 47. Full data was available for 843 individuals. The presence of LBP and LBP-related disability (numerical rating scale, range 0-10) were assessed using a questionnaire. LDD was assessed by a Pfirrmann-based sum score (range 0-15, higher values indicating higher LDD). The role of insomnia (according to the five-item Athens Insomnia Scale) and mental distress (according to the Hopkins Symptom Check List-25) in the association between the LDD sum score and LBP-related disability was analyzed using linear regression with adjustments for sex, smoking, body mass index, education, leisure-time physical activity, occupational physical exposure, Modic changes, and disc herniations. A positive association between LDD and LBP-related disability was observed among those with absence of both mental distress and insomnia (adjusted B = 0.132, 95% CI = 0.028-0.236, p = 0.013), and among those with either isolated mental distress (B = 0.345 CI = 0.039-0.650, p = 0.028) or isolated insomnia (B = 0.207, CI = 0.040-0.373, p = 0.015). However, among individuals with co-occurring insomnia and mental distress, the association was not significant (B = -0.093, CI = -0.346-0.161, p = 0.470). LDD does not associate with LBP-related disability when insomnia and mental distress co-occur. This finding may be useful when planning treatment and rehabilitation that aim to reduce disability among individuals with LDD and LBP. Future prospective research is warranted.


Pharmacological profile of FK881(ASP6537), a novel potent and selective cyclooxygenase-1 inhibitor.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are now understood to fall into one of two agent classes in clinical use. Traditional NSAIDs inhibit both cyclooxygenases-1 and 2 (COX-1, 2), which act as key enzymes catalyzing the same reaction in the production of prostaglandins (PGs), while the second class of NSAIDs selectively inhibit COX-2. Inhibition of the inducible COX-2 isoform is believed to be responsible for the therapeutic effects of NSAIDs, such as anti-inflammatory, analgesic, and antipyretic effects, while COX-1 inhibition results in side-effects on the gastrointestinal (GI) system. In the present study, however, we changed this notion that inhibiting only COX-1 causes adverse effects. We discovered FK881, a specific COX-1 inhibitor which exhibits a 650-fold ratio for human whole blood COX-1/COX-2 and rats in vivo. In rats, FK881 dose dependently inhibited carrageenan-induced paw edema (ED30: 22 mg/kg; diclofenac ED30: 3.6 mg/kg, rofecoxib ED30: 26 mg/kg) and paw swelling associated with adjuvant arthritis (ED50: 17 mg/kg; diclofenac ED50: 1.4 mg/kg, rofecoxib ED50: 1.8 mg/kg). Further, FK881 dose dependently inhibited acetic acid-induced writhing in mice (ED50: 19 mg/kg; diclofenac ED50: 14 mg/kg, rofecoxib ED50: >100mg/kg) and adjuvant arthritis hyperalgesia in rats (ED50: 1.8 mg/kg; diclofenac ED50: 1.0mg/kg, rofecoxib ED50: 0.8mg/kg). However, unlike traditional NSAIDs, GI tolerability was improved, although the antipyretic effect of FK881 was weak (NOEL: >320 mg/kg; diclofenac NOEL: <1mg/kg, rofecoxib NOEL: 100 mg/kg). These results suggest that FK881 may be useful in treating symptoms of rheumatoid arthritis and osteoarthritis.


Photofuel cell coupling with redox cycling as a highly sensitive and selective self-powered sensing platform for the detection of tyrosinase activity.
A visible light-induced self-powered sensor for the detection of tyrosinase activity was proposed. A tyrosinase-responsive photoelectrochemical-chemical redox cycling strategy was integrated with a photofuel cell for signal amplification.


Seroprevalence of pestivirus infections is low in Belgian small ruminant flocks and is significantly associated with the presence of cattle.
A study was implemented to estimate the pestivirus seroprevalence in sheep and goats in Belgium, to identify circulating species and to check for a potential association between seropositivity of small ruminants and presence of cattle in the same farm. It was based on the testing of serum samples and bulk tank milk samples (BTM) collected in sheep and goat flocks in 2018-2019 all over the country. 7460 serum samples collected from 410 flocks were tested by a commercial ELISA able to detect antibodies (Ab) against Border Disease Virus (BDV), and Bovine Viral Diarrhea Virus (BVDV). BTM samples (n = 144) were collected from dairy flocks in November 2019 and tested with the same Ab ELISA. ELISA positive serum samples were also tested by virus neutralization test (VNT) for neutralizing antibodies against BDV, BVDV-type1 and BVDV-type2. Virological tests (RT-PCR) were performed on pools of serum samples from pestivirus-exposed flocks with at least two seropositive animals and on all Antibody-positive BTM samples. Information about serum and milk samples (identification, test results, farm of origin and location, presence of cattle) were gathered in animal-level and farm-level databases. Based on this study, the apparent animal seroprevalence for pestiviruses in small ruminant flocks in Belgium in 2018 was estimated to be 0.87 % (95 % C.I. [0.68 %-1.11 %]). The prevalence of flocks exposed to pestivirus (i.e. with at least one seropositive animal) was estimated to be 8.5 % (95 % C.I. [6.4 % - 11.6 %]). In exposed flocks, the average within-flock seroprevalence was 9.9 %. In dairy sheep and goats, the estimated proportion of exposed flocks in 2019, based on the detection of pestivirus antibodies in the bulk tank milk, was 9.7 % [5.9 %-15.7 %]. All PCR tests were negative, indicating the likely absence of active pestivirus circulation in these flocks. Although the observed pestivirus seroprevalence was found to be low in Belgian small ruminants, this study also showed, based on VNT results, that they are exposed to several pestivirus species: BDV, BVDV-1 and BVDV-2. 22.4 % of the farms included in the serological survey were holding both a small ruminant flock and a cattle herd, hence with a potential risk of contact between the two species. There was a significant positive association between pestivirus seropositivity in the sheep/goat flocks and the presence of a cattle herd in the same farm (OR = 2.42 (95 %C.I. [1.18-4.94]) but this association was not found for Ab-positive BTM in dairy flocks.


Adaptation of the Signal Noise Quotient MRI classification for graft ligamentization analysis following ATFL and CFL anatomical reconstruction: Validation of the SNQA.
Chronic ankle instability is the most frequent clinical sign of an antero tibiofibular (ATFL) and/or calcaneo fibular ligament (CFL) tear. One common surgical technique is to use the distal tendon of the gracilis muscle to reconstruct both the ATFL and CFL. In the knee, the hamstring tendons used in anterior cruciate ligament (ACL) reconstruction may go through structural modifications called "ligamentization ". A noninvasive MRI technique has been developed using the Signal/Noise Quotient to compare the signal of the graft following reconstruction to that of the posterior cruciate ligament. To our knowledge no studies have ever evaluated radiographic changes in the graft over time. The main goal of this study was to develop a specific MRI protocol to evaluate graft remodeling following ATFL and CFL reconstruction over time. A prospective study of the changes in the MRI signal of the ATFL-CFL graft 3-months postoperatively was performed in 20 patients. The main outcome was a comparison of the graft signal to that of the peroneal fibular tendon and the surrounding noise to determine the Ankle SNQ (SNQA). MRI images were evaluated by two senior radiologists to assess inter-rater reliability and then 2 weeks later for the intra-rater reproducibility. The intraclass correlation (ICC) showed excellent inter- and intra rater reliability for the ATFL SNQA (0.96 and 0.91, respectively); and for the CFL SNQA, the ICC was 0.97 and 0.99, respectively. Bland-Altman analysis showed very limited bias in the interpretation of SNQA. This preliminary study confirmed the inter- and intra- rater reliability of a new tool using the SNQA.


The role of psychological factors in cancer onset and progression.
Psychological factors have been presumed to play a role in cancer initiation and progression. This article critically reviews the literature on cancer and its potential connections to affective states, coping/defensive styles and personality traits, behaviors, and stressful life events. Much of the existing research is flawed by poor study design and analysis that have limited the reliability and validity of both negative and positive studies. While some psychological factors can be associated with cancer onset and progression, no direct links have been established. Recent studies have documented some medical and psychosocial benefits of psychotherapeutic intervention in patients with cancer.


Survey of human lymphoblastoid cell lines and primary cultures of normal and leukaemic leukocytes for oncornavirus production.
Velocity sedimentation of uridine-labelled cultures was found to be more reliable than isopycnic sedimentation in detecting oncornavirus production in lymphoid cells. Of 13 cell lines (including six derivea from Burkitt's lymphomas and two from leukaemic leukocytes) only one, the leukaemia-derived, Epstein-Barr virus-producing line QIMR-WIL, showed any activity. The nature of the QIMR-WIL particles was further defined by isolation of uridine-labelled 70S RNA and by the simultaneous assay for reverse transcriptase and 70S RNA, but production of such particles was detected in only three of 10 assays. Pretreatment of cells with 5'-iododeoxyuridine or culture in arginine-free medium did not induce particle production. Syncytia assays using XC cells were negative. Of 13 primary cultures (nine samples of leukaemic leukocytes and four of cord leukocytes) treated with mitogens and subjected to inducing conditions, one (leukocytes from a patient with acute myelogenous leukaemia) showed evidence in successive assays of oncornavirus synthesis. The low and transient yield of oncornavirus-like particles obtained in this work parallels that reported in previous studies of fresh lymphoid cells and primary cultures.


Light absorption potential of water-soluble organic aerosols in the two polluted urban locations in the central Indo-Gangetic Plain.
PM2.5 (particulate matter having aerodynamic diameter ≤2.5 μm) samples were collected during wintertime from two polluted urban sites (Allahabad and Kanpur) in the central Indo-Gangetic Plain (IGP) to comprehend the sources and atmospheric transformations of light-absorbing water-soluble organic aerosol (WSOA). The aqueous extract of each filter was atomized and analyzed in a high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS). Water-soluble organic carbon (WSOC) and WSOA concentrations at Kanpur were ∼1.2 and ∼1.5 times higher than that at Allahabad. The fractions of WSOC and secondary organic carbon (SOC) to total organic carbon (OC) were also significantly higher ∼53% and 38%, respectively at Kanpur compared to Allahabad. This indicates a higher abundance of oxidized WSOA at Kanpur. The absorption coefficient (babs-365) of light-absorbing WSOA measured at 365 nm was 46.5 ± 15.5 Mm-1 and 73.2 ± 21.6 Mm-1 in Allahabad and Kanpur, respectively, indicating the dominance of more light-absorbing fractions in WSOC at Kanpur. The absorption properties such as mass absorption efficiency (MAE365) and imaginary component of refractive index (kabs-365) at 365 nm at Kanpur were also comparatively higher than Allahabad. The absorption forcing efficiency (Abs SFE; indicates warming effect) of WSOA at Kanpur was ∼1.4 times higher than Allahabad. Enhancement in light absorption capacity was observed with the increase in f44/f43 (fraction of m/z 44 (f44) to 43 (f43) in organic mass spectra) and O/C (oxygen to carbon) ratio of WSOA at Kanpur while no such trend was observed for the Allahabad site. Moreover, the correlation between carbon fractions and light absorption properties suggested the influence of low-volatile organic compounds (OC3 + OC4 fraction obtained from thermal/optical carbon analyzer) in increasing the light absorption capacity of WSOA in Kanpur.


Ibrutinib combined with venetoclax for the treatment of relapsed/refractory diffuse large B cell lymphoma.
Treatment outcomes of relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) are far from satisfactory. Certain efficacy of ibrutinib has been observed in non-GCB subtype DLBCL patients. This study aimed to investigate the efficacy and safety of ibrutinib plus BCL2 inhibitor venetoclax in R/R DLBCL patients with non-GCB subtype and BCL2 overexpression. Combinational therapy (ibrutinib 560mg/day; venetoclax started 1 week later, oral dose increased from 100 to 400mg/day in 3 weeks) was conducted, and one cycle was 4 weeks. Both drugs were stopped when disease progress or serious adverse reactions appear. The primary end-point was overall response rate (ORR) at two cycles. From December 2018 to July 2020, a total of 13 patients were treated with the combined therapy. Among them, eleven (84.6%) patients previously received at least two treatment regimens, eight (61.5%) patients were C-myc and BCL2 double expression. The ORR at two cycles was 61.5%, with 3 (23.1%) patients achieved complete remission (CR) and 5 (38.4%) patients achieved partial remission (PR). The ORR at four cycles and six cycles was 53.8% and 46.2%, respectively. The median duration of response was 11 months (range, 1.5-13.6 months). The median progression-free survival and overall survival were 5.6 months (range, 0.4-15.6) and 11.3 months (range, 2.8-17.2), respectively. The most common adverse event was grade 1/2 neutropenia (53.8%), and nonhematologic toxicities included Grade1/2 diarrhea (46.2%) and elevated liver enzymes (30.8%). Combined therapy of ibrutinib and venetoclax showed promising efficacy and synergistic effects in R/R DLBCL patients with non-GCB subtype and BCL2 overexpression, and the toxicities were well-tolerated.


Conicity index as an indicator of abdominal obesity in individuals with chronic kidney disease on hemodialysis.
The conicity index is indicated as a tool for assessing the nutritional status of renal individuals undergoing hemodialysis. Thus, this study aimed to estimate the prevalence of abdominal obesity using the conicity index in individuals with chronic kidney disease undergoing hemodialysis to verify its association with sociodemographic, clinical, and lifestyle factors. This is a cross-sectional study with 941 individuals undergoing hemodialysis in a metropolitan area in southeastern Brazil. The conicity index was estimated and cutoffs of 1.275 and 1.285 for men and women, respectively, were used. For the analysis of the results, binary logistic regression was performed and the odds ratio (OR) was estimated with their respective confidence intervals (95% CI). The conicity index was high in 56.54% of men (95% CI: 34.34-70.16) and 43.46% of women (95% CI: 38.45-55.20). We found that both adult men (OR = 3.71; 95% CI: 2.27-6.07) and adult women (OR = 4.06; 95% CI: 2.41-6.84) were more likely to have abdominal obesity, as well as self-declared mixed-raced (OR: 1.74; 95% CI: 1.01-3.00) and single men (OR: 1.64; 95% CI: 1.00-2.68). The conicity index is an important anthropometric indicator to estimate abdominal obesity in individuals with chronic kidney disease on hemodialysis.


Designer zinc-finger proteins and their applications.
The Cys(2)His(2) zinc finger is one of the most common DNA-binding motifs in Eukaryota. A simple mode of DNA recognition by the Cys(2)His(2) zinc finger domain provides an ideal scaffold for designing proteins with novel sequence specificities. The ability to bind specifically to virtually any DNA sequence combined with the potential of fusing them with effector domains has led to the technology of engineering of chimeric DNA-modifying enzymes and transcription factors. This in turn has opened the possibility of using the engineered zinc finger-based factors as novel human therapeutics. One such synthetic factor-designer zinc finger transcription activator of the vascular endothelial growth factor A gene-has recently entered clinical trials to evaluate the ability of stimulating the growth of blood vessels in treating the peripheral arterial obstructive disease. This review concentrates on the aspects of natural Cys(2)His(2) zinc fingers evolution and fundamental steps in design of engineered zinc finger proteins. The applications of engineered zinc finger proteins are discussed in a context of the mechanism mediating their effect on the targeted DNA. Furthermore, the regulation of the expression of zinc finger proteins and their targeting to various cellular compartments and to chromatin and non-chromatin target templates are described. Also possible future applications of designer zinc finger proteins are discussed.


Air packaging is obviously beneficial to the heterogeneous hygrothermal degradation of konjac glucomannan.
Heterogeneous hygrothermal degradation (HHTD) is a cost-effective and environmentally friendly method for the successful preparation of partially depolymerized konjac glucomannan (DKGM). This study investigated the degradation of konjac glucomannan (KGM) in two packaging methods and detected that compared with natural KGM, the Mw of vacuum-packaged DKGM with 20 % moisture content treated at 130 °C for 40 min was reduced by 23.34 %, while that of air-packaged DKGM was decreased by 63.14 %, the vacuum-packaged DKGM with only 0.5 % H2O2 added was dropped by 69.36 %. It was verified that oxygen in air-packaging plays a crucial role in HHTD. Furthermore, the effects of moisture content, treatment temperature and time on the Mw and apparent viscosity of air-packaged DKGM were explored. The properties and structure of DKGM were characterized by rheometer, TGA, XRD, FT-IR and SEM. Results established that treatment temperature had a stronger promoting effect on HHTD. The rheological properties of DKGM samples changed markedly, and the thermal decomposition temperature and crystallinity were increased, with its infrared absorption peaks very close. This research is expected to provide theoretical bases and reference ideas for efficient HHTD method of KGM in actual production.


Placenta percreta leading to spontaneous complete uterine rupture in the second trimester. Example of a fatal complication of abnormal placentation following uterine scarring.
A 30-year-old gravida 2 para 1 was admitted to hospital 2 years after cesarean section at 20 weeks' gestation with acute onset of abdominal pain and hypovolaemic shock. Emergency laparotomy revealed a uterine rupture located in the anterior uterine wall caused by a placenta percreta and supracervical hysterectomy was performed. This site of invasion and finally rupture was in projection of the previous lower-segment cesarean section. This report illustrates the dramatic consequences of abnormal placentation after prior uterine surgery, which can already occur early during pregnancy and prior to the onset of labour.


The effect of dendritic cells on the retinal cell transplantation.
The potential of bone marrow cell-derived immature dendritic cells (myeloid iDCs) in modulating the efficacy of retinal cell transplantation therapy was investigated. (1) In vitro, myeloid iDCs but not BMCs enhanced the survival and proliferation of embryonic retinal cells, and the expression of various neurotrophic factors by myeloid iDCs was confirmed with RT-PCR. (2) In subretinal transplantation, neonatal retinal cells co-transplanted with myeloid iDCs showed higher survival rate compared to those transplanted without myeloid iDCs. (3) CD8 T-cells reactive against donor retinal cells were significantly increased in the mice with transplantation of retinal cells alone. These results suggested the beneficial effects of the use of myeloid iDCs in retinal cell transplantation therapy.


Molecular Hydrogen Promotes Adipose-derived Stem Cell Myogenic Differentiation via Regulation of Mitochondria.
Acute skeletal muscle injuries are common physical or sports traumas. Cellular therapy has excellent potential for regeneration after skeletal muscle injury. Adipose-derived stem cells (ADSCs) are a more accessible type of stem cell. However, it has a low survival rate and differentiation efficiency in the oxidative stress-rich microenvironment after transplantation. Although molecular hydrogen (H2) possesses anti-inflammatory and antioxidant biological properties, its utility in mitochondrial and stem cell research has not been adequately explored. This study aimed to reveal the role of H2 on adipose-derived stem cells' myogenic differentiation. The protective effects of H2 in ADSCs were evaluated by MTT assay, live-dead cell staining, western blot analysis, immunofluorescence staining, confocal imaging, and transmission electron microscopy. An appropriate volume fraction of H2 significantly decreased mitochondrial reactive oxygen species (ROS) levels, increased the number of mitochondria, and promoted mitophagy, thus enhancing the survival and myogenic differentiation of ADSCs. This study reveals the application potential of H2 in skeletal muscle diseases or other pathologies related to mitochondrial dysfunction.


Conditions of error priming in number-fact retrieval.
Analysis of errors in simple multiplication has shown that answers retrieved on previous trials are initially inhibited (negative error priming) but later are promoted as errors to subsequent problems (positive error priming). Two experiments investigated whether error priming is associated either with problem-specific retrieval processes or with representations of answers that can be manipulated independently of problems. In Experiment 1, answers were primed by visually presenting products for 200 msec prior to problems. Correct-answer primes facilitated retrieval, related-incorrect primes interfered with retrieval more than unrelated primes, and both effects were greater for more difficult problems. Primes affected only the trial on which they were presented, however, whereas both negative and positive error priming from previous problems were observed across trials. In Experiment 2, subjects named and retrieved multiplication products on alternating trials. Just-named products were inhibited as errors to the following multiplication problem (i.e., negative error priming), but, compared to positive priming from previous retrieved products, positive error priming from previously named numbers was weak. The results indicate that positive error priming is due mainly to an encoding or retrieval bias produced by previous problems, whereas negative error priming entails suppression, or de-selection, of answer representations.


The effects of single infusion of hypertonic sodium bicarbonate on body composition in neonates with acidosis.
Acid-base equilibrium and plasma and red blood cell water and solute were evaluated in a group of asphyxiated, acidotic neonates prior to and following infusion of hypertonic NaHCO3. The dose was calculated to correct the deficit of base in a bicarbonate space of 400 ml/kg and was given at a rate of 0.3 mM NaHCO3/kg/minute. All of the infants with RDS and two of the five with other forms of asphyxia received ventilatory assistance during the infusion. The quantity of base infused was sufficient to alter acid-base balance and shift whole blood and red blood cell pH values toward normal. The changes in body composition 3 minutes following the infusion indicate that the osmotic load imposed by the hypertonic NaHCO3 caused a shift of solute-free water into the interstitial and intravascular fluids. During the period from 3 to 30 minutes following the infusion there was redistribution of extracellular water and solute so that plasma volume and [Na]PL decreased. Since there was no evidence of an intracellular shift of solute, we hypothesize that the changes in body composition between 3 and 30 minutes postinfusion were in part the consequence of gradual penetration of transcellular fluids by Na. Osmotic inactivation of ECF Na by sequestration with connective tissue polyelectrolytes may also play a role. These studies' do not provide an answer to the clinical problem of whether the beneficial effects of prompt correction metabolic acidosis outweigh the potenially harmful effect of the osmotic alterations that accompany rapid infusion of hypertonic NaHCO3.


A model of the cost-effectiveness of intensity-modulated radiotherapy in comparison with three-dimensional conformal radiotherapy for the treatment of localised prostate cancer.
To determine the cost-effectiveness of intensity-modulated radiotherapy (IMRT) compared with three-dimensional conformal radiotherapy (3DCRT) for men with localised prostate cancer from a UK National Health Service perspective. A discrete event simulation model was developed to simulate the progress of patients through advancing disease states until death from prostate cancer or other causes. Clinical effectiveness data for IMRT and 3DCRT were derived from a systematic review. Four scenarios were modelled based on different clinical studies. A probabilistic sensitivity analysis was undertaken and the incremental cost per quality adjusted life years (ICER) calculated. In scenarios where estimated survival was greater for IMRT than 3DCRT, IMRT was clearly cost-effective (ICER <£20 000). For scenarios where only a difference in late gastrointestinal toxicity was assumed, the ICER was highly sensitive to uncertain model parameters, including the magnitude of the difference, the duration of gastrointestinal toxicity and the cost difference between treatments. For the most likely scenario, a 15% difference in late gastrointestinal toxicity, the ICER was £35 000, with a 20% probability that it is cost-effective at a maximum threshold of £20 000 and a 48% probability at a threshold of £30 000. If IMRT can be used to prolong survival, it is very cost-effective. Otherwise cost-effectiveness is uncertain.


Adipose Tissue-Mesenchymal Stem Cells Caused to Change the Methylation Status of hTERT Gene Promoter CpG Islands of Molt-4 Leukemia Cells as Cell-based Therapy.
DNA methylation was considered as prognostic information in some hematological malignancies. Previous studies have reported the in vitro and in vivo biology role of mesenchymal stem cells (MSCs) on leukemic cells. The aim of this study was to investigate the effect of MSCs on the promoter methylation status of hTERT as a catalytic subunit of telomerase enzyme. In the experimental study, the Molt-4 leukemic cells were co-cultured with MSCs for 7 days. At the end of the co-culture period, the Molt-4 cells were collected, DNA and protein were extracted. Then methylation specific-PCR and western blotting were done for evaluating the hTERT gene promoter methylation status and cyclin D1 and hTERT protein expression, respectively. In the following, the flow cytometry was done for cell cycle distribution assay. It was found that MSCs resulted in a significant decrease in the cyclin D1 and hTERT protein expression levels. Also, MSCs caused changes in the methylation status of the CpG islands in the hTERT gene promoter region. The following results showed that MSCs caused a significant increase in the number of cells at G0/G1 phase and arrest the G0/G1 phase as well as decrease in the cell proliferation of Molt-4 cells. It is concluded that co-culture of MSCs with Molt-4 cells could be involved in changing the methylation status of hTERT gene promoter, cell cycle and hTERT protein expression; it could be potentially beneficial for further investigations regarding the cell transplantation and cell-based therapy.


In-hospital cost-effectiveness analysis of open versus staged fenestrated/branched endovascular elective repair of thoracoabdominal aneurysms.
To compare costs and effectiveness of elective open (OR) vs fenestrated/branched endovascular (ER) repair of thoracoabdominal aneurysms (TAAAs) in a high-volume center. This single-center retrospective observational study (PRO-ENDO TAAA Study, NCT05266781) was designed as part of a larger health technology assessment analysis. All electively treated TAAAs between 2013 and 2021 were analyzed and propensity-matched. End points were clinical success, major adverse events (MAEs), hospital direct costs, and freedom from all causes and aneurysm-related mortality and reinterventions. Risk factors and outcomes were homogeneously classified according to the Society of Vascular Surgery reporting standards. Cost-effectiveness value and incremental cost-effectiveness ratio were calculated, considering the absence of MAEs as a measure of effectiveness. Propensity matching identified 102 pairs of patients out of 789 TAAAs. Mortality, MAE, permanent spinal cord ischemia rates, respiratory complications, cardiac complications, and renal injury were higher for OR (13% vs 5%, P = .048; 60% vs 17%, P < .001; 10% vs 3%, P = .045; 91% vs 18%, P < .001; 16% vs 6%, P = .024; 27% vs 6%, P < .001, respectively). Access complication rate (6% vs 27%; P < .001) was higher in the ER group. Intensive care unit stay was longer (P < .001) for OR, and ER patients were discharged home more frequently (3% vs 94%; P < .001). No differences in midterm end points were observed at 2 years. Despite ER reducing all the hospital cost items (-42% to -88%, P < .001), the higher expenses (P < .001) of the endovascular devices increased the overall cost of ER by 80%. Cost-effectiveness value for ER was favorable to OR (56,365 vs 64,903 €/patient) with an incremental cost-effectiveness ratio of 48,409 € per MAE saved. ER of TAAA reduces perioperative mortality and morbidity compared with OR, with no differences in reinterventions and survival rates at midterm follow-up. Despite the expenses for endovascular grafts, ER was found to be more cost-effective in preventing MAEs.


Effect of trimethoprim-sulfamethoxazole on Na and K+ transport properties in the rabbit cortical collecting duct perfused in vitro.
In this study, the membrane mechanisms of hyperkalemia caused by trimethoprim-sulfamethoxazole (TMP-SMX) combination antibiotics were assessed in the cortical collecting duct (CCD). We used the microelectrode technique and flux measurements, and examined the effects of TMP and SMX on electrical properties of the apical and basolateral membranes in the rabbit CCD perfused in vitro. TMP in the lumen caused increases in apical membrane voltage, fractional apical membrane resistance (fRA), and transepithelial resistance (RT), all effects which were completely inhibited by luminal amiloride, but not by luminal Ba2+. The luminal TMP inhibited both net Na+ reabsorption and K+ secretion in the CCD. TMP in the bath slightly but significantly depolarized transepithelial voltage and basolateral membrane voltage without influencing fRA or RT. SMX in the lumen or bath had no effect on barrier voltages or resistances. TMP mainly acts on the apical membrane of the CCD, inhibits the amiloride-sensitive macroscopic Na+ conductance in this membrane, and thereby decreases the net driving force for K+ exit across the membrane, resulting in an inhibition of K+ secretion. SMX in the lumen or bath had no effect on the CCD.


Expandable stents for malignant esophageal disease.
Esophageal cancer is diagnosed in about 400,000 patients each year worldwide, and its incidence is increasing faster than that of any other malignancy. This makes it the ninth most common malignancy and sixth on the list of cancer mortality causes. Most patients with esophageal cancer present at a stage that is too advanced for curative therapy, and many die within a few months. Treatment of dysphagia is the main goal of palliative care in more than 50% of incurable cases. Although many different palliative options for malignant dysphagia are available, expandable stent placement is the most commonly performed treatment modality.


Comparison of the effects of gelatin, Ringer's solution and a modern hydroxyl ethyl starch solution after coronary artery bypass graft surgery.
The aim of this study was to compare the effect of 6% hydroxyl ethyl starch solution with 4% gelatin and Ringer's solutions on the haemodynamic stability of patients after coronary artery bypass graft (CABG) surgery and immediately after discontinuation of cardiopulmonary bypass (CPB). This was a randomised, double-blind clinical trial of 92 patients who were candidates for on-pump CABG. After discontinuation of CPB, all patients were transferred to the intensive care unit (ICU) and divided randomly into three groups. The first group received Ringer's solution, the second group 4% gelatin, and the third 6% hydroxyl ethyl starch (HES) solution (Voluven). Haemodynamic parameters such as heart rate, mean arterial pressure, systolic blood pressure, diastolic blood pressure, central venous pressure, cardiac output and the presence of arrhythmias were documented. The volume needed for maintaining normal blood pressure and central venous pressure in the range of 10-14 mmHg was less in the HES group than in the other groups. The volume was similar however in the gelatin and Ringer's groups in the first 24 hours after surgery. Urinary output in the first four and 24 hours after surgery were significantly higher in the HES group than in the other two groups. Mean creatinine levels were significantly lower in the HES group. HES (6%) had a better volume-expanding effect than gelatin (4%) and Ringer's solutions, and its short-term effects on renal function were also better than gelatin and Ringer's solutions.


Sentinel lymph node biopsy in high-grade endometrial cancer: a systematic review and meta-analysis of performance characteristics.
A sentinel lymph node biopsy is widely accepted as the standard of care for surgical staging in low-grade endometrial cancer, but its value in high-grade endometrial cancer remains controversial. The aim of this systematic review and meta-analysis was to evaluate the performance characteristics of sentinel lymph node biopsy in patients with endometrial cancer with high-grade histology (registered in the International Prospective Register of Systematic Reviews with identifying number CRD42020160280). We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Embase databases all through the OvidSP platform. The search was performed between January 1, 2000, and January 26, 2021. ClinicalTrials.gov was searched to identify ongoing registered clinical trials. We included prospective cohort studies in which sentinel lymph node biopsy were evaluated in clinical stage I patients with high-grade endometrial cancer (grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, undifferentiated or dedifferentiated, and high-grade not otherwise specified) with a cervical injection of indocyanine green for sentinel lymph node detection and at least a bilateral pelvic lymphadenectomy as a reference standard. If the data were not reported specifically for patients with high-grade histology, the authors were contacted for aggregate data. We pooled the detection rates and measures of diagnostic accuracy using a generalized linear mixed-effects model with a logit and assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. We identified 16 eligible studies of which the authors for 9 of the studies provided data on 429 patients with high-grade endometrial cancer specifically. The study-level median age was 66 years (range, 44-82.5 years) and the study-level median body mass index was 28.6 kg/m2 (range, 19.4-43.7 kg/m2). The pooled detection rates were 91% per patient (95% confidence interval, 85%-95%; I2=59%) and 64% bilaterally (95% confidence interval, 53%-73%; I2=69%). The overall node positivity rate was 26% (95% confidence interval, 19%-34%; I2=44%). Of the 87 patients with positive node results, a sentinel lymph node biopsy correctly identified 80, yielding a pooled sensitivity of 92% per patient (95% confidence interval, 84%-96%; I2=0%), a false negative rate of 8% (95% confidence interval, 4%-16%; I2=0%), and a negative predictive value of 97% (95% confidence interval, 95%-99%; I2=0%). Sentinel lymph node biopsy accurately detect lymph node metastases in patients with high-grade endometrial cancer with a false negative rate comparable with that observed in low-grade endometrial cancer, melanoma, vulvar cancer, and breast cancer. These findings suggest that sentinel lymph node biopsy can replace complete lymphadenectomies as the standard of care for surgical staging in patients with high-grade endometrial cancer.


Solvation model dependency of helix-coil transition in polyalanine.
Helix-coil transitions in polyalanine molecules of length 10 are studied by multi-canonical Monte Carlo simulations. The solvation effects are included by either a distance-dependent dielectric permittivity or by a term that is proportional to the solvent-accessible surface area of the peptide. We found a strong dependence of the characteristics of the helix-coil transition from the details of the solvation model.


Cervical cancer survival prediction by machine learning algorithms: a systematic review.
Cervical cancer is a common malignant tumor of the female reproductive system and is considered a leading cause of mortality in women worldwide. The analysis of time to event, which is crucial for any clinical research, can be well done with the method of survival prediction. This study aims to systematically investigate the use of machine learning to predict survival in patients with cervical cancer. An electronic search of the PubMed, Scopus, and Web of Science databases was performed on October 1, 2022. All articles extracted from the databases were collected in an Excel file and duplicate articles were removed. The articles were screened twice based on the title and the abstract and checked again with the inclusion and exclusion criteria. The main inclusion criterion was machine learning algorithms for predicting cervical cancer survival. The information extracted from the articles included authors, publication year, dataset details, survival type, evaluation criteria, machine learning models, and the algorithm execution method. A total of 13 articles were included in this study, most of which were published from 2018 onwards. The most common machine learning models were random forest (6 articles, 46%), logistic regression (4 articles, 30%), support vector machines (3 articles, 23%), ensemble and hybrid learning (3 articles, 23%), and Deep Learning (3 articles, 23%). The number of sample datasets in the study varied between 85 and 14946 patients, and the models were internally validated except for two articles. The area under the curve (AUC) range for overall survival (0.40 to 0.99), disease-free survival (0.56 to 0.88), and progression-free survival (0.67 to 0.81), respectively from (lowest to highest) received. Finally, 15 variables with an effective role in predicting cervical cancer survival were identified. Combining heterogeneous multidimensional data with machine learning techniques can play a very influential role in predicting cervical cancer survival. Despite the benefits of machine learning, the problem of interpretability, explainability, and imbalanced datasets is still one of the biggest challenges. Providing machine learning algorithms for survival prediction as a standard requires further studies.


A preseason booster prolongs the increase of allergen specific IgG4 levels, after basic allergen intralymphatic immunotherapy, against grass pollen seasonal allergy.
Allergen specific IgG4 levels have been monitored as a surrogate marker for the tolerance inducing effect of subcutaneous immunotherapy (SCIT) in many studies. Its accuracy at group level has been well established, but IgG4 has not yet found its place in the daily care of immunotherapy patients. Intralymphatic immunotherapy (ILIT) is a novel route for allergy vaccination against pollen allergy, where an ultrasound-guided injection of 1000 SQ-U Alutard is given directly into a groin lymph node. The suggested standard dosing so far has been one injection with 4 weeks in-between. In total 3000 SQ-U with the treatment completed in 2 months. IgG4 was measured with Immulite technique and rhinoconjunctivitis symptoms were estimated with daily online questionnaires. Mann-Whitney U-test and Wilcoxon Signed Rank test were applied for comparisons between groups and within groups, respectively. The present study demonstrates that a single, preseason ILIT booster of 1000 SQ-U Alutard 5-grasses®, re-increases the allergen specific timothy-IgG4 levels, in patients already treated with ILIT before the previous pollen season. It also shows the feasibility of the ILIT-route for allergy vaccination of rhinitis patients, with or without concomitant asthma, with low degree of side effects and reconfirms high and sustained patient satisfaction. It is tempting to suggest that the allergen specific IgG4 levels can be used to build an intuitive algorithm for future clinical guidance of ILIT patients.Trial registration Is Intralymphatic Allergen Immunotherapy Effective and Safe?, ClinicalTrials.gov Identifier NCT04210193. Registered 24 December 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT04210193?term=NCT04210193&draw=2&rank=1.


Motion-picture recording of ultrafast behavior of polarized light incident at Brewster's angle.
Observing light propagation plays an important role in clarifying ultrafast phenomena occurring on femtosecond to picosecond time scales. In particular, observing the ultrafast behavior of polarized light is useful for various fields. We have developed a technique based on Polarization Light-in-Flight Holography, which can record light propagation as a motion picture that can provide information about the polarization direction. Here we demonstrate motion-picture recording of a phenomenon, which is characteristic of polarized light, by using the proposed technique. As a phenomenon, we adopted the behavior of a light pulse incident at Brewster's angle. We succeeded in recording the light reflection of specific polarized light by the proposed optical setup. The method of recording the motion-picture, reconstruction procedure, and the quantitative evaluation of the results are demonstrated.


Nucleotide sequence study of mouse 5.8S ribosomal RNA.
The primary structure of 5.8S mouse ribosomal RNA has been studied and compared to the structures previously established for other animal species. The results obtained show that mouse 5.8S ribosomal RNA yields pancreatic oligonucleotides with the same nucleotide sequence as the homologous oligonucleotides from rat cells. Furthermore T1 oligonucleotides of 5.8S ribosomal RNA from rat, mouse and human cells behave identically on fingerprinting fractionation and have the same composition as judged by pancreatic digestion. These results strongly suggest that the primary structures of 5.8S ribosomal RNA from rat, mouse and human cells are identical. This identity of structure is also found when the presence of several modified bases (psi and methylated bases) is considered. The findings emphasize the remarkable evolutionary stability of ribosomal gene structure. Comparison of the terminal regional of 5.8S RNA with those of 18S RNA reveals differences which imply a more complex mechanism underlying the maturation of 45S precursor RNA than the finding of identical structure would have suggested.


Combined CT, Fluoroscopic and IVUS Guidance for Percutaneous Treatment of a Postsurgical Pseudoaneurysm Following Repair of Ascending Thoracic Aortic Aneurysm.
Thoracic aortic pseudoaneurysms are a recognized complication following aortic arch replacement. The established first line treatment is surgical repair; however, this may not be feasible in all patients. Percutaneous treatment of ascending thoracic pseudoaneurysms has been described as an alternative for nonsurgical candidates. Utilization of multimodality imaging can prove invaluable in minimizing the risk of potentially fatal intra-procedural complications. We present a case of successful embolization using computer tomography-guided direct percutaneous puncture of the pseudoaneurysm, with concomitant endovascular treatment under fluoroscopic and intravascular ultrasound guidance in a patient with challenging vascular anatomy.


A Spectrum of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)-Diagnostic Utility of Perinatal Autopsy.
To describe the spectrum of congenital renal anomalies and emphasize the critical role of comprehensive autopsy examination in identifying CAKUT, especially of lower urinary tract malformations correlating with prenatal imaging methods. Retrospective analyses of CAKUT diagnosed at fetal autopsy were analyzed over a 7-y period and correlated with prenatal imaging findings. Among the 255 fetal autopsies, 45 cases were detected with CAKUT. Isolated (27%), syndromic CAKUT (51%), and CAKUT associated with other system anomalies (22%) were found. Hydronephrosis, followed by cystic renal diseases and agenesis were the common renal malformations. The gastrointestinal tract (GIT) was the commonest system associated with CAKUT. Among the syndromic CAKUT, the urorectal septum malformation (URSM) was the most frequent one, followed by VACTER-L, acrorenal syndrome, and OEIS complex. When correlating prenatal USG and autopsy findings, a significant change in final diagnosis was observed in 60% of cases. Extrarenal malformations and syndromic associations of CAKUT predominated over isolated ones. Detection of lower urinary tract anomalies in CAKUT is difficult through antenatal imaging methods if associated with oligohydramnios. In these circumstances, the perinatal autopsy has a significant role in arriving at the final diagnosis which guides the clinician in predicting the recurrence risk and the need for genetic workup.


Acute Ischemic Stroke Revealing ChAdOx1 nCov-19 Vaccine-Induced Immune Thrombotic Thrombocytopenia: Impact on Recanalization Strategy.
Vaccine-induced immune thrombotic thrombocytopenia is a rare syndrome following the ChAdOx1 nCov-19 or Ad26.COV2.S vaccine. Reported patients developed mainly venous thrombosis. We describe a case of a young healthy women suffering from acute ischemic stroke due to large vessel occlusion without cerebral venous thrombosis 8 days after vaccination and its consequences on recanalization strategy. Considering the thrombocytopenia, intravenous thrombolysis was contraindicated. She underwent mechanical thrombectomy with complete recanalization and dramatically improved clinically. Positive detection of anti-PF4-heparin-antibodies confirmed vaccine-induced immune thrombotic thrombocytopenia diagnosis. In case of acute ischemic stroke after recent ChAdOx1 nCov-19 or Ad26.COV2.S vaccine, platelet count should be systematically checked before giving thrombolysis, and direct mechanical thrombectomy should be proposed in patients with large vessel occlusion.


Synergetic Lipid Extraction with Oxidative Damage Amplifies Cell-Membrane-Destructive Stresses and Enables Rapid Sterilization.
Here, we introduce an innovative "poison arrowhead" approach for disinfection based on a nanosheet bacterial inactivation system that acts synergistically to achieve sterilization rates of >99.99 % (Escherichia coli) over an ultrashort time period (≈0.5 min). The two-dimensional MoS2 "arrowhead" configuration has a sharp edge structure that enables the vigorous extraction of lipids from cell membranes and subsequent membrane disruptions. In the presence of permonosulfate, a strong oxidant, sulfur vacancies containing MoS2 activate the stable molecules, which in turn produce reactive oxygen species (ROS) from edge sites to basal areas. This process not only scavenges some portion of the phospholipids to allow for MoS2 surface refreshment but also directly attacks proteins thereby inflicting further damage to injured cells and amplifying the cell-membrane-destructive stresses toward pathogenic microorganisms. With small amounts of the new material, we successfully disinfected natural water (≈99.93 % inactivation in terms of total bacteria) within 30 s.


Evolutionary insights into genome-wide nucleosome positioning.
A new study takes an evolutionary approach to investigate to what extent nucleosome positioning is determined by underlying sequence or by trans-acting factors.


Roles of RUNX in B Cell Immortalisation.
RUNX1 and RUNX3 are the main RUNX genes expressed in B lymphocytes. Both are expressed throughout B-cell development and play key roles at certain key developmental transitions. The tumour-associated Epstein-Barr virus (EBV) has potent B-cell transforming ability and manipulates RUNX3 and RUNX1 transcription through novel mechanisms to control B cell growth. In contrast to resting mature B cells where RUNX1 expression is high, in EBV-infected cells RUNX1 levels are low and RUNX3 levels are high. Downregulation of RUNX1 in these cells results from cross-regulation by RUNX3 and serves to relieve RUNX1-mediated growth repression. RUNX3 is upregulated by the EBV transcription factor (TF) EBNA2 and represses RUNX1 transcription through RUNX sites in the RUNX1 P1 promoter. Recent analysis revealed that EBNA2 activates RUNX3 transcription through an 18 kb upstream super-enhancer in a manner dependent on the EBNA2 and Notch DNA-binding partner RBP-J. This super-enhancer also directs RUNX3 activation by two further RBP-J-associated EBV TFs, EBNA3B and 3C. Counter-intuitively, EBNA2 also hijacks RBP-J to target a super-enhancer region upstream of RUNX1 to maintain some RUNX1 expression in certain cell backgrounds, although the dual functioning EBNA3B and 3C proteins limit this activation. Interestingly, the B-cell genome binding sites of EBV TFs overlap extensively with RUNX3 binding sites and show enrichment for RUNX motifs. Therefore in addition to B-cell growth manipulation through the long-range control of RUNX transcription, EBV may also use RUNX proteins as co-factors to deregulate the transcription of many B cell genes during immortalisation.


The impact of lurasidone on functioning and indirect costs in adults with bipolar depression: a post-hoc analysis.
The aim of this post-hoc analysis was to assess the impact of lurasidone monotherapy on functional impairment, productivity, and associated indirect costs in patients with bipolar depression. Data were analyzed from a 6-week randomized, double-blind (DB; NCT00868699), placebo-controlled trial of lurasidone monotherapy and a 6-month open label extension (OLE; NCT00868959) study. Patients with bipolar depression who completed the 6-week DB trial were subsequently enrolled in the OLE. Analysis of the OLE was limited to patients who either continued lurasidone (LUR-LUR) or switched from placebo to lurasidone monotherapy (PBO-LUR). The Sheehan Disability Scale (SDS), which measures functional impairment and productivity, was collected at DB baseline, DB week 6/OLE baseline, OLE month 3, and OLE month 6. Annual indirect costs were calculated based on days lost or unproductive from work/school due to symptoms. Effect sizes (ES) in functioning and days lost/unproductive were reported for the DB trial and mean changes for the OLE. A total of 485 patients were enrolled in the DB trial (lurasidone: n = 323; placebo: n = 162) and 316 were in the lurasidone monotherapy group during the OLE (LUR-LUR: n = 210; PBO-LUR: n = 106). In the DB trial, improvements in functioning (work: ES = 0.36, p = .0071; social: ES = 0.55, p < .0001; family: ES = 0.50, p < .0001) were significantly greater for lurasidone compared to placebo. Reductions in days lost (ES = 0.33, p = .0050) and unproductive (ES = 0.45, p = .0001) were significantly higher for lurasidone vs. placebo. This resulted in a greater reduction in indirect costs for lurasidone vs. placebo (least squares mean (standard error) = -$32,322 ($2,100) vs. -$20,091 ($2,838)). Improvements in functioning and productivity were sustained during the 6-month OLE for both LUR-LUR and PBO-LUR. Lurasidone monotherapy for the treatment of bipolar depression significantly improved functioning and reduced indirect costs vs. placebo at week 6. Significant improvements in functioning and productivity were sustained for 6 months for both LUR-LUR and PBO-LUR.


The benefits of tourism for rural community development.
While the main benefits of rural tourism have been studied extensively, most of these studies have focused on the development of sustainable rural tourism. The role of tourism contributions to rural community development remains unexplored. Little is known about what tourism contribution dimensions are available for policy-makers and how these dimensions affect rural tourism contributions. Without a clear picture and indication of what benefits rural tourism can provide for rural communities, policy-makers might not invest limited resources in such projects. The objectives of this study are threefold. First, we outline a rural tourism contribution model that policy-makers can use to support tourism-based rural community development. Second, we address several methodological limitations that undermine current sustainability model development and recommend feasible methodological solutions. Third, we propose a six-step theoretical procedure as a guideline for constructing a valid contribution model. We find four primary attributes of rural tourism contributions to rural community development; economic, sociocultural, environmental, and leisure and educational, and 32 subattributes. Ultimately, we confirm that economic benefits are the most significant contribution. Our findings have several practical and methodological implications and could be used as policy-making guidelines for rural community development.


Alkyl chain engineering on a dithieno[3,2-b:2',3'-d]silole-alt-dithienylthiazolo[5,4-d]thiazole copolymer toward high performance bulk heterojunction solar cells.
A new copolymer of dithienosilole and dithienylthiazolo[5,4-d]thiazole with a hexyl side chain on the 4-position of thiophene units was designed and synthesized. Polymer solar cells based on the polymer as a donor and PC(70)BM as an acceptor demonstrated a power conversion efficiency up to 5.88% with a high fill factor of 71.6%.


Effectiveness and safety of chronic hepatitis C treatment with direct-acting antivirals in patients with rheumatic diseases: A case-series.
Objectives: To assess the effectiveness and safety of interferon-free direct-acting antiviral (DAA) therapy for patients with concomitant hepatitis C virus (HCV) infection and rheumatic diseases (RDs), including rheumatoid arthritis (RA).Methods: This was a single-center observational case-series study conducted in Japan from 2014 to 2018. The primary endpoint was the sustained virological response (SVR) rate 24 weeks after the end of therapy (EoT24). We also evaluated hepatological and rheumatological outcomes and adverse events.Results: Of the 2314 patients with RDs, 18 received DAA therapy (RA = 11, other RDs = 7). The SVR rate for the initial DAA therapy was 89% (16/18). The remaining two achieved SVR with secondary DAA therapy. Along with HCV elimination, hepatological parameters improved significantly from baseline to EoT24. During the study period, no patients newly developed cirrhosis or HCC after HCV elimination. Several patients showed improvement in RDs activity. In RA patients, the simplified disease activity index decreased significantly from baseline to EoT24 (median [interquartile range]: 11.53 [5.14-14.89] vs. 4.06 [2.08-9.05], respectively). On-treatment adverse events were minimal, while two patients experienced tuberculosis reactivation after EoT.Conclusion: DAA therapy was effective and safe, providing hepatological and rheumatological benefits in HCV-infected patients with RDs. Immune reconstitution following HCV elimination should be noted.


Phosphodiesterase inhibitors--are they potential neuroleptic drugs?
It was suggested that phosphodiesterase (PDE) inhibitors may be potential neuroleptic drugs with a low risk of extrapyramidal symptoms. In the study presented, we compared the effects of the neuroleptics, haloperidol, and risperidone and the PDE10A inhibitor papaverine as well as the PDE4 inhibitor rolipram on retrieval of conditioned avoidance responding in the pole-jumping task and on locomotor activity. After acute administration, the substances used reduced locomotor activity dose-dependently. Both PDE inhibitors interfered with conditioned avoidance responding, suggesting neuroleptic-like effects. Risperidone showed a favourable profile of action. In all the doses tested, no signs of unspecific impairments in the performance of the instrumental task occurred. The profile of rolipram was similar. In the doses tested, only minor impairments in the performance of the instrumental task were found. Rolipram showed a similar effect to risperidone, suggesting therapeutic usefulness as an atypical neuroleptic. However, the use of this substance is limited by its emetic effects in therapeutically relevant doses.


Glenoid lateralization influences active internal rotation after reverse shoulder arthroplasty.
Improvement in internal rotation (IR) is not reliably achieved after reverse total shoulder arthroplasty (RSA). The purpose of this study was to evaluate the relationship between postoperative IR and glenoid-sided lateralization following RSA in an implant using metallic lateralization. A multicenter retrospective study of RSAs with minimum 1-year clinical follow-up was performed. Patients were stratified based on the amount of glenoid-sided implant lateralization into 4 groups: 0-2 mm (n = 57), 4 mm (n =238), 6 mm (n = 95), and 8 mm (n = 65). The primary study outcome was active IR at a minimum of 1 year postoperatively, measured both by spinal level and in degrees with the shoulder abducted to 90°. Secondary outcomes were active forward flexion and external rotation, belly press strength, and subjective patient-reported outcome (PRO) measures. Comparisons were made with 1-way analyses of variance. Linear regression analyses evaluating for the association of glenoid lateralization with active IR were also performed to control for additional confounders, including demographics and other implant variables such as glenosphere diameter, humeral lateralization, humeral version, and whether the subscapularis was repaired. A total of 455 patients were included in the study. The mean age was 69 years, and 48% of patients were male. IR differences varied by the method of measurement (spinal level vs. IR in degrees with arm abducted). Overall, patients with 8 mm of glenoid lateralization had significantly improved IR compared with all other lateralization groups. Patients with 6 mm of glenoid lateralization had significantly improved IR compared with the 0-2- and 4-mm groups. There were no significant differences in the secondary outcomes or PROs between lateralization groups. In the regression analysis, glenoid lateralization was the only implant-related variable that was significantly associated with improved IR for both measurement methods. Glenosphere diameter and humeral version were both significantly associated with IR measured in degrees with the arm abducted but not spinal level. For the studied implant system, glenoid lateralization of 6-8 mm was associated with improved active IR at 1 year compared to patients with less glenoid lateralization with no significant differences in active forward flexion, external rotation, or PROs. In a multivariable analysis, increased humeral retroversion was associated with increased IR at 90° and increasing glenosphere diameter was associated with decreased IR at 90°, whereas BMI, subscapularis repair, and humeral lateralization did not significantly affect active IR.


The Microbiome-Gut-Brain Axis, a Potential Therapeutic Target for Substance-Related Disorders.
Substance addiction is a complex worldwide public health problem. It endangers both personal life and social stability, causing great loss on economy. Substance-related disorder is considered to be a complicated chronic brain disorder. It resulted from interactions among pharmacological properties of addictive substances, individual susceptibility, and social-environmental factors. Unfortunately, there is still no ideal treatment for this disorder. Recent lines of evidence suggest that gut microbiome may play an important role in the pathogenesis of neuropsychiatric disorders, including substance-related disorders. This review summarizes the research on the relationship between gut microbiome and substance-related disorders, including different types of substance, different individual susceptibility, and the occurrence and development of substance-induced mental disorders. We also discuss the potentiation of gut microbiome in the treatment of substance-related disorders, especially in the treatment of substance-induced mental disorders and manipulation on individuals' responsiveness to addictive substances.


Neural activation to loss and reward among alcohol naive adolescents who later initiate alcohol use.
Adolescent alcohol use is associated with adverse psychosocial outcomes, including an increased risk of alcohol use disorder in adulthood. It is therefore important to identify risk factors of alcohol initiation in adolescence. Research to date has shown that altered neural activation to reward is associated with alcohol use in adolescence; however, few studies have focused on neural activation to loss and alcohol use. The current study examined neural activation to loss and reward among 64 alcohol naive 12-14 year olds that did (n = 20) and did not initiate alcohol use by a three year follow-up period. Results showed that compared to adolescents that did not initiate alcohol use, adolescents that did initiate alcohol use by the three year follow-up period had increased activation to loss in the left striatum (i.e., putamen), right precuneus, and the brainstem/pons when they were alcohol naive at baseline. By contrast, alcohol initiation was not associated with neural activation to winning a reward. These results suggest that increased activation in brain regions implicated in salience, error detection/self-referential processing, and sensorimotor function, especially to negative outcomes, may represent an initial vulnerability factor for alcohol use in adolescence.


Topical Tranexamic Acid: Risks, Benefits and Novel Complications in Aesthetic Plastic Surgery.
Antifibrinolytics, particularly tranexamic acid (TXA), are agents used to reduce bleeding. TXA is a synthetic reversible competitive inhibitor to the lysine receptor found on plasminogen. By reversibly binding to this site, it leads to plasminogen being unable to bind to fibrin and so prevents fibrinolysis, this stabilizes the clot and thus prevents hemorrhage. (Pekrul in Der Anaesth 70:515-521, 2021) It can be used either intravenously or topically but has never entered mainstream use in plastic surgery. (Pekrul in Der Anaesth 70:515-521, 2021) This is most likely due to understandable fears of thromboembolic events. On the other hand, the tempting benefits are reduced bleeding (perioperatively) decreased bruising and swelling, and thus increased aesthetic, important for obvious reasons. A review of the literature was done to go deeper on this issue, examining topical use in aesthetic surgery. Clear benefit was shown in the literature, it could be postulated that it would not be unwise to consider more research on topical use of TXA in certain cases, the benefits could greatly outweigh the risks. Old fears and conceptions, unsupported by the literature at the time of writing, should not hold back further research, and the benefits shown could even potentially justify the topical use of these agents in the near future. Further studies evaluating the utility of TXA in Panniculectomy and Abdominoplasty surgery should be performed especially, since only one was found which reported no significant benefit. Minor complications were present, such as minor delayed post-auricular skin healing, temporary unilateral marginal mandibular neuropraxia and increased cumulative seroma volume. These were novel findings and could warrant further investigation as well. After performing a review of the literature, it was seen that topical TXA generally adds benefit in aesthetic plastic surgery, with no particularly significant complications. We would like to bring more attention to the issue and support more studies on TXA use. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Cardiorespiratory fitness and acute aerobic exercise effects on neuroelectric and behavioral measures of action monitoring.
Cardiorespiratory fitness and acute aerobic exercise effects on cognitive function were assessed for 28 higher- and lower-fit adults during a flanker task by comparing behavioral and neuroelectric indices of action monitoring. The error-related negativity, error positivity, and N2 components, as well as behavioral measures of response speed, accuracy, and post-error slowing were measured following a 30-minute acute bout of treadmill exercise or following 30-minutes of rest. A graded maximal exercise test was used to measure cardiorespiratory fitness by assessing maximal oxygen uptake. Results indicated that higher-fit adults exhibited reduced error-related negativity amplitude, increased error positivity amplitude, and increased post-error response slowing compared with lower-fit adults. However, acute exercise was not related to any of the dependent measures. These findings suggest that cardiorespiratory fitness, but not acute aerobic exercise, may be beneficial to behavioral and neuroelectric indices of action monitoring following errors of commission by increasing top-down attentional control.