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Introduction Accounting for an estimated 1.10-1.76% of all lumbar herniations, lumbar intradural disc herniation (IDH) occurs primarily in males during the fourth to fifth decades of life. While not validated, congenital lumbar spinal stenosis (CLSS) is implicated as one precipitating factor for IDH. Case report We report 28-year-old Hispanic female with CLSS, severe obesity, and degenerative disk disease, with a history of minimally invasive surgical (MIS) decompression for a large paracentral L4-5 disc herniation at 25. After three years, the patient developed sudden burning dysesthesias in the L4-5 dermatomes bilaterally and temporary leg weakness. Lumbar magnetic resonance imaging exhibited severe L4-5 spinal stenosis, and the patient underwent repeat MIS decompression, which again provided her with adequate symptom resolution. However, 20 days postoperatively she developed cauda equina syndrome with anal dysfunction, and bilateral leg and foot weakness. Upon open surgical exploration we discovered a tense L4-5 dural protrusion. After a dorsal durotomy, a large IDH with a ventral dural tear was identified. Subsequent to adequate debulking of the IDH, the ventral tear was repaired, and an expansile duraplasty was performed. Overall, the patient's bladder and bowel function, pain, hypoesthesia, and motor strength all improved. Two weeks after surgery she presented with a lumbar pseudomeningocele that was managed conservatively. Conclusion This report not only highlights an atypical presentation of IDH and is the first case of CLSS linked with IDH, lending support to the hypothesis that CLSS can lead to IDH, but also provides a comprehensive review of IDHs.

Fibroblast growth factor receptor (FGFR) inhibitor treatment has become the first clinically approved targeted therapy in bladder cancer. However, it requires previous molecular testing of each patient, which is costly and not ubiquitously available.To determine whether an artificial intelligence system is able to predict mutations of the FGFR3 gene directly from routine histology slides of bladder cancer.We trained a deep learning network to detect FGFR3 mutations on digitized slides of muscle-invasive bladder cancers stained with hematoxylin and eosin from the Cancer Genome Atlas (TCGA) cohort (n = 327) and validated the algorithm on the "Aachen" cohort (n = 182; n = 121 pT2-4, n = 34 stroma-invasive pT1, and n = 27 noninvasive pTa tumors).The primary endpoint was the area under the receiver operating curve (AUROC) for mutation detection. Performance of the deep learning system was compared with visual scoring by an uropathologist.In the TCGA cohort, FGFR3 mutations were detected with an AUROC of 0.701 (p0.0001). In the Aachen cohort, FGFR3 mutants were found with an AUROC of 0.725 (p0.0001). When trained on TCGA, the network generalized to the Aachen cohort, and detected FGFR3 mutants with an AUROC of 0.625 (p = 0.0112). A subgroup analysis and histological evaluation found highest accuracy in papillary growth, luminal gene expression subtypes, females, and American Joint Committee on Cancer (AJCC) stage II tumors. In a head-to-head comparison, the deep learning system outperformed the uropathologist in detecting FGFR3 mutants.Our computer-based artificial intelligence system was able to detect genetic alterations of the FGFR3 gene of bladder cancer patients directly from histological slides. In the future, this system could be used to preselect patients for further molecular testing. However, analyses of larger, multicenter, muscle-invasive bladder cancer cohorts are now needed in order to validate and extend our findings.In this report, a computer-based artificial intelligence (AI) system was applied to histological slides to predict genetic alterations of the FGFR3 gene in bladder cancer. We found that the AI system was able to find the alteration with high accuracy. In the future, this system could be used to preselect patients for further molecular testing.

Introduction Spinal meningiomas constitute the majority of primary spinal neoplasms, yet their pathogenesis remains elusive. By investigating the distribution of these tumors across sociodemographic variables can provide direction in etiology elucidation and healthcare disparity identification. Methods To investigate benign and malignant spinal meningioma incidences (per 100,000) with respect to sex, age, income, residence, and race/ethnicity, we queried the largest American administrative dataset (1997–2016), the National (Nationwide) Inpatient Sample (NIS), which surveys 20% of United States (US) discharges. Results Annual national incidence was 0.62 for benign tumors and 0.056 for malignant. For benign meningiomas, females had an incidence of 0.81, larger (P = 0.000004) than males at 0.40; yet for malignant meningiomas, males had a larger (P = 0.006) incidence at 0.062 than females at 0.053. Amongst age groups, peak incidence was largest for those 65–84 years old (2.03) in the benign group, but 45–64 years old (0.083) for the malignant group. For benign and malignant meningiomas respectively, individuals with middle/high income had an incidence of 0.67 and 0.060, larger (P = 0.000008; P = 0.04) than the 0.48 and 0.046 of low income patients. Incidences were statistically similar (P = 0.2) across patient residence communities. Examining race/ethnicity (P = 0.000003) for benign meningiomas, incidences for Whites, Asian/Pacific Islanders, Hispanics, and Blacks were as follows, respectively: 0.83, 0.42, 0.28, 0.15. Conclusions Across sociodemographic strata, healthcare inequalities were identified with regards to spinal meningiomas. For benign spinal meningiomas, incidence was greatest for patients who were female, 65–84 years old, middle/high income, living in rural communities, White, and Asian/Pacific Islander. Meanwhile, for malignant spinal meningiomas incidence was greatest for males, those 45–65 years old, and middle/high income.

Poor aqueous solubility is a major limiting factor during the development of BCS Class II drug candidates in a solid oral dosage form. Conventional amorphous solid dispersion (ASD) systems focus on maximizing the rate and extent of release by employing water-soluble polymeric crystallization inhibitors; however, they often encounter rapid supersaturation and solution-mediated phase transformation (SMPT). Therefore, in this work, a controlled release membrane was introduced onto ASD beads to mitigate the SMPT problem. A membrane-reservoir controlled release amorphous solid dispersion (CRASD) bead system was designed, and the effects of the coating thickness and pore former content on drug release profiles were investigated. CRASD beads were manufactured by spray-coating polyvinyl acetate with polyvinylpyrollidone (PVP) as a pore former onto sugar bead substrates layered with the ASD reservoir of celecoxib and PVP. Raising the pore former content and/or lowering the coating level imparted higher release rates and supersaturation levels. The extent of release, measured by the area under the curve, was greatest when an optimal balance between the release rate and peak concentration could be established, corresponding to a high pore former/high coating level combination. Attributed to a thicker membrane structure with a higher pore former, rapid initial release could be achieved, yet controlled gradually for several hours, avoiding the critical threshold where the onset of SMPT predominates. The greater membrane capacity to transiently immobilize drug molecules (i.e., preserve amorphicity) and gradually release drug over a prolonged duration may be key to balancing supersaturation on both sides of the membrane; hence coating variables should be tactfully selected to exploit this benefit.

Time-resolved fluorescence spectroscopy (TRFS), i.e., measurement of fluorescence decay curves for different excitation and/or emission wavelengths, provides specific and sensitive local information on molecules and on their environment. However, TRFS relies on multiexponential data fitting to derive fluorescence lifetimes from the measured decay curves and the time resolution of the technique is limited by the instrumental response function (IRF). We propose here a multivariate curve resolution (MCR) approach based on data slicing to perform tailored and fit-free analysis of multiexponential fluorescence decay curves. MCR slicing, taking as a basic framework the multivariate curve resolution-alternating least-squares (MCR-ALS) soft-modeling algorithm, relies on a hybrid bilinear/trilinear data decomposition. A key feature of the method is that it enables the recovery of individual components characterized by decay profiles that are only partially describable by monoexponential functions. For TRFS data, not only pure multiexponential tail information but also shorter time delay information can be decomposed, where the signal deviates from the ideal exponential behavior due to the limited time resolution. The accuracy of the proposed approach is validated by analyzing mixtures of three commercial dyes and characterizing the mixture composition, lifetimes, and associated contributions, even in situations where only ternary mixture samples are available. MCR slicing is also applied to the analysis of TRFS data obtained on a photoswitchable fluorescent protein (rsEGFP2). Three fluorescence lifetimes are extracted, along with the profile of the IRF, highlighting that decomposition of complex systems, for which individual isomers are characterized by different exponential decays, can also be achieved.

Background and aim The liver is the primary organ affected by cholestasis, and complications such as renal injury, renal failure, and the need for renal transplantation are associated with cholestatic liver disease. There is substantial evidence indicating that reactive oxygen species (ROS) and mitochondrial impairment are fundamental mechanisms underlying cholestasis-induced hepatic and renal injury. Edaravone (EDV) is a potent radical scavenger and antioxidant that may prevent oxidative stress and improve impaired mitochondrial function in various diseases. This study was performed to evaluate the effects and mechanisms of action of EDV on hepatic and renal injury in an animal model of cholestasis. Methods Rats subjected to bile duct ligation (BDL) were treated with EDV 1 or 10 mg/kg/day intraperitoneally for 14 consecutive days. Biomarkers of oxidative stress and mitochondrial impairment in the liver and kidney were assessed in EDV-treated and untreated rats with cholestasis. Results Significant increases in tissue ROS level, lipid peroxidation, protein carbonylation, and oxidized glutathione level were detected in rats subjected to BDL. Additionally, significant decreases in tissue glutathione level and antioxidant capacity were observed in the hepatic and renal tissues of rats with cholestasis. Markers of mitochondrial impairment, including mitochondrial depolarization, lipid peroxidation, mitochondrial permeabilization, depleted adenosine triphosphate content, and decreased dehydrogenase activity, were also detected in rats subjected to BDL. Furthermore, portal inflammation, necrosis, and tissue fibrosis were detected in the liver and significant tubular atrophy and interstitial inflammation, as well as fibrotic lesions, were detected in the kidneys of rats with cholestasis. EDV treatment significantly mitigated cholestasis-associated hepatic and renal injury. Conclusions The antioxidative properties of EDV and its positive effects on the indices of mitochondrial function may be critical factors contributing to protection against cholestasis-associated hepatic and renal injury.

Objective To assess the contribution of large and small nerve fiber alteration in erythromelalgia (EM). Methods Thirty-three EM patients were included and underwent clinical evaluation based on EM severity score, DN4, and Utah Early Neuropathy Scale (UENS) score. Neurophysiological evaluation consisted in nerve conduction studies (NCS) for large nerve fibers and specific tests for small nerve fibers: electrochemical skin conductance, cold and warm detection thresholds, and laser evoked potentials. Finally, the evaluation of vascular changes was based on the presence of clinical feature of microvascular disorders and the measurement of the Toe Pressure Index (TPI). Results While 28 patients (85%) had vascular alteration on TPI or clinical features, 23 patients (70%) had small-fiber neuropathy on neurophysiological tests, and only 10 patients (30%) had large fiber neuropathy on NCS. Regarding clinical scores, there was no difference between groups (presence or absence of large- or small-fiber neuropathy or microvascular disorder) except for a higher UENS score in patients with large fiber neuropathy. Conclusion Peripheral neuropathy, mostly involving small nerve fibers, is almost as common as microvascular changes in EM, but remains inconstant and not related to a specific neuropathic pattern or higher clinical severity. Significance The association of neuropathic and vascular factors is not systematic in EM, this syndrome being characterized by different pathophysiological mechanisms leading to a common clinical phenotype.

Lung cancer is the second most common cancer and the main cause of cancer-related mortality worldwide. In spite of various efforts that have been made to facilitate the early diagnosis of lung cancer, most patients are diagnosed when the disease is already in stage IV, which is generally associated with the occurrence of distant metastases and a poor survival. Moreover, a large proportion of these patients will relapse after treatment, heralding the need for the stratification of lung cancer patients in addition to identifying those who are at a higher risk of relapse and, thus, require alternative and/or additional therapies. Recently, circulating tumor cells (CTCs) have been considered as valuable markers for the early diagnosis, prognosis and risk stratification of cancer patients, and they have been found to be able to predict the survival of patients with various types of cancer, including lung cancer. Additionally, the characterization of CTCs has recently provided fascinating insights into the heterogeneity of tumors, which may be instrumental for the development of novel targeted therapies. Here we review our current understanding of the significance of CTCs in lung cancer metastasis. We also discuss prominent studies reporting the utility of enumeration and characterization of CTCs in lung cancer patients as prognostic and pharmacodynamic biomarkers for those who are at a higher risk of metastasis and drug resistance.

miRNAs are evolutionarily conserved non-coding ribonucleic acids with a length of between 19 and 25 nucleotides. Because of their ability to regulate gene expression, miRNAs have an important function in the controlling of various biological processes, such as cell cycle, differentiation, proliferation, and apoptosis. Owing to the long-standing regulative potential of miRNAs in tumor-suppressive pathways, scholars have recently paid closer attention to the expression profile of miRNAs in various types of cancer. Melatonin, an indolic compound secreted from pineal gland and some peripheral tissues, has been considered as an effective anti-tumor hormone in a wide spectrum of cancers. Furthermore, it induces apoptosis, inhibits tumor metastasis and invasion, and also angiogenesis. A growing body of evidence indicates the effects of melatonin on miRNAs expression in broad spectrum of diseases, including cancer. Due to the long-term effects of the regulation of miRNAs expression, melatonin could be a promising therapeutic factor in the treatment of cancers via the regulation of miRNAs. Therefore, in this review, we will discuss the effects of melatonin on miRNAs expression in various types of cancers.

Lower limb disability is common in chronic stroke patients, and aquatic therapy is one of the modalities used for the rehabilitation of these patients.To summarize the evidence of the effects of aquatic therapy on lower limb disability compared to land-based exercises in post-stroke patients.MEDLINE, PsycInfo, CENTRAL, SPORTDiscus, PEDro, PsycBITE, and OT Seeker were searched from inception to January 2019. The search included only randomized clinical trials. Two reviewers independently examined the full text and conducted study selection, data extraction, and quality assessment. Data synthesis was applied to summarize information from the included studies. The quantitative analysis incorporated fixed-effect models.Of the 150 studies identified in the initial search, 17 trials (629 participants) satisfied the eligibility criteria. Aquatic therapy improved balance based on the Berg Balance Scale (BBS) (standardized mean difference [SMD], 0.72; 95% confidence interval [CI], 0.50-0.94; IAquatic therapy had a more positive effect on walking speed, balance, and mobility than land-based exercises. Further research is needed to confirm the clinical utility of aquatic therapy for patients following stroke in the long term.

Background This study aimed to investigate the effect of melatonin supplementation on endothelial function in patients with heart failure with reduced ejection fraction (HFrEF). Methods This is an analysis of the MeHR trial, a randomized double‐blinded placebo‐controlled clinical trial with two parallel arms of 1:1. Oral 10 mg melatonin tablets or placebo was administered for 24 weeks. Deference in the percentage of flow‐mediated dilatation (FMD) after the intervention was the primary outcome. Results Ninety‐two patients were included in the study (age: 62.7±10.3 years, 87.0% male, ejection fraction (EF): 28.6±8.1). After adjustment for baseline FMD and age, a statistically significant difference in post‐treatment FMD in favor of the melatonin group was seen (estimated marginal means [95%CI], melatonin: 7.84% [6.69–8.98], placebo: 5.98% [4.84–7.12], p = .027). There was no significant difference in the mean of post‐treatment systolic/diastolic blood pressure, serum total antioxidant capacity, and serum malondialdehyde (MDA) between groups. Subgroup analysis showed significant improvement in FMD and MDA in the melatonin group in nondiabetic patients, while no difference was seen between study groups in diabetic patients. Conclusions Melatonin supplementation in HFrEF might improve endothelial function; however, this beneficial effect might not be seen in diabetic patients.

Background Recent trials have revealed that sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are effective against hyperglycemia and also reduce micro- and macro-vascular complications in patients with type 2 diabetes mellitus (T2DM). Most of the beneficial cardiovascular effects have been investigated in patients with heart failure and coronary artery disease (CAD). Yet, few human studies have been conducted to investigate the molecular mechanisms underlying these clinically beneficial effects in patients with CAD. Accordingly, the EMPA-CARD trial was designed to focus on the molecular effects of empagliflozin in patients with T2DM and CAD. Methods In this multicenter, triple-blind randomized controlled trial, patients with documented known T2DM and CAD will be recruited. They will be randomized on a 1:1 ratio and assigned into two groups of empagliflozin 10 mg/daily and placebo. The primary endpoint is the effect of empagliflozin on changes of plasma interleukin 6 (IL-6) after 26 weeks of treatment. The secondary endpoints will consist of changes in other inflammatory biomarkers (Interleukin 1-beta and high-sensitive C-reactive protein), markers of oxidative stress, platelet function, and glycemic status. Discussion The EMPA-CARD trial mainly tests the hypothesis that SGLT2 inhibition by empagliflozin may improve inflammatory status measured as reduction in inflammatory biomarkers in patients with T2DM and CAD. The results will provide information about the underlying mechanisms of SGLT2 inhibition that mediate the beneficial effects of this medication on clinical outcomes. Trial registration Iranian Registry of Clinical Trials. www.IRCT.ir, Identifier: IRCT20190412043247N2. Registration Date: 6/13/2020. Registration timing: prospective.

Diabetic cardiomyopathy (DC) is associated with impaired endoplasmic reticulum (ER) function, development of ER stress, and induction of cardiac cell apoptosis. Preventive effects of BiP inducer X (BIX) were investigated against DC characteristic changes in a type 2 diabetes rat model. To establish diabetes, a high-fat diet and a single dose of streptozotocin were administered. Then, animals were assigned into the following groups: control, BIX, diabetic animals monitored for one, two, and three weeks. Diabetic rats were treated with BIX for one, two, and three weeks. Expressions of various ER stress and apoptotic markers were assessed by immunoblotting method. CHOP gene expression was assessed by Real-time PCR. Tissue expression of BiP was evaluated by immunohistochemistry method. Hematoxylin and eosin and Masson's trichrome staining were performed to assess histological changes in the left ventricle. Cardiac cell apoptosis was examined using TUNEL assay. BIX administration suppressed the activation of the ER stress markers and cleavage of procaspase-3 in the diabetic rats. Likewise, tissue expression of BiP protein was increased, while CHOP mRNA levels were decreased. These results were accompanied by reducing cardiac fibrosis and myocardial cell apoptosis suggesting protective effects of BIX against the development of DC by decreasing cardiomyocyte apoptosis and fibrosis.

Objective Evaluation of vitamin D supplementation on ovarian reserve in women with diminished ovarian reserve and vitamin D deficiency. Methods The study is a before-and-after intervention study that was performed on women with diminished ovarian reserve referred to Shahid Mofteh Clinic in Yasuj, Iran. Eligible women were prescribed vitamin D tablets at a dose of 50,000 units weekly for up to 3 months. Serum levels of vitamin D and AMH were evaluated at the end of 3 months. Significance level was also considered P ≤ 0.05. Results Our results have been showed there was a statistically significant difference in vitamin D levels of participants before [12.1(6.5)] and after [26(9.15)] the intervention (P P=0.02 ). Conclusion In conclusion, the results of the current study support a possible favorable effect of vitamin D on increase AMH expression by acting on the AMH gene promoter. Therefore, it is possible that vitamin D increases AMH levels without changing the antral follicle count/ovarian reserve.

BACKGROUND: The inborn errors of immunity (IEIs) are a group of heterogeneous disorders mainly characterized by severe and recurrent infections besides other complications including autoimmune and inflammatory diseases. In this study, we aim to evaluate clinical, immunological, and molecular data of monogenic IEI patients with and without autoimmune manifestations. METHODS: We have retrospectively screened cases of monogenic IEI in the Iranian PID registry for the occurrence of autoimmunity and immune dysregulation. A questionnaire was filled for all qualified patients with monogenic defects to evaluate demographic, laboratory, clinical, and molecular data. RESULTS: A total of 461 monogenic IEI patients (290 male and 171 female) with a median (IQR) age of 11.0 (6.0-20.0) years were enrolled in this study. Overall, 331 patients (72.1) were born to consanguineous parents. At the time of the study, 330 individuals (75.7) were alive and 106 (24.3) were deceased. Autoimmunity was reported in 92 (20.0) patients with a median (IQR) age at autoimmune diagnosis of 4.0 (2.0-7.0) years. Sixteen patients (3.5) showed autoimmune complications (mostly autoimmune cytopenia) as the first presentation of the disease. Most of the patients with autoimmunity were diagnosed clinically with common variable immunodeficiency (42.4). The frequency of sinusitis and splenomegaly was significantly higher in patients with autoimmunity than patients without autoimmunity. In patients with autoimmunity, the most common pathogenic variants were identified in LRBA (in 21 patients, 23.0), ATM (in 13 patients, 14.0), and BTK (in 9 patients, 10.0) genes. In the evaluation of autoimmunity by different genes, 4 of 4 IL10RB (100), 3 of 3 AIRE (100), 21 of 30 LRBA (70.0) mutated genes had the highest prevalence of autoimmunity. CONCLUSIONS: Autoimmune phenomena are common features among patients with monogenic IEI and are associated with a more complicated course of the disease. Therefore, when encountering autoimmune disorders especially in the setting of dysgammaglobulinemia, it would be appropriate to conduct next generation sequencing (due to phenocopies of IEI genes) to discover responsible genes for the immune dysregulation at an early stage of the disease.

Introduction Coronavirus 2019 (COVID-19) has led to an unprecedented global pandemic. Given highly variable clinical presentations, readily obtainable predictive biomarkers are urgently needed to identify patients are risk of severe disease and death. Anemia is commonly present in hospitalized patients yet its prognostic potential in COVID-19 remains largely unexplored. Methods We evaluated all adult patients at a large tertiary health system during the month of March 2020 who were diagnosed with COVID-19, excluding patients without a complete blood count (CBC) obtained at the time of diagnosis. Anemia was defined by as a hemoglobin (hgb) Results During the study period, 3,777 adults with COVID-19 were identified, of which 2,439 had a CBC. 861 patients (35.4%) met criteria for anemia, as shown in the Table, and they were significantly older and had a higher comorbidity burden. Mechanical ventilation was required in 531 patients (14.1%) and 629 patients (17%) were deceased. On multivariable logistic regression adjusting for age, sex, race, and Charlson comorbidity index (CCI), anemia was significantly associated with higher risk of mortality (adjusted OR [ORadj]: 1.45, 95% Confidence Interval [CI]: 1.17-1.80) and need for mechanical ventilation (ORadj: 2.03, 95% CI: 1.64-2.51). For mortality, the optimal cutoff of hgb by ROC curve was 12.5 g/dL in males and 12.1 g/dL in females. These hgb cutoff for mechanical ventilation were 13.5 g/dL for male and 11.0 g/dL for females. When applying these cutoffs to the definition of anemia, a stronger association was observed between anemia and mortality (ORadj 1.68, 95% CI: 1.22-1.93) and need for mechanical ventilation (ORadj 2.09, 95% CI: 1.68-2.61). We also performed a subgroup analysis of patients with a normal hemoglobin to assess the independent predictive value of red blood cell distribution width (RDW). Of the 1578 patients without anemia, 139 (8.8%) had an elevated RDW (>15%). On multivariable logistic regression adjusting for age, sex, race, and CCI, an elevated RDW was statistically associated with need for mechanical ventilation (ORadj: 1.74, CI: 1.12-2.69) and mortality (ORadj: 1.93, CI: 1.26-2.95). Conclusions In this single health system study, anemia was significantly associated with both need for mechanical ventilation and mortality in patients with COVID-19. Based on ROC analysis, the ideal cutoff for considering anemias a significant contributor to these outcomes was just below normal, suggesting that even mild anemia in the context of COVID-19 is an independent predictor of mortality and need for intubation. In addition, an elevated RDW in non-anemic patients was also independently predictive of mortality. Our analysis is limited by inability to determine the chronicity of baseline anemia. Given that a CBC is almost universally obtained on patients with COVID-19, this study identifies a readily accessible predictive biomarker to inform risk adaptive clinical care. The mechanisms by which anemia impacts outcomes in COVID-19 are likely to be multiple in nature and require further investigation. Table Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution).

Mammalian motor systems adapt to the demands of their environment. For example, muscle fibre types change in response to increased load or endurance demands. However, for adaptations to be effective, motoneurons must adapt such that their properties match those of the innervated muscle fibres. We used a rat model of chronic functional overload to assess adaptations to both motoneuron size and a key modulatory synapse responsible for amplification of motor output, C-boutons. Overload of Extensor Digitorum Longus (EDL) muscles was induced by removal of their synergists, Tibialis Anterior (TA) muscles. Following 21 days survival, EDL muscles showed an increase in fatigue resistance and a decrease in force output, indicating a shift to a slower phenotype. These changes were reflected by a decrease in motoneuron size. However, C-bouton complexes remained largely unaffected by overload. The C-boutons themselves, quantified by expression of vesicular acetylcholine transporter, were similar in size and density in the control and overload conditions. Expression of the post-synaptic voltage-gated potassium channel (KV2.1) was also unchanged. Small conductance calcium activated potassium channels (SK3) were expressed in most EDL motoneurons, despite this being an almost exclusively fast motor pool. Overload induced a decrease in the proportion of SK3+ cells, however there was no change in density or size of clusters. We propose that reductions in motoneuron size may promote early recruitment of EDL motoneurons, but that C-bouton plasticity is not necessary to increase the force output required in response to muscle overload.

We report two cases of foot ischemia combining microvascular thrombosis related to essential thrombocytemia (ET) and a proximal ulcerating atherosclerotic plaque. This suggests that myeloproliferative neoplasms could also trigger distal embolism from an unstable atherosclerotic plaque by creating a prothrombotic status. These distal ischemic events were the first ET manifestation and therefore lead to myeloproliferative neoplasm diagnosis. In ET, thrombosis event can occur with a normal platelet count. Furthermore, hemogram should be regularly controlled among JAK2 muted patients considering the frequent evolution from isolated JAK2 mutation to ET.

Background Burnout threatens patient care and clinicians are experiencing challenges within the practice environment. Little is known about nurse practitioner (NP) perceptions of burnout and its relationship to care quality and practice environment. We investigate the relationship between primary care NP burnout on perceptions of care quality and if the practice environment moderates the relationship between burnout and care quality. Methods This is a secondary analysis of cross-sectional survey data from 396 NPs. Burnout and care quality were measured using a single item, but the practice environment was measured using the Nurse Practitioner Primary Care Organizational Climate Questionnaire. Multi-level proportional odds cumulative logit models were built to test for associations between burnout and care quality and for moderation. Results Total, 25.3% of NPs reported burnout. Odds of perceiving higher quality of care was 85% less for NPs experiencing burnout compared to those not experiencing burnout. Practice environment did not moderate the relationship between burnout and care quality, but with a one unit increase in the practice environment subscales, the odds of NPs perceiving higher care quality increased anywhere from 3.83 to 7.57 times. Conclusion Burnout is related to lower perceptions of care quality but favorable environments were related to higher perceptions of quality.

The global pandemic appears to be a never ending challenge. With the authorities' reach shrinking, we can assume that Bacha Bazi is celebrated more than before. Perpetrators not only harass individuals but also put public health in peril by organizing gathering and parties. With both individual and public health and rights at stake, this pandemic could also be a chance to contain Bacha Bazi practices. It may be early to say this and we definitely need to collect more information before we reach any conclusion, but most importantly, we, from healthcare workers and youth workers to policymakers, need to take action. Awareness is the spark of our mobilization. As citizens we can be more critical towards traditions involving any kind of abuse. As healthcare workers, we can be alert when treating boys, adolescents and young adults. We can probably spot a hidden case of abuse and refer the victim accordingly. As citizens we can support policymakers who are committed to take action against harassment of this, and any other, kind and this can also be a crucial chance to address the shadows haunting our societies once and for all.

Undergoing a rhinoplasty can affect an individual's mental health either positively or negatively, depending upon how he or she perceives the results. Because of the impact that rhinoplasty may have on an individual's mental health and the cost of this surgery, it is important to understand the reasons that men decide to undergo rhinoplasty and the challenges they face when making the decision to have a rhinoplasty. Using a grounded theory method, we collected data by conducting interviews with 20 participants. We analyzed the data and initially obtained 684 initial codes. After we removed duplicate codes and carefully analyzed participants' interviews, a total of 497 codes remained. We developed these codes into 10 main categories and 32 subcategories. We found that the causal factors affecting the decision of Iranian men to undergo rhinoplasty included the following 5 categories: a lack of confidence; a desire to improve their appearance; a desire for attention from others; a need to keep up with the Joneses (i.e., a desire to show that one is as good as other people by getting what others have and doing what others do); and persuasion by others. Intervening factors affecting the decision of Iranian men to undergo rhinoplasty included the following 4 categories: family challenge; social atmosphere; financial problems; and unwanted consequences. Iranian men make the decision to undergo rhinoplasty by overcoming and ignoring these intervening factors. The primary variable in participants' decision to undergo rhinoplasty was the desire to improve their appearance.

This study intended to classify ad libitum–fed calves according to their milk replacer (MR) meal size using the K-means clustering approach. This study aimed to investigate the effects of MR meal size on feed intake, growth performance, and blood metabolic and hormones of ad libitum MR-fed calves. German Holstein calves (16 male and 16 female) were studied from birth until d 77 of age. All calves received first colostrum (2.5 kg) milked from their dams within 2 h after birth. Subsequent colostrum meals (subsequent 4 meals until 2.5 d of age; 2 meals/d) and MR (125 g of powder/L; 21.7% crude protein, 18.6% crude fat) were fed ad libitum by teat bucket until d 10 ± 2 of age. Afterward, calves were housed in group pens with automatic feeders for MR (maximum of 25 L/d) and concentrate from 10 ± 3 d of age. Half of the calves received MR supplemented with butyrate to improve growth performance. Milk intake was stepped down to 2 L/d from wk 9 to 10, and 2 L/d of MR were offered until the end of the study. On d 1, 2, 4, and 7, and then weekly until wk 11 of age, blood samples were collected for measurement of metabolites and hormones related to energy metabolism and growth. The K-means cluster analysis on the MR meal size data collected from the automatic feeder resulted in 3 clusters (n = 14, n = 12, and n = 6). Two clusters with a sufficient cluster size (n = 14 and n = 12) were included for further statistical analysis using repeated measures mixed-model ANOVA. In both clusters, butyrate supplementation was equally distributed and failed to affect a difference in MR meal size. Cluster 1 showed calves with higher MR meal size (HI; 2.2 ± 0.11 L/visit of MR) and cluster 2 with lower meal size (LO; 1.8 ± 0.07 L/visit of MR) supplemented MR without (HIB−; n = 6; LOB−, n = 7) or with 0.33% calcium-sodium butyrate (HIB+; n = 6; LOB+, n = 7). Dry matter intake of MR did not differ between HI and LO, but intakes of concentrate and total dry matter tended to be greater in HI than in LO and increased more distinctly in HI than in LO at the end of the study. The average daily gain (g/d) was greater in HI than in LO. Plasma concentrations of total protein (g/L), albumin (g/L), glucose (mmol/L), urea (mmol/L), insulin (µg/L), and glucagon (ng/L) were higher, and the concentrations of insulin-like growth factor I tended to be higher, in HI than in LO calves. Plasma β-hydroxybutyrate was higher in LO than in HI at d 63 and lower in calves fed MR with butyrate at d 77. In conclusion, clustering analysis discriminates 2 main groups of calves with different MR meal size and indicates an effect of MR meal size on solid feed intake, growth performance, and metabolic changes.

Background: Fetal heart rate (FHR) extracted from abdominal electrocardiogram (ECG) is a powerful non-invasive method in appropriately assessing the fetus well-being during pregnancy. Despite significant advances in the field of electrocardiography, the analysis of fetal ECG (FECG) signal is considered a challenging issue which is mainly due to low signal to noise ratio (SNR) of FECG. Objective: In this study, we present an approach for accurately locating the fetal QRS complexes in non-invasive FECG. Materials and Methods: In this experimental study, the proposed method included 4 steps. In step 1, comb notching filter was employed to pre-process the abdominal ECG (AECG). Furthermore, low frequency noises were omitted using wavelet decomposition. In next step, principal component analysis (PCA) and signal quality assessment (SQA) were used to obtain an optimal AECG reference channel for maternal R-peaks detection. In step 3, maternal ECG (MECG) was removed from mixture signal and FECG was extracted. In final step, the extracted FECG was first decomposed by discrete wavelet transforms at level 10. Then, by employing details of levels 2, 3, 4, the new FECG signal was reconstructed in which various noises and artifacts were removed and FECG components whose frequency were close to the fetal QRS complexes remained which increased the performance of the method. Results: For evaluation, 15 recordings of PhysioNet Noninvasive FECG database were used and the average F1 measure of 98.77% was obtained. Conclusion: The results indicate that use of both an efficient analysis of major component of AECG along with a signal quality assessment technique has a promising performance in FECG analysis.

Hematopoietic cell transplantation is a critical curative approach for many blood disorders. However, obtaining grafts with sufficient numbers of hematopoietic stem cells (HSCs) that maintain long-term engraftment remains challenging; this is due partly to metabolic modulations that restrict the potency of HSCs outside of their native environment. To address this, we focused on mitochondria. We found that human HSCs are heterogeneous in their mitochondrial activity as measured by mitochondrial membrane potential (MMP) even within the highly purified CD34+CD38−CD45RA−CD90+CD49f+ HSC population. We further found that the most potent HSCs exhibit the lowest mitochondrial activity in the population. We showed that the frequency of long-term culture initiating cells in MMP-low is significantly greater than in MMP-high CD34+CD38−CD45RA−CD90+ (CD90+) HSCs. Notably, these 2 populations were distinct in their long-term repopulating capacity when transplanted into immunodeficient mice. The level of chimerism 7 months posttransplantation was >50-fold higher in the blood of MMP-low relative to MMP-high CD90+ HSC recipients. Although more than 90% of both HSC subsets were in G0, MMP-low CD90+ HSCs exhibited delayed cell-cycle priming profile relative to MMP-high HSCs. These functional differences were associated with distinct mitochondrial morphology; MMP-low in contrast to MMP-high HSCs contained fragmented mitochondria. Our findings suggest that the lowest MMP level selects for the most potent, likely dormant, stem cells within the highly purified HSC population. These results identify a new approach for isolating highly potent human HSCs for further clinical applications. They also implicate mitochondria in the intrinsic regulation of human HSC quiescence and potency.

Peri-implantitis (PI) is a multifactorial condition caused by the interactions of pathogens and the host immune response. Previous studies have demonstrated a relationship between PI and specific gene polymorphisms, particularly cytokine genes involved in the pathogenesis of PI. This study aimed to evaluate the frequency of single nucleotide polymorphisms (SNPs) of interleukin-10 (IL-10), interleukin 1s (IL-1s), and tumor necrosis factor-α (TNF-α) genes in PI patients and healthy controls. A total of 50 patients with PI and 89 periodontally healthy controls were recruited for this study. Venous blood samples (5 cc) were collected, and DNA was extracted. After DNA purification, the relevant gene segments were amplified by polymerase chain reaction (PCR). Restriction fragment length polymorphism (RFLP) and electrophoresis were performed to assess the polymorphisms of the related genes. The analysis revealed that allele and genotype frequencies of IL-10 ─ 819 C/T, IL-10 ─ 592 C/A, and IL-1s + 3954 C/T significantly differed between PI patients and healthy controls. The analysis revealed no significant association between TNF-α ─ 857 G/A and TNF-α ─ 308 G/A polymorphisms and PI. Our results indicated that specific gene polymorphisms of IL-10 ─ 819 C/T, IL-10 ─ 592 C/A, and IL-1s + 3954 C/T may play a role in the pathogenesis of PI, and increase its risk of occurrence.

Introduction: The cholestatic liver disease primarily affects hepatic tissue. Cholestasis could also influence the function of other organs rather than the liver. Cholestasis-induced renal injury is a severe clinical complication known as "cholemic nephropathy" (CN). Bile duct ligation (BDL) is a reliable experimental tool for inducing CN. Although the precise mechanism of renal injury in cholestasis is not fully recognized, several studies mentioned the role of oxidative stress in this complication. There is no promising pharmacological intervention against CN. Carnosine (CAR) is a dipeptide widely investigated for its pharmacological effects. Radical scavenging and antioxidative stress are major features of CAR. The current study was designed to evaluate the role of CAR supplementation on the CN. Methods: CAR (250 and 500 mg/kg, i.p) was administered to BDL rats for 14 consecutive days. Serum and urine markers of renal injury, biomarkers of oxidative stress in the kidney tissue, and renal histopathological alterations were monitored. Results: Significant elevation in oxidative stress biomarkers, including ROS formation, oxidized glutathione (GSSG) levels, lipid peroxidation, and protein carbonylation were found in the kidney of BDL rats. Moreover, renal tissue antioxidant capacity and reduced glutathione (GSH) levels were significantly decreased in the renal tissue of cholestatic animals. Renal histopathological alterations, including tubular atrophy, interstitial inflammation, tissue fibrosis, and cast formation, were detected in the kidney of BDL rats. It was found that CAR administration significantly protected the renal tissue of cholestatic animals. Conclusion: The antioxidative properties of this peptide might play a fundamental role in its protective properties during cholestasis.

Background Apathy in patients with epilepsy is associated with a wide range of consequences that reduce the patient’s ability to perform social functions and participate in self-care and rehabilitation programs. Therefore, apathy is one of the important diagnoses of the healthcare team in the process of caring for epileptic patients and its dimensions need to be examined and recognized. Therefore, appropriate instruments with the sociocultural milieu of each community should be provided to health care providers. The aim of the present study was to design and measure epilepsy–related apathy scale (E-RAS) in adults with epilepsy. Methods This study of sequential exploratory mixed methods design was conducted in Iran from April 2019 to December 2019. In the Item generation stage, two inductive (face-to-face and semi-structured interviews with 17 adult epileptic patients) and deductive (literature review) were used. In item reduction, integration of qualitative and literature reviews and scale evaluation were accomplished. For Scale Evaluation, face, content, construct [exploratory factor analysis (EFA) (n = 360) and confirmatory factor analysis (CFA) (n = 200)], convergent and divergent Validity and reliability (internal consistency and stability) were investigated. Results The results of EFA showed that E-RAS has four factors, namely, motivation; self-regulatory; cognition and emotional-effective. These four latent factors accounted for a total of 48.351% of the total variance in the E-RAS construct. The results of CFA showed that the 4-factor model of E-RAS has the highest fit with the data. The results of convergent and divergent validity showed that the values of composite reliability (CR) and average variance extracted (AVE) for the four factors were greater than 0.7 and 0.5, respectively, and the value of AVE for each factor was greater than CR. The Cronbach’s alpha coefficient for the whole scale was obtained 0.815. The results of the test-retest showed that there was a significant agreement between the test and retest scores (P Conclusion E-RAS is a multidimensional construct consisting of 24 items, and has acceptable validity and reliability for the study of epilepsy-related apathy in adult epileptic patients.

Brugada syndrome (BrS) is a rare hereditary arrhythmia syndrome that increases an individual's risk for sudden cardiac death (SCD) due to ventricular fibrillation. This disorder is regarded as a notable cause of death in individuals aged less than 40 years, responsible for up to 40% of sudden deaths in cases without structural heart disease, and is reported to be an endemic in Asian countries. Mutations in SCN5A are found in approximately 30% of patients with Brugada syndrome. This study aimed to investigate mutations in the SCN5A gene in a group of Iranian Brugada syndrome patients. Nine probands (n = 9, male, mean age = 39) diagnosed with Brugada syndrome were enrolled in this study. Exon 2 to 29 were amplified by PCR and subjected to direct sequencing. Eight in silico prediction tools were used to anticipate the effects of non-synonymous variants. Seven known polymorphisms and 2 previously reported disease-causing mutations, including H558R and G1406R, were found in the studied cases. Twenty novel variants were identified: 15 missense, 2 frameshift, 2 synonymous, and one nonsense variants. In silico tools predicted 11 non-synonymous variants to have damaging effects, whereas frameshift and nonsense variants were considered inherently pathogenic. The novel variants identified in this study, alongside previously reported mutations, are highly likely to be the cause of the Brugada syndrome phenotype observed in the patient group. Further analysis is required to understand the physiological effects caused by these variants.

What is known and objective Brimonidine is increasingly used in the treatment of intraocular hypertension. Case summary We report on five paediatric patients suffering from brimonidine eye drop intoxication. The most frequent signs of the intoxication were a lowered level of consciousness and hypotonia. Other complications were apnea, bradycardia, hypotension and seizure. One of the patients needed cardiopulmonary resuscitation. Apnea in one of the cases was resistant to naloxone. Pupils were unremarkable in two cases. What is new and conclusion Brimonidine is potentially lethal for young infants. The absence of miosis and absence of response to naloxone is not a reason to rule out brimonidine poisoning.

Robotics can overcome some obstacles of conventional laparoscopy and even highly complex procedures become feasible using a minimally invasive approach. Repair of complex ventral hernia using a myofascial flap and mesh augmentation, a technique called transversus abdominis release (TAR), for ventral abdominal hernia repair is one example. Herein, we present our institutional experience with this novel technique. Patients undergoing robot-assisted TAR for repair of complex ventral hernia between September 2017 and October 2020 were included. Demographic as well as peri- and postoperative details were collected in a prospective database. A total of 48 (17 female) patients were operated using robot-assisted TAR during the study period. Median BMI was 29 kg/m2 (range: 22.0–40.5), age at operation was 69 years (median; range: 39–79). Duration of the procedure was 242 min (median), length of postoperative hospital stay was 4 days. One on-table complication was observed: during extubation, an audible tear of suture material was heard by OR staff. The patient had to be re-intubated and closure of the ventral defect was now done using an open access. Prolonged respiratory support was necessary in this patient. Urosepsis occurred in one patient following TAR combined with TURB (transurethral resection of bladder cancer), which was treated with intravenous antibiotics. In addition, one patient was re-admitted at 5 weeks postoperatively, suffering from small bowel obstruction which was solved using a minimally invasive approach. Late complications included three seromas (n = 3; 6.3%), one recurrent hernia (2.1%), and one trocar site hernia (2.1%). None of the latter patients needed an operative revision. No patient died. Robot-assisted TAR for complex ventral hernia repair is a viable option in our setting with low complication and recurrence rates.

Objectives Toxoplasma gondii (T. gondii), an obligate intracellular apicomplexan parasite, could affect numerous warm-blooded animals, such as humans. Calcium-dependent protein kinases (CDPKs) are essential Ca2+ signaling mediators and participate in parasite host cell egress, outer membrane motility, invasion, and cell division. Results Several bioinformatics online servers were employed to analyze and predict the important properties of CDPK4 protein. The findings revealed that CDPK4 peptide has 1158 amino acid residues with average molecular weight (MW) of 126.331 KDa. The aliphatic index and GRAVY for this protein were estimated at 66.82 and – 0.650, respectively. The findings revealed that the CDPK4 protein comprised 30.14% and 34.97% alpha-helix, 59.84% and 53.54% random coils, and 10.02% and 11.49% extended strand with SOPMA and GOR4 tools, respectively. Ramachandran plot output showed 87.87%, 8.40%, and 3.73% of amino acid residues in the favored, allowed, and outlier regions, respectively. Also, several potential B and T-cell epitopes were predicted for CDPK4 protein through different bioinformatics tools. Also, antigenicity and allergenicity evaluation demonstrated that this protein has immunogenic and non-allergenic nature. This paper presents a basis for further studies, thereby provides a fundamental basis for the development of an effective vaccine against T. gondii infection.

Tumor suppressor miRNAs, miR-15a and miR-16–1, with high-specificity and oncogenic targeting of Bcl-2, can target tumor tissues. Disadvantages of the clinical application of free miRNAs include poor cellular uptake and instability in plasma, which can be partially improved by using nanocarriers to deliver anti-cancer agents to the tumor cell. In this study, cationic niosomes were designed and optimized with the specific formulation. Then, the physical characteristics, the cytotoxicity, the impact of transfected miRNAs on the expression of the Bcl-2 gene, and the apoptosis rate of the different formulation into prostate cancer cell were determined. The optimum formulation containing tween-60: cholesterol: DOTAP: DSPE-PEG2000 at 70:30:25:5 demonstrated that the vesicle size and zeta potentials were 69.7 nm and + 14.83 mV, respectively. Additionally, noisome-loaded miRNAs had higher toxicity against cancer cells comparing with free forms. The transfection of PC3 cells with the combination therapy of nanocarriers loaded of two miRNAs led to a significant decrease in the expression of the Bcl-2 gene and increased the degree of cell death in PC3 cells compared with other treatment groups, and the synergistic effects of co-delivery of miR-15a and miR-16–1 on prostate cancer cells were shown. According to the results, it seems the designed niosomes containing miR-15a and miR-16–1 can target the Bcl-2 gene and provide a cheap, applicable, cost-effective, and safe drug delivery system against prostate cancer.

PurposeThe purpose of this study is to determine how transtheoretical model (TTM) constructions change through nutrition education for fat intake modification among overweight and obese women living in Shazand city, Iran.Design/methodology/approachA semi-experimental design with intervention and control groups (50 women in each group) was performed. TTM constructions for dietary fat intake were measured through a questionnaire in four phases: before the intervention, immediately, one month and six months after the intervention. Participants in two groups were classified into inactive and active subgroups, based on their determined stage of change. Then in the intervention group, each subgroup received a separate education program of five or eight sessions for the active and inactive subgroups, respectively.FindingsThe intervention resulted in significant progress in participants' stage of change compared to the control group (p = 0.002). Also, it resulted in an increase in the self-efficacy and decisional balance scores in both of the intervention subgroups, with these effects being more pronounced in the inactive subgroup, and these significant differences, compared to the control group, remained in the third and fourth phases. The intervention also positively impacted the behavioral processes, but this effect was not so long-lasting and decreased after six months.Originality/valueThe results indicated the intervention effectiveness and the necessity of planning educational interventions to change fat consumption behavior. This study provides further insight into effective and sustainable nutrition education strategies based on behavioral change stages rather than traditional approaches. These methods should be used to design group interventions to change individuals' health behavior in future works.

Background Prevalence of electronic health records (EHRs) has significantly increased, and EHRs are a known contributor to clinician burnout. However, it is unknown whether the use of multifunctional EHRs is associated with nurse practitioner (NP) burnout in primary care practices. This is a major gap in the literature because 69% of practicing NPs deliver primary care services to patients. Purpose This study aimed to investigate whether the use of multifunctional EHRs is associated with primary care NP burnout. Method This study is a secondary analysis of cross-sectional survey data collected from NPs in two states (Pennsylvania and New Jersey). Nurse practitioners completed surveys measuring burnout, use of multifunctional EHRs, demographics, and characteristics of their practice. Use of multifunctional EHRs was operationalized using two items-computerized capabilities and electronic reminder systems. Burnout was measured using a validated, single item asking NPs to self-report their feelings of burnout. A multilevel cox regression model was built to test for associations between the use of multifunctional EHRs and NP burnout. Results Of 396 NPs included, 25.3% reported burnout. The use of multifunctional EHRs did not increase primary care NP burnout (risk ratio = 0.30, 95% confidence interval = 0.13-0.71, p = .01). Implications for practice With 25.3% of NPs burned out, it is imperative to reduce NP burnout. However, computerized capabilities and electronic reminder systems did not contribute to feelings of NP burnout. Future research examining other EHR components is needed to understand which features of the EHR contribute to NP burnout.

Aims and background: Obesity is recognised as a significant public health burden worldwide. Recently the cross-talk between gut microbiota and obesity has attracted much attention. To that end, Akkermansia muciniphila has been proposed as a promising microbe to manage obesity. In the present systematic review, we evaluated evidence on the effectiveness and mechanisms of action of Akkermansia muciniphila supplementation in the management of obesity. Methods: Electronic databases of MEDLINE, PubMed, Scopus, Web of Science, and Google Scholar were searched thought March 2020 to identify relevant published articles, and eligible articles were systematically reviewed. Results and conclusions: Fifteen studies were included in the present study. Findings from the present review, which included human and animal (rodent) models support the effectiveness of Akkermansia supplementation as a novel therapeutic approach for the management of obesity and metabolic complications associated with obesity. However, future clinical trials are warranted to verify these outcomes. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

This Study was designed to answer the question: what are the intervention goals of women for ceasing to smoke. The present research was part of a larger study and was a pioneering systematic research conducted between September 23, 2018 and September 26, 2019 through an intervention mapping in southern Iran among professional hookah Smoking (HS) women. In order to know more about the HS among women, the behavioral and environmental correlates of HS/cessation and the determiners or fundamental causes of these factors were extracted via a systematic review and a local qualitative study. As the results revealed, the expected outcomes of the educational program concerning hookah cessation were achieved. As the realization of these outcomes requires certain changes to the behavioral and environmental dimensions, in the next step, the intervention goals of hookah cessation were identified. As the results showed, four behavioral factors involved in the unhealthy HS behavior were individual HS, Being in the Company of hookah smokers, Visiting tempting and contaminated places and Physical and mental dependence on HS (habit), In addition, four effective environmental factors were found at different interpersonal, organizational, community and policy levels. These include, respectively: recommendation and motivation for cessation by influential figures, care providers' poor inadequate knowledge and skill, Easy acceptance of hookah in society, and the lack of effective rules. Knowledge, awareness, social norms, Motivation to comply, skill and self-efficacy, habit, were among the determining factors of hookah cessation. Employment of a systematic is based on evidence and cooperation and is guided by a assessing the needs of the target population. Such a method can suggest more purposive and relevant intervention goals so as to cease HS. The aim would be to intervene in the purposes of the above-mentioned change, as compared in predetermined interventions, and increase the chances of HS cessation among women.

Bone morphogenetic protein-9 (BMP-9) is a circulating cytokine that is known to play an essential role in the endothelial homeostasis and the binding of BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence. Previously, using an unbiased screen, we identified ALK-1 as a high-capacity receptor for low-density lipoprotein (LDL) in endothelial cells that mediates its transcytosis in a nondegradative manner. Here we examine the crosstalk between BMP-9 and LDL and how it influences their interactions with ALK-1. Treatment of endothelial cells with BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin heavy chain. Knockdown of CAV-1 reduces BMP-9-mediated internalization of ALK-1, BMP-9-dependent signaling and gene expression. Similarly, treatment of endothelial cells with LDL reduces BMP-9-induced SMAD1/5 phosphorylation and gene expression and silencing of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization. Interestingly, BMP-9-mediated ALK-1 internalization strongly re-duces LDL transcytosis to levels seen with ALK-1 deficiency. Thus, BMP-9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and LDL transcytosis.

Hydroponic systems are known to provide a platform for uniform growth conditions until the reproductive stage. However, many plant species, including sunflower, show poor growth and survivability under conventional hydroponic systems due to poor nutrient availability, hypoxia and algal contamination. Thus, we tested various hydroponic systems to select a hydroponic system suitable for screening of sunflower germplasm. Sunflower accessions showed better growth and leaf gas exchange in newly-designed over conventional hydroponic systems. Selected hydroponic systems were further engaged in sunflower accession screening under heat and osmotic stress in a two-pan system (210 cm × 60 cm). Heat stress treatment was applied by growing sunflower germplasm at 42 °C and osmotic stress by adding polyethylene glycol 8000 which decreased the osmotic potential to − 0.6 MPa. There was significant variability among the sunflower accessions for their ability to survive under stress. Accessions such as C-2721 (43%), C-291 (46%) and D-14 (43%) had lower cell membrane injury percentage under osmotic stress and high seedling survivability (60‒80%) under heat stress when compared with susceptible accessions. Moreover, resistant accessions exhibited greater cuticular waxes and root length but lower transpiration losses. The newly designed hydroponic platform proved reliable for the selection of resistant sunflower accessions. Selected parental lines were validated by assessing their hybrids under field trials across two seasons under water and temperature stress during the reproductive phase (autumn). Hybrid H3 obtained by crossing drought and heat resistant parents had the highest seed yield and water use efficiency.

The interrelationships between silage preference of ruminants and compounds that may affect forage choice are not yet fully enlightened. Analysis of the forage metabolome in addition to conventional chemical analysis and preference trials can provide new insights. Six silage treatments each of alfalfa (AL) and red clover (RC), with different dry matter concentrations (222–391 g/kg), silage additives, and intended addition of soil, were produced in quadruplicate to obtain a range of qualities. After 120 d of ensiling, silages were sampled for chemical analysis, vacuum-packed, and refrigerated for subsequent preference trials with goats. Within 21 d, each possible combination of 2 silages and an AL hay that served as control (n = 21) was presented to goats (Saanen-type wethers, n = 8, body weight 105 ± 2.7 kg) for 3 h for ad libitum intake. Comparisons among means for 3-h dry matter intake (DMI) for forages offered in choice situations were made using variance analysis, including terms for treatment and animal and the Waller-Duncan k-ratio t-test to separate means. The most preferred and avoided treatments of AL and RC silage amounted to 863, 858, 226, and 282 g DMI/3 h, respectively. To further explore relations between silage composition and preference, a metabolome analysis of the most preferred and most avoided AL and RC treatments were conducted. Metabolites (all low molecular weight molecules) were analyzed by a nontargeted metabolite profiling in the range of 50–1,700 Da. Metabolites showing the most distinct difference between preferred and avoided silages were identified by partial least squares discriminant analysis. In the 2 selected treatments of each plant species (those that were most different in forage preference), more than 6,400 compounds were detected and 2,010 were identified. Between preferred and avoided treatments, 934 of the detected compounds differed in RC and 1,860 in AL, of which 475 were altered in both plant species (251 were reduced and 186 were increased; only 38 behaved contrarily, meaning that they were increased in one substrate and decreased in the other). The database provides a useful foundation for the approach of explaining silage preference by ruminants.

Undergraduate students participating in the UCLA Undergraduate Research Consortium for Functional Genomics (URCFG) have conducted a two-phased screen using RNA interference (RNAi) in combination with fluorescent reporter proteins to identify genes important for hematopoiesis in Drosophila. This screen disrupted the function of approximately 3500 genes and identified 137 candidate genes for which loss of function leads to observable changes in the hematopoietic development. Targeting RNAi to maturing, progenitor, and regulatory cell types identified key subsets that either limit or promote blood cell maturation. Bioinformatic analysis reveals gene enrichment in several previously uncharacterized areas, including RNA processing and export and vesicular trafficking. Lastly, the participation of students in this course-based undergraduate research experience (CURE) correlated with increased learning gains across several areas, as well as increased STEM retention, indicating that authentic, student-driven research in the form of a CURE represents an impactful and enriching pedagogical approach.

In the dark path of tumorigenesis, the more carefully the cancer biology is studied, the more brilliant answers could be given to the countless questions about its orchestrating derivers. The identification of the correlation between Toll‐like receptors (TLRs) and different processes involved in carcinogenesis was one of the single points of blinding light highlighting the interconnection between the immune system and cancer. TLRs are a wide family of single‐pass membrane‐spanning receptors that have developed through the evolution to recognize the structurally conserved molecules derived from microorganisms or damaged cells. But this is not everything about these receptors as they could orchestrate several downstream signalling pathways leading to the formation or suppression of cancer cells. The present review is tempted to provide a concise schematic about the biology and the characters of TLRs and also summarize the major findings of the regulatory role of TLRs and their associated signalling in the pathogenesis of human cancers.

The rapid spread of coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2, poses a huge demand for immediate diagnosis. Real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) of nasopharyngeal (NP) and oropharyngeal (OP) swabs have been used to confirm the clinical diagnosis. To avoid the risk of viral-exposure of laboratory workers, thermal inactivation is currently recommended but has unknown effects on the accuracy of the rRT-PCR results. Thirty-six NP/OP specimens were collected from COVID-19 patients and subjected to thermal inactivation (60°C for 30 min) or the RNA extraction processes to activate the form. Here, our data showed that the concentration of extracted-RNA increases upon thermal inactivation compared to the active form (p = .028). Significantly higher levels of RNA copy number were obtained in inactivated compared to the active samples for both N and ORF1ab genes (p = .009, p = .032, respectively). Thermal inactivation elevated concentration and copy number of extracted-RNA, possibly through viral-capsid degradation and/or nucleoprotein denaturation.

Congenital goiter (CG) is one of the rarest disorders observed in a newborn at birth diagnosed with hypothyroidism. Considering the simultaneity of pregnancy and baby's hypothyroidism at birth, the goiter can be caused by diabetes during pregnancy and hypothyroidism emergence in the baby.

A 2 × 2 factorial study was conducted to evaluate the effects of milk allowance and physical forms of starter on growth performance, ruminal fermentation, and blood metabolites of Holstein dairy calves. A total of 48 calves [40.4 ± 1.55 kg of body weight (BW), n = 12 per treatment: 6 males and 6 females] were randomly assigned to 1 of the 4 treatments: (1) calves fed low milk allowance and finely ground (FG) starter feed [low-FG; 1.47 ± 2.12-mm geometric mean particle size (GMLP)], (2) calves fed low milk allowance and textured (TS) starter feed [low-TS, includes steam-flaked grains (corn and barley) with a pelleted supplement, GMLP 4.15 ± 1.77 mm], (3) calves fed high milk allowance and FG starter feed (high-FG); and (4) calves fed high milk allowance and TS starter feed (high-TS). The starter diets were blended with 7% of chopped alfalfa hay as a proportion of diet dry matter (DM). No milk refusal was observed in any treatments, and calves on both treatments were weaned from milk by wk 8 of the study using a gradual weaning procedure. We observed no interaction between milk allowance and physical forms of starter on feed intake, average daily gain, feed efficiency, BW, and structural growth. Calves fed high milk allowance had lower starter feed intake but greater feed efficiency and overall BW compared with those fed low allowance. Total DM intake and average daily gain were not different among treatments. Regardless of the physical form of starter feed, hip height, heart girth, the molar proportion of ruminal acetate, acetate to propionate ratio, plasma cholesterol, and high-density lipoprotein were greater, but ruminal total volatile fatty acids, the molar proportion of propionate, and plasma β-hydroxybutyrate were lower in calves fed high milk allowance compared with those fed low allowance. Regardless of the milk allowance, calves fed the FG starter feeds had greater blood urea nitrogen concentrations compared with calves fed the TS starter diets. In conclusion, both forms of the starter feeds can be used when calves are fed high milk allowance with no negative effect on their performance.

The aim of this work is to prepare nanofibrous scaffolds based on poly ( l -lactide- d , l -lactide)/poly (acrylic acid) [PLDLLA/PAAc] blends in the presence of Dexamethasone [Dexa]-loaded poly (2-hydroxyethyl methacrylate) [HEMA] as molecular imprinted polymer [MIP] nanoparticles [NPs] for enhancing osteogenesis. By adding 10 wt% of PAAc to the PLDLLA and employing response surface methodology, the average diameter of the electrospun nanofibers is approximately 237 nm. To increase the osteogenesis performance of the optimized nanofibrous scaffolds, the MIP nanoparticles are synthesized using HEMA monomer and Dexa template with a molar ratio of 10 to 1. Accordingly, these crosslinked drug nanocarriers exhibit an average diameter of around 122 nm and imprinting factor of approximately 1.8, enabling to adsorb Dexa molecules around 57%. Afterward, the Dexa-loaded MIP NPs have capability of a controlled drug release with ultimate value of 60% during 72 h. The simultaneous use of PLDLLA/PAAc-10 nanofibrous scaffold and Dexa-loaded MIP NPs within the cultivation media of fibroblast and mesenchymal stem cells is carried out by thiazolyl blue assay and acridine/ethidium bromide staining as well as alkaline phosphate/calcium content test, and alizarin red staining. The results reveal the remarkable efficiency of the blend nanofibers besides the MIP containing Dexa, thereby using for bone tissue engineering applications, potentially.

The current study evaluated the effects of step-down weaning implementation time on starter feed intake, growth performance, blood metabolites, and ruminal pH in dairy calves. A total of 48 Holstein dairy calves (24 male and 24 female; 3 ± 1 d old; 41.2 ± 1.8 kg of body weight) were assigned (n = 12 per treatment; 6 male and 6 female) to 4 experimental treatments in a completely randomized block design. All calves were fed 6 L/d of milk from d 3 to 10 of age, and the treatments consisted of the following: calves were offered 8 L/d of milk from d 11 to 28 of age and then 4 L/d from d 29 to 63 (Step-28; total milk offered = 326 L); calves were offered 8 L/d of milk from d 11 to 42 of age and then 4 L/d from d 43 to 63 (Step-42; total milk offered = 382 L); calves were offered 8 L/d of milk from d 11 to 56 of age and 4 L/d from d 57 to 63 (Step-56; total milk intake = 438 L); and calves were fed 8 L/d of milk from d 11 to 63 of age and abruptly weaned (control; total milk offered = 466 L). All calves were housed individually in pens and had ad libitum access to water and solid feed throughout the experiment. All calves were completely milk weaned on d 64, and their performance was measured until d 80 of age. During the experiment, the starter intake (kg/d and % of body weight) was greater in calves in the Step-28 group compared with those in the other groups. However, the total metabolizable energy intake was greater in the Step-56 calves compared with the other calves. Overall, the average daily gain (ADG), feed efficiency (ADG/dry matter intake), and ADG/total metabolizable energy intake were similar across the treatments. Circulating glucose, β-hydroxybutyrate, blood urea nitrogen, albumin, total protein, alanine aminotransferase, and aspartate aminotransferase, as well as ruminal pH, were not affected by the treatments. The implementation of step-down weaning in early life (4-6 wk of age) could stimulate solid feed intake compared with weaning at a later age with no negative effect on performance.

Recently, manipulation of gene expression and switching genes on or off highlight the potential of nucleic acid-based therapies (NA-BTs). Alzheimer’s Disease (AD) is a common devastating neurodegenerative disease (NDs) responsible for 60-80% of all cases of dementia and predicted as a main public health concern among aged populations. The aim of this study was to outline the current research in the field of NA-BTs for the treatment of AD disabilities, including strategies to suppress the memory and learning defects, to promote recovery processes, and to reinforce social relationships in these patients. This review was performed via evaluating PubMed reported studies from January 2010 to November 2019. Also, reference lists were checked to find additional studies. All intermediation or complementarity of animal models, case-control and cohort studies, and controlled trials (CTs) on specific NA-BTs to AD were acceptable, although in vitro studies were excluded due to the considerable diversities and heterogeneities. After removing the duplicates according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) instruction, we merged remaining titles across search databases. There are 48 ongoing studies related to the application of nucleic acids in the treatment and diagnosis of AD where more consideration is given to DNA targeting strategies (18 targets for vectors and aptamers), antisense oligonucleotides (10 targets), micro-RNAs mimics (7 targets), antagomiRs (6 targets), small interferences-RNAs (5 targets), as well as mRNAs (2 targets) respectively. All of these targets are grouped into 4 categories according to their role in molecular pathways where amyloid-β (18 targets), neural survival (11 targets), memory and cognition (8 targets), and tau (3 targets) are more targeted pathways, respectively. With recent successes in the systemic delivery of nucleic acids via intravenous injection; it is worth investing in the production of new-generation medicines. There are still several challenges for NA-BTs including, their delivery to the effective modulators, mass production at low cost, sustaining efficacy and minimizing off‐target effects. Regarding miRNA-based therapies, given the obvious involvement of miRNAs in numerous facets of brain disease, and the many sophisticated techniques for delivery to the brain, miRNA-based therapies will make new hope for the treatment of neurological diseases such as AD.

Primary hyperparathyroidism (PHPT) is associated with increased risk of cardiovascular morbidity and mortality. We aim to determine whether parathyroidectomy (PTX) can change cardiometabolic risk factors including serum lipids, glycemic parameters, systolic and diastolic blood pressure, C reactive protein (CRP), and body mass index (BMI). MEDLINE, Web of Science, Scopus, and Google Scholar were searched for relevant articles published till June 2020. Fixed-effect or random-effects models were used to estimate the weighted mean difference (WMD) and 95% CI for outcomes where applicable. In total, 34 studies were eligible to be included in the current meta-analysis. Our results indicated no favorable change in serum triglyceride (n = 13, WMD = −0.06, 95% CI: −0.15, 0.03 mmol/L), total cholesterol (n = 15, WMD = 0.01, 95% CI: −0.14, 0.16 mmol/L), LDL-C (n = 10, WMD = −0.01, 95% CI: −0.17, 0.19 mmol/L), HDL-C (n = 10, WMD = 0.03, 95% CI: −0.001, 0.06 mmol/L), and CRP (n = 5, WMD = 0.82, 95% CI: −0.01, 1.64 mg/L) after PTX in PHPT patients. However, glucose (n = 24, WMD = −0.16, 95% CI: −0.26, −0.06 mmol/L), serum insulin (n = 12, WMD = −1.11, 95% CI: −1.73, −0.49 µIU/mL), systolic (n = 17, WMD = −10.14, 95% CI: −12.27, −8.01 mmHg), and diastolic (n = 16, WMD = −5.21, 95% CI: −7.0, −3.43 mmHg) blood pressures were decreased after PTX, whilst a significant increase was observed in BMI (n = 13, WMD = 0.35, 95% CI: 0.19, 0.51 kg/m2). PTX could improve glycemic parameters and blood pressure, without any significant change in serum lipoproteins and CRP.

Atopic dermatitis (AD) is a chronic relapsing eczematous skin disease, which primarily affects infants and young children. Due to the side effects of commonly used drugs for its treatment, the development of safer therapeutic strategies is needed. There are many reports on the topical use of marshmallow (Althaea officinalis) for a range of skin diseases in Persian medicine. The main aim of the present investigation was evaluating the efficacy of marshmallow in children with mild-to-moderate atopic dermatitis. Another aim of the study was screening the anti-allergic and anti-inflammatory potential of phytocomponents against target proteins, including TNF-alpha, IL6, and PDEs A, B, and D enzymes with PDB IDs: 2AZ5, 1P9M, 3I8V, 4KP6, and 1Y2K, respectively, along with their respective standard ligands using computational docking analysis. A pilot clinical trial was designed to investigate the safety and efficacy of Althaea officinalis in children with AD. The diagnosis of AD was made according to the criteria of Hanifin and Rajka. Children between 3 months and 12 years old were participated in this trial and randomly allocated into two parallel intervention and control groups. The intervention group used Althaea officinalis 1% ointment while the positive control group used Hydrocortisone 1% ointment twice a day for a week and after that, three times per week for a period of 3 weeks. The severity of AD was measured using the SCORAD score at the end of each assessment visits. A total number of 22 patients completed the study. A significant decrease of the SCORAD score was observed in both groups. At the end of the study, this score change, which indicates the improvement of the patients was significantly higher in the intervention group in comparison to the baseline (p-value = .015) and week 1 (p-value = .018). In the docking analysis of the study, 33 phytochemical compounds were identified, which were docked into the active site of IL6, TNF-alpha, and human PDE4 isoenzymes. Affinity toward the selected enzymes was significantly higher in glycosylated compounds. The results of this pilot study showed that the efficacy of Althaea officinalis 1% ointment in a decrease of disease severity is more than Hydrocortisone 1% in children with AD. However, further studies are needed to confirm this finding. Moreover, the docking analysis revealed that the inhibitory activity of compounds with free hydroxyl groups such as glycosylated compounds was better than others, probably due to the hydrogen bond interaction of hydroxyl groups of the ligands with the enzymes.

Vitrification of embryos has been known as the most efficient cryopreservation method in assisted reproductive technology clinics. Vitrification of preimplantation embryo might be associated with altered gene expression profile and biochemical changes of vitrified embryos. Stringent regulation of gene expression in early embryonic stages is very critical for normal development. In the present study, we investigated the effect of vitrification on the canonical miRNA biogenesis pathway, and also the expression of developmental related miRNAs, in 8-cell and blastocyst mouse embryos. Although the expression pattern of the miRNA biogenesis pathway genes differed between 8-cell and blastocyst mouse embryos, vitrification did not affect the expression level of these genes in preimplantation embryos. The expression levels of miR-21 and let-7a were significantly decreased in vitrified 8-cell embryos and fresh blastocysts when compared with fresh 8-cell embryos. The expression of Stat3 was significantly reduced in blastocysts after vitrification. The alteration in the expression pattern of miRNAs, due to their mode of action, can affect broad downstream key developmental signaling pathways. Therefore, the blastocyst stage is the preferred point for embryo vitrification as they are less susceptible to cryo-damages regarding the stability of miRNAs related to the developmental and implantation competence of embryo.