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Objective: To study the relationship between consumption of milk and milk products, calcium, lactose and vitamin D and occurrence of colorectal cancers. Design: Prospective cohort study. Subjects: A total of 9959 men and women aged 15 y or older without history of cancer at baseline. During a 24 y follow-up, 72 new cancers of the large bowel (38 in the colon and 34 in the rectum) were detected. Results: Consumption of milk and total milk products was suggested to be inversely related to colon cancer incidence, whereas no similar association was seen for rectal cancer. The relative risk between the highest and lowest quartiles of intake adjusted for potential confounding factors was 0.46 (95% confidence interval 0.14–1.46, P for trend 0.09) for milk and 0.37 (95% CI=0.12–1.39, P for trend 0.06) for total milk products. Lactose intake showed a similar inverse relationship with colon cancer: the relative risk was 0.31 (95% CI=0.08–1.15, P for trend 0.03). Intake of vitamin D or total dietary calcium was not significantly related to colorectal cancer risk, whereas calcium provided by fermented milk products was associated with increased colorectal cancer incidence; in the highest quartile the multivariate adjusted relative risk for colorectal cancer was 2.07 (95% CI=1.00–4.28). Conclusions: Our results indicate that individuals showing high consumption of milk have a potentially reduced risk of colon cancer; however, the association does not appear to be due to intake of calcium, vitamin D, or to specific effects of fermented milk. Sponsorship: This study was supported by a grant from the Swedish Cancer Foundation. European Journal of Clinical Nutrition (2001) 55, 1000–1007

ZusammenfassungLokale Wundinfektionen sind ein multidisziplinär relevantes Problem und sollten möglichst frühzeitig diagnostiziert und adäquat therapiert werden. Neben einer Stagnation der Wundheilung sind es insbesondere die drohende Weiterentwicklung zu systemischen Infektionen bis hin zur Sepsis, die gefürchtete, potenziell lebensbedrohliche Komplikationen darstellen. Einen besonders hohen und multidisziplinären Stellenwert hat diese Thematik bei der Behandlung von Patienten mit chronischen Wunden. Bislang gab es für die Diagnostik keine einheitlich akzeptierten Kriterien. Hier ermöglicht jetzt der neu entwickelte und validierte TILI-Score als Ergänzung zu den Vitalparametern und serologischen Werten die rasche Objektivierung lokaler Wundinfektionen. Ergänzend können mit dem W.A.R.-Score zudem Patienten mit erhöhtem Infektionsrisiko identifiziert werden. Durch diese einfach einzusetzenden Hilfsmittel kann die Indikation einer antiseptischen Wundtherapie individuell, schnell und unproblematisch eingeschätzt werden. Für viele Patienten mit chronischen Wunden ist dann Polihexanid das Wundantiseptikum der ersten Wahl. Die Indikation von Wundantiseptika sollte aber spätestens nach einer Therapiedauer von 14 Tagen kritisch überprüft werden.

Purpose: The use of FDG-PET/TC for cancer staging has been leading to the increasing diagnosis of adrenal lesions, which usually represent a clinical challenge. Our aim was to characterize the adrenal lesions found in FDG-PET of patients followed in a cancer center.Methods: Retrospective analysis of all FDG-PET studies performed in our center in the last 10 years. Exams reporting adrenal lesions in the CT component and/or anomalous adrenal FDG uptake were selected. Cases were characterized regarding clinical, laboratorial, imaging and pathological findings. Results: We identified 27,427 FDG-PET studies. Of those, 7.6% evidenced adrenal findings. We included 1364 exams corresponding to 1021 patients. Only 15.6% were referred to the endocrinology department and 38% of the lesions were not studied.Malignant lesions were present in 38.9% of the studied patients: metastases in 37.5%, carcinoma in 1.2% and other malignant tumors in 0.4%. Median SUVmax of malignant lesions was significantly higher than the SUVmax of the benign findings (p0.05). Conclusion: Occult adrenal lesions discovered during FDG-PET/CT are common in cancer context and are frequently benign. SUVmax may be a useful tool in the workup of adrenal lesions but with several important caveats.

Psychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the etiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1−/−) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens of Gria1−/− mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons in Gria1−/− mice. Furthermore, dopamine signals were initially similar in Gria1−/− mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations in Gria1−/− mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia.

The aim of this study was to evaluate the vision-related quality of life (VR-QOL) before and after intravitreal ranibizumab injections (IVR) for central retinal vein occlusion (CRVO) and investigate subscale items of VR-QOL in detail. This multicenter, open-label, prospective study included 23 patients with treatment naïve CRVO and 22 age-matched normal controls. VR-QOL was assessed by the 25-Item Visual Function Questionnaire (VFQ-25) before and up to 12 months post-treatment. The VFQ-25 composite score and 12 subscales were compared between groups. The VFQ-25 composite scores in CRVO showed significant improvement throughout the treatment period compared with those at the baseline. The VFQ-25 composite score before and after treatment in CRVO was significantly lower than that in normal controls. The subscale items, including general health, general vision, near activities, social functioning, mental health, role difficulties, dependency, and peripheral vision, in CRVO were significantly lower than those in the normal controls even after treatment. Vision-related QOL was low in patients with CRVO before treatment and improved with IVR. Even after treatment, the values of several subscale items were lower than those in normal controls. Patients with CRVO require treatment aimed at further improving visual function as well as social and psychological care.

Schizophrenia (SZ) is a mental disorder with a strong genetic basis as well as epigenetic aspects. Siblings of patients with SZ can share certain endophenotypes with the patients, suggesting that siblings may be important for distinguishing between trait and state markers. In the current study, we aimed to characterize the balance between pro-BDNF/mature BDNF and its receptors p75NTR/TrkB, which are tPA-BDNF pathways proteins and are thought to play a role in synaptic pruning, as a possible endophenotype of schizophrenia. Forty drug-naive patients with first-episode psychosis (FEP) matched for age, gender, and level of education, 40 unaffected siblings (UAS) of patients with FEP, and 67 healthy controls (HC) were included in the study. Blood samples were collected from all participants to determine BDNF, pro-BDNF, TrkB and p75NTR, PAI1, tPA, ACTH, and cortisol levels. We showed that levels of proteins of the tPA-BDNF pathway as well as the pro-BDNF/m-BDNF and p75NTR/TrkB ratios could successfully differentiate FEP and their siblings from the HCs by using ROC analysis. Plasma levels of m-BDNF were found to be the lowest in the healthy siblings and highest in the HCs with statistically significant differences between all 3 groups. The plasma level of pro-BDNF in the HC group was similar to the FEP patients, the same in the healthy siblings of the FEP patients. Our data support the hypothesis that imbalance between neurotrophic and apoptotic proteins might occur in SZ and this imbalance could be an endophenotype of the disease. University of (University of Health Sciences Turkey) Research Projects Unit

Cisplatin, 5FU and docetaxel (TPF) are the most common chemotherapy regimen used for advanced OSCC. However, many cancer patients experience relapse, continued tumor growth, and spread due to drug resistance, which leads to treatment failure and metastatic disease. Here, using a CRISPR/Cas9 based kinome knockout screening, Misshapen-like kinase 1 (MINK1) is identified as an important mediator of 5FU resistance in OSCC. Analysis of clinical samples demonstrated significantly higher MINK1 expression in the tumor tissues of chemotherapy non-responder as compared to chemotherapy responders. The in-vitro and xenograft experiments indicate that knocking out MINK1 restores 5FU mediated cell death in chemoresistant OSCC. An antibody based phosphorylation array screen revealed MINK1 as a negative regulator of p53. Mechanistically, MINK1 modulates AKT phosphorylation at Ser473, which enables p-MDM2 (Ser 166) mediated degradation of p53. We also identified lestaurtinib as a potent inhibitor of MINK1 kinase activity. Lestaurtinib significantly induces 5FU mediated cell death in chemoresistant OSCC lines. The patient derived chemoresistant cell based xenograft data suggest that lestaurtinib restores 5FU sensitivity and facilitates a significant reduction of tumor burden. Overall, our study suggests that MINK1 is a major driver of 5FU resistance in OSCC. The novel combination of MINK1 inhibitor lestaurtinib and 5FU needs further clinical investigation in advanced OSCC. One sentence summary Lestaurtinib reverses 5FU sensitivity in drug resistant OSCC.

BackgroundWe aimed to investigate corneal densitometry and correlations with corneal morphological parameters in bilateral keratoconus (KCN) patients with unilateral Vogt's striae.MethodsOne hundred and-twelve patients (224 eyes) with bilateral KCN and unilateral Vogt's striae were enrolled in this cross-sectional contralateral eye study. Corneal densitometry and morphological parameters were measured using Pentacam HR.ResultsOur study revealed that corneal densitometry values of the anterior 0–2 mm and 2–6 mm, intermediate 0–2 mm and 2–6 mm, posterior 2–6 mm, and total cornea 2–6 mm in eyes with Vogt’s striae were significantly higher than those in eyes without Vogt's striae (P P P P P

Cues involved in mate seeking and recognition prevent hybridization and can be involved in speciation processes. In malaria mosquitoes, females of the two sibling species Anopheles gambiae s.s. and An. coluzzii mate in monospecific male swarms and hybrids are rare. Long-range sex pheromones driving this behavior have been debated in literature but to date, no study has proven their existence or their absence. Here, we attempted to bring to light their existence. To put all the odds in our favor, we used different chemical ecology methods such as behavioral and electrophysiological assays as well chemical analyses, and we worked with mosquitoes at their optimal physiological mating state i.e. with swarming males during their natural swarming windows. Despite all our efforts, our results support the absence of long-range sex pheromones involved in swarm detection and recognition by females. We briefly discuss the implications of this finding in ecology, evolution and for control strategies.

On-target–off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates1,2. In diseases of the central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition of mammalian target of rapamycin (mTOR) while sparing mTOR activity elsewhere through the use of the brain-permeable mTOR inhibitor RapaLink-1 and the brain-impermeable FKBP12 ligand RapaBlock. We show that this drug combination mitigates the systemic effects of mTOR inhibitors but retains the efficacy of RapaLink-1 in glioblastoma xenografts. We further present a general method to design cell-permeable, FKBP12-dependent kinase inhibitors from known drug scaffolds. These inhibitors are sensitive to deactivation by RapaBlock, enabling the brain-restricted inhibition of their respective kinase targets.

Purpose This study aimed to evaluate the effects of thyroid-stimulating hormone (TSH) suppressive therapy on bone mineral density (BMD) and bone turnover markers (BTMs) in differentiated thyroid cancer (DTC) patients after postoperative 1-2 years in Northeast China. Methods Five male, sixteen premenopausal, and eight postmenopausal female DTC patients receiving TSH suppressive therapy after thyroidectomy were enrolled. Patients were matched with healthy controls in a ratio of 1:2. All participants completed postoperative 1-year follow-up, and postmenopausal women completed 2-year follow-up. We measured BMD of the lumbar spine (LS), femoral neck (FN), and total hip (TH) using dual-energy X-ray absorptiometry (DXA). Bone formation marker P1NP and bone resorption marker β-CTX were also evaluated. Fracture risks were assessed by FRAX. Results There was no difference in BMD and BTMs between DTC patients and controls in the male group at 1-year follow-up. In the premenopausal women, the LS-BMD, FN-BMD, and TH-BMD in DTC patients were all higher than those in controls, but only FN-BMD showed a significant difference. The change rate of P1NP showed a significant difference between DTC patients and controls, while no difference was found in the β-CTX level. In the postmenopausal women, no difference in BMD and BTMs were observed between DTC patients and controls at the 1-year and 2-year follow-up. Conclusion Our study indicated that postoperative 1-year TSH suppressive therapy did not show detrimental effects on BMD and BTMs in men, premenopausal, and postmenopausal DTC patients. The 2-year postoperative TSH suppressive therapy did not lead to additional loss of bone mass in postmenopausal DTC patients.

Purpose Proximal hamstring tendinopathy (PHT) presents as localised lower buttock pain with tasks such as squatting and sitting. It is a condition that occurs at all ages and levels of sporting participation and can cause disability with sport, work, and activities of daily living. This paper details a pilot trial protocol for investigating the effectiveness of individualised physiotherapy compared to extracorporeal shockwave therapy (ESWT) on pain and strength in people with PHT. Methods The study is an assessor-blinded, pilot randomised controlled trial (RCT). One hundred participants with PHT will be recruited from the local community and sporting clubs. Participants will be randomised to receive six sessions of either individualised physiotherapy or ESWT, with both groups also receiving standardised education and advice. Primary outcomes will be global rating of change on a 7-point Likert scale, and the Victorian Institute of Sport—Hamstring (VISA-H) scale, measured at 0, 4, 12, 26 and 52 weeks. Secondary outcomes will include sitting tolerance, the modified Physical Activity Level Scale, eccentric hamstring strength, modified Tampa scale for kinesiophobia, the Örebro Musculoskeletal Pain Screening Questionnaire Short Form (ÖMPSQ-SF), Numerical Pain Rating Scale (NPRS) for average and worst pain, participant adherence, the Pain Catastrophizing scale, satisfaction scores, and quality of life. Data will be analysed on an intention to treat basis, with between-group effects estimated using linear mixed models for continuous data and Mann Whitney U tests for ordinal data. Conclusions This pilot RCT will compare individualised physiotherapy versus ESWT for PHT. The trial will determine feasibility and estimated treatment effects to inform a definitive trial in the future. Trial registration The trial has been prospectively registered with the Australia & New Zealand Clinical Trials Registry (ACTRN12621000846820), registered 1 July 2021, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373085

Background Hepatitis B and C viruses are the major public health concerns of the globe. The two hepatotropic viruses share common modes of transmission and their co-infection is common. Despite the provision of an effective prevention mechanism, the infections caused by these viruses remain a significant problem worldwide, particularly among developing countries like Ethiopia. Methods This institutional-based retrospective study was conducted between January 2014 December and December 2019 from documented laboratory logbooks of Adigrat general hospital serology laboratory, Tigrai, Ethiopia. data were collected and checked for completeness on a daily based, coded, entered, and cleaned using Epinfo version 7.1, exported and analyzed using SPSS version 23. Binary logistic regression analysis and Chi-square test (X2) assessed the association between dependent and independent variables. The corresponding variables with a P-value (P Results Out of 20,935 clinically suspected individuals, 20,622 were given specimens and tested for hepatitis B and C viruses with total completeness of 98.5%. The overall prevalence of hepatitis B and hepatitis C virus was found to be 3.57% (689/19,273) and 2.13% (30/1,405), respectively. The positivity rate of the hepatitis B virus was 8.0% (106/1317) and 3.24% (583/17,956) among males and females, respectively. Additionally, 2.49%( 12/481) of males and 1.94% (18/924) of females were positive for hepatitis C virus infection. The overall prevalence of co-infection for both hepatitis B and hepatitis C virus was 7.4% (4/54). Sex and age were significantly associated with hepatitis B and C virus infection. Conclusions The overall prevalence of hepatitis B and C is low intermediate according to the WHO criteria. Although there was a fluctuating trend of hepatitis B and C through the years 2014–2019, the result shows moreover declining trend. Both hepatitis B and C share similar routes of transmission and affect all age categories but males were more highly affected than females. Therefore, awareness creation of the community about the methods of transmission, education about prevention, and control of hepatitis B and C virus infection, and improving coverage of youth-friendly services in health facilities should be strengthened.

Background It is imperative that non-compliance with statins be identified and addressed to maximize their clinical benefits. Patient self-reporting methods are convenient to apply in clinical practice but need to be validated. Objective We studied the concordance of a patient self-report method, Morisky eight-item medication adherence scale (MMAS)), with the pill count method in measuring adherence with statins and their correlation with extended lipid profile parameters and serum hydroxyl-methylglutaryl coenzyme A reductase (HMGCoA-R) enzyme levels. Methods MMAS and the pill count method were used to measure the adherence with statins in patients on statins for any duration. Patients were subjected to an estimation of extended lipid profile and serum HMGCoA-R levels at the end of three months follow-up. Results Out of a total of 200 patients included in the study, 117 patients had a low adherence (score less than 6 on MMAS) whereas 65 and 18 patients had medium (score 6 or 7) and high adherence (score of 8), respectively. The majority of patients who had low adherence to statins by MMAS were nonadherent by the pill count method yielding a concordance of 96.5%. Medium or high adherence to statins by the MMAS method had a concordance of 89.1% with the pill count method. The levels of total cholesterol, low-density lipoprotein-cholesterol, apolipoprotein B, and HMGCoA-R were negatively correlated with compliance measured by pill count and MMAS in a statistically significant way and with similar correlation coefficients. HMGCoA-R levels demonstrated a plateau phenomenon, with levels being 9-10 ng/ml when compliance with statin therapy was greater than 60% by pill count and greater than 6 on the Morisky scale. Conclusion In conclusion, MMAS and the pill count method showed concordance in measuring adherence to statins. These methods need to be explored further for their interchangeability as surrogates for biomarker levels.

Background Tumors are complex tissues containing collections of phenotypically diverse malignant and nonmalignant cells. We know little of the mechanisms that govern heterogeneity of tumor cells nor of the role heterogeneity plays in overcoming stresses, such as adaptation to different microenvironments. Osteosarcoma is an ideal model for studying these mechanisms—it exhibits widespread inter- and intra-tumoral heterogeneity, predictable patterns of metastasis, and a lack of clear targetable driver mutations. Understanding the processes that facilitate adaptation to primary and metastatic microenvironments could inform the development of therapeutic targeting strategies. Results We investigated single-cell RNA-sequencing profiles of 47,977 cells obtained from cell line and patient-derived xenograft models as cells adapted to growth within primary bone and metastatic lung environments. Tumor cells maintained phenotypic heterogeneity as they responded to the selective pressures imposed during bone and lung colonization. Heterogenous subsets of cells defined by distinct transcriptional profiles were maintained within bone- and lung-colonizing tumors, despite high-level selection. One prominent heterogenous feature involving glucose metabolism was clearly validated using immunofluorescence staining. Finally, using concurrent lineage tracing and single-cell transcriptomics, we found that lung colonization enriches for multiple clones with distinct transcriptional profiles that are preserved across cellular generations. Conclusions Response to environmental stressors occurs through complex and dynamic phenotypic adaptations. Heterogeneity is maintained, even in conditions that enforce clonal selection. These findings likely reflect the influences of developmental processes promoting diversification of tumor cell subpopulations, which are retained, even in the face of selective pressures.

Background We investigated the effect of the number of laser shots applied on the myopic variables to elucidate the mechanism of myopia development in laser-treated retinopathy of prematurity (ROP) eyes. Methods A total of 33 eyes of 17 infants with ROP who underwent laser treatment were included in the analysis. Cycloplegic retinoscopic refraction testing was carried out and the spherical equivalent (SE) was calculated. Relationships between SE and various variables (including the number of laser shots applied) were examined. In addition, an age-matched control group without ROP was prepared and ocular structural parameters were compared. Results Although there was no statistical difference in axial length (AL) between two groups (p = 0.88), SE was significantly more myopic in the ROP group (p Conclusions In laser-treated ROP eyes, AL, CR, and CLP were related to the degree of myopia. Moreover, the number of shots applied also affected the myopic status in laser-treated ROP eyes. Among AL, CR, and CLP, only CLP was correlated with the laser shots applied.

Background It has previously been shown that CT scans performed for other indications can be used to identify patients with osteoporosis. This has not yet been tested in a British population. We sought to evaluate the use of vertebral CT attenuation measures for predicting osteoporosis in a British cohort, using dual-energy X-ray absorptiometry (DEXA) as a reference standard. Methods Patients who underwent abdominal CT in 2018 and concomitantly underwent DEXA within a six-month interval were retrospectively included. CT attenuation values in Hounsfield units (HU) were measured by placement of a region-of-interest at the central portion of the L1 vertebral body and then compared to their corresponding DEXA score. Receiver operating characteristic (ROC) curves were generated to evaluate the performance of a logistic regression model and to determine sensitivity and specificity thresholds. Results 536 patients (394 females, mean age 65.8) were included, of which 174 had DEXA-defined osteoporosis. L1 attenuation measures were significantly different (p Conclusions Routine abdominal CT can be used to opportunistically screen for osteoporosis without additional cost or radiation exposure. The thresholds identified in this study are comparable with previous studies in other populations. We recommend radiologists engage with primary care and rheumatology providers to determine appropriate cut-off values for further investigation.

Background Early heart failure prevention is central in patients with type 2 diabetes, and mineralocorticoid receptor antagonists (MRAs) have shown to improve prognosis. We investigated the effect of high-dose MRA, eplerenone, on cardiac function and structure in patients with type 2 diabetes and established or increased risk of cardiovascular disease but without heart failure. Methods In the current randomized, placebo-controlled clinical trial, 140 patients with high-risk type 2 diabetes were randomized to high-dose eplerenone (100–200 mg daily) or placebo as add-on to standard care for 26 weeks. Left ventricular systolic and diastolic function, indexed left ventricular mass (LVMi), and global longitudinal strain (GLS) were assessed using echocardiography at baseline and after 26 weeks of treatment. Results Of the included patients, 138 (99%) had an echocardiography performed at least once. Baseline early diastolic in-flow velocity (E-wave) indexed by mitral annulus velocity (e’) was mean (SD) 11.1 (0.5), with 31% of patients reaching above 12. No effect of treatment on diastolic function was observed measured by E/e’ (0.0, 95%CI [-1.2 to 1.2], P = 0.992) or E/A (-0.1, 95%CI [-0.2 to 0.0], P = 0.191). Mean left ventricular ejection fraction (LVEF) at baseline was 59.0% (8.0). No improvement in systolic function was observed when comparing groups after 26 weeks (LVEF: 0.9, 95%CI [-1.1 to 2.8], P = 0.382; GLS: -0.4%, 95%CI [-1.5 to 0.6], P = 0.422), nor in LVMi (-3.8 g/m2 95%CI [-10.2 to 2.7], P = 0.246). Conclusion In the present echo sub-study, no change in left ventricular function was observed following high-dose MRA therapy in patients with type 2 diabetes when evaluated by conventional echocardiography. Trial registration Date of registration 25/08/2015 (EudraCT number: 2015–002,519-14).

Aging-related impairment of the blood brain barrier (BBB) and neurovascular unit (NVU) increases risk for neurodegeneration. Among the various cells participating in BBB and NVU function, spontaneous Ca2+ signals in astrocytic endfeet are crucial for maintaining BBB and NVU integrity. To assess if aging is associated with changes in spontaneous Ca2+ signals within astrocytic endfeet of the dorsolateral striatum (DLS), we expressed a genetically encoded Ca2+ indicator, Lck-GCaMP6f in DLS astrocytes of young (3-4 month) and aging (20-24 month) mice. Compared to young mice, endfeet in the DLS of aging mice demonstrated a decrease in calreticulin (CALR) expression, and dramatic alterations in the dynamics of endfoot membrane-associated and mitochondrial Ca2+ signals. While young mice required both extracellular and endoplasmic reticulum (ER) Ca2+ sources for generating endfoot Ca2+ signals, aging mice showed exclusive dependence on ER Ca2+. These data suggest that aging is associated with significant changes in Ca2+ buffers and Ca2+ signals within astrocytic endfeet, which has important implications for understanding mechanisms involved in aging-related impairment of the BBB and NVU.Graphical abstractHighlightsAging mice show reduced calreticulin expression in astrocytic endfeetAging astrocytic endfeet show dramatic changes in spontaneous Ca2+ activityCa2+ signals in aging endfeet depend exclusively on endoplasmic reticulum Ca2+

Ovarian cancer remains one of the most lethal gynecological cancers in the world despite extensive progress in the areas of chemotherapy and surgery. Many studies have postulated that this is because of the profound heterogeneity that underpins response to therapy and prognosis. Standard imaging evaluation using CT or MRI does not take into account this tumoral heterogeneity especially in advanced stages with peritoneal carcinomatosis. As such, newly emergent fields in the assessment of tumor heterogeneity have been proposed using radiomics to evaluate the whole tumor burden heterogeneity as opposed to single biopsy sampling. This review provides an overview of radiomics, radiogenomics, and proteomics and examines the use of these newly emergent fields in assessing tumor heterogeneity and its implications in ovarian cancer.

Esophageal squamous cell carcinoma (ESCC) is malignant while the carcinogenesis is still unclear. Here, we perform a comprehensive multi-omics analysis of 786 trace-tumor-samples from 154 ESCC patients, covering 9 histopathological stages and 3 phases. Proteogenomics elucidates cancer-driving waves in ESCC progression, and reveals the molecular characterization of alcohol drinking habit associated signatures. We discover chromosome 3q gain functions in the transmit from nontumor to intraepithelial neoplasia phases, and find TP53 mutation enhances DNA replication in intraepithelial neoplasia phase. The mutations of AKAP9 and MCAF1 upregulate glycolysis and Wnt signaling, respectively, in advanced-stage ESCC phase. Six major tracks related to different clinical features during ESCC progression are identified, which is validated by an independent cohort with another 256 samples. Hyperphosphorylated phosphoglycerate kinase 1 (PGK1, S203) is considered as a drug target in ESCC progression. This study provides insight into the understanding of ESCC molecular mechanism and the development of therapeutic targets.

Purpose Cardiac myxoma (CM), the most common cardiac tumor in adults, accounts for 50–75% of benign cardiac tumors. The diagnosis of CM is often elusive, especially in young stroke survivors and transthoracic echocardiography (TTE) is the initial technique for the differential diagnostics of CM. Less invasive cardiac computed tomography (CT) and magnetic resonance imaging (MRI) are not available for the majority of cardiac patients. Here, a robust imaging approach, ortho-Positronium (o-Ps) imaging, is presented to determine cardiac myxoma extracted from patients undergoing urgent cardiac surgery due to unexpected atrial masses. We aimed to assess if the o-Ps atom, produced copiously in intramolecular voids during the PET imaging, serves as a biomarker for CM diagnosing. Methods Six perioperative CM and normal (adipose) tissue samples from patients, with primary diagnosis confirmed by the histopathology examination, were examined using positron annihilation lifetime spectroscopy (PALS) and micro-CT. Additionally, cell cultures and confocal microscopy techniques were used to picture cell morphology and origin. Results We observed significant shortening in the mean o-Ps lifetime in tumor with compare to normal tissues: an average value of 1.92(02) ns and 2.72(05) ns for CM and the adipose tissue, respectively. Microscopic differences between tumor samples, confirmed in histopathology examination and micro-CT, did not influenced the major positronium imaging results. Conclusions Our findings, combined with o-Ps lifetime analysis, revealed the novel emerging positronium imaging marker (o-PS) for cardiovascular imaging. This method opens the new perspective to facilitate the quantitative in vivo assessment of intracardiac masses on a molecular (nanoscale) level.

Acknowledgements: The authors would like to acknowledge critical assistance provided by Dr Ekaterina Ostashchenko, former postdoctoral researcher at the University of Cambridge and now a lecturer in psychology at Manchester Metropolitan University, with expertise in psycholinguistics and social cognition in autism. Dr Ostashchenko checked sections of this paper drawn from the Russian-language literature and also reviewed Russian transliteration. Thanks are due to Richard Turner at Green Templeton College Library and librarians at the Bodleian Library, University of Oxford, for helping locate articles written by Sukhareva in journals which have since ceased publication. The authors also acknowledge Thomas Maisel at the University of Vienna archives, Kathy Lafferty and Becky Schulte of the Spencer Research Library, University of Kansas, and Christopher Henry, Christine Ruggere, and Will Bryant of the Welch Medical Library at Baltimore’s John Hopkins University for their help in addressing enquiries and locating archive material. Thanks are due to Professor Jimmy Potash and Professor James Harris, both of John Hopkins University, for directing our attention to important material concerning autism history., Grunya Efimovna Sukhareva's seminal role in being the first to publish a clinical description of autistic traits in 1925, before both Kanner and Asperger, has been revealed relatively recently. Nevertheless, Sukhareva's work is little known and largely unrecognised beyond Russia. Amidst calls for greater recognition of her pivotal contribution in the genesis of autism conceptualisation and categorisation, this article provides a biographical and historical background. Sukhareva's wide-ranging psychiatric work is adumbrated and her pioneering efforts in conceptualising both schizophrenia and autism are elucidated. The article reflects on possible explanations for the belated and incomplete recognition of Sukhareva's role. The current article indicates how Sukhareva's work was ahead of its time in reflecting modern criteria for autism diagnoses and in its focus on female case studies. Sukhareva's somewhat precarious position as a foremost psychiatrist condemned in the Stalinist years for being anti-Marxist is explicated. The article outlines further directions for academic research on Sukhareva's work and contributions.

Diagnostik und Therapie des primaren Prostatakarzinoms (PCA) haben in den letzten Jahren einen signifikanten Wandel durch moderne Bildgebung erfahren. Etablierte und innovative diagnostische und therapeutische Verfahren zur Detektion und Behandlung des primaren PCA werden dargelegt und gegeneinander abgewogen. Hintergrundwissen und behandlungsrelevante Leitlinienempfehlungen zum primaren PCA werden veranschaulicht und um aktuelle Studienergebnisse erganzt. Die Integration moderner Bildgebung, insbesondere der multiparametrischen Magnetresonanztomographie (mpMRT), in den diagnostischen Algorithmus hat die Primardiagnostik des PCA wesentlich verbessert. Aggressive Karzinome werden bei gleichzeitiger Reduktion von Uberdiagnostik klinisch insignifikanter PCA sowohl in der initialen als auch in der Rebiopsie signifikant besser detektiert. Kurative Therapieansatze wie „active surveillance“, radikale Prostatektomie und fokale Therapien orientieren sich zunehmend an der im Rahmen der mpMRT ermittelten Tumorausdehnung und -aggressivitat. Neben ihrer etablierten Rolle in der Rezidivdiagnostik wird aktuell der mogliche Einsatz der PSMA-PET/CT (PSMA: prostataspezifisches Membranantigen, PET/CT: Positronen-Emissions-Tomographie/Computertomographie) in der Primardiagnostik evaluiert. Moderne Bildgebung, allen voran mpMRT und PSMA-PET/CT, hat einen signifikanten Mehrwert fur Diagnostik und Therapie des primaren PCA. Der multiparametrische Ultraschall ist eine zukunftstrachtige Erganzung des radiologischen Armamentariums beim primaren PCA.

4069 Background: BKM120 is an oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, which showed promising activity in breast cancer and squamous cell carcinoma of head and neck. We prospectively investigated clinical activity, safety and biomarkers of BKM120 in advanced esophagus squamous cell carcinoma (ESCC). Methods: We conducted a multicenter phase II study of BKM120 monotherapy in patients with pretreated advanced ESCC. All the patients had a treatment history of fluoropyrimidine and platinum. BKM120 of 100 mg/day was orally administered in a 28-day cycle. A primary end-point was a disease control rate (DCR). Using Simon’s minimax two-stage design, total of 41 patients were required for primary analysis (promising DCR of 60%, non-promising one of 40%, one-sided alpha level of 10% and power of 90%). The response rate (RR), progression-free survival (PFS), overall survival (OS), and safety were also evaluated as secondary endpoints. Tumor samples for all the patients were required for gene alternation analysis in comprehensive genomic profiling assay (FoundationOne). Results: A total of 42 patients (median age, 62.5 years; performance status 0/1 = 28/14) were enrolled. One ineligible patient was excluded from primary analysis. Nineteen and two patients had SD and unconfirmed PR. DCR was 51.2% (95% CI, 35.1% to 67.1%), which met the primary endpoint of the study. Median PFS and OS was 2.0 months (95% CI, 1.8 to 3.2 months) and 9.0 months (95% CI, 6.4 to 11.7 months), respectively. Common grade 3 or 4 adverse events were anorexia, rash, hyponatremia, lipase increased, and abnormal hepatic function (including increased transaminase levels), which were profiles similar to previous studies of BKM120 monotherapy. No treatment-related deaths occurred. Further analyses of the gene alternation are ongoing. Conclusions: BKM120 monotherapy showed promising efficacy and mild toxicity profile in patients with pretreated advanced ESCC. BKM120 is worth evaluating in a further confirmatory study. Result of subgroup analyses with respect to gene alternation status will be presented. Clinical trial information: UMIN000011217.

The invasion of cancer cells into the surrounding tissues is one of the hallmarks of cancer. However, a precise quantitative understanding of the spatiotemporal patterns of cancer cell migration and invasion still remains elusive. A promising approach to investigate these patterns are 3D cell cultures, which provide more realistic models of cancer growth compared to conventional 2D monolayers. Quantifying the spatial distribution of cells in these 3D cultures yields great promise for understanding the spatiotemporal progression of cancer. In the present study, we present an image processing and segmentation pipeline for the detection of 3D GFP-fluorescent Triple-Negative Breast Cancer cell nuclei, and we perform quantitative analysis of the formed spatial patterns and their temporal evolution. The performance of the proposed pipeline was evaluated using experimental 3D cell culture data, and was found to be comparable to manual segmentation, outperforming four alternative automated methods. The spatiotemporal statistical analysis of the detected distributions of nuclei revealed transient, non-random spatial distributions that consisted of clustered patterns across a wide range of neighbourhood distances, as well as dispersion for larger distances. Overall, the implementation of the proposed framework revealed the spatial organization of cellular nuclei with improved accuracy, providing insights into the 3 dimensional inter-cellular organization and its progression through time.

Contains fulltext : 283431.pdf (Publisher’s version ) (Closed access) Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells reflected gene expression changes characteristic of human breast tumors with higher LMNA expression, and specifically affected pathways related to cell-ECM interactions, cell metabolism, and PI3K/Akt signaling. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels, Akt signaling, and decreased disease-free survival. These findings suggest that downregulation of lamin A/C in breast cancer cells may influence both cellular physical properties and biochemical signaling to promote metastatic progression.

Most available firearm violence data are summary and they lack sufficient incident and victim details to inform policy and practice. The lack of a national definition for a nonfatal shooting also hinders research. There is evidence to suggest that law enforcement data are a valid and reliable sources for firearm violence data. This exploratory study uses law enforcement data to examine unintentional nonfatal shooting incident and victim characteristics in a large Midwestern city. Data for this project come from law enforcement sources and include all unintentional nonfatal shooting incidents (n=177) occurring between January 1, 2017 and December 31, 2019. Exploratory analyses were conducted to describe incidents and victims. Incidents most commonly occurred in the fall season, during nighttime hours, and at a residence. Victims were most likely male, non-white, and 18-34 years old. When injury cause was known, injuries resulted from improper firearm handling. The majority of victims were wounded in their extremities and did not engage emergency medical services before arriving at the emergency department. This study demonstrates the utility of law enforcement data as a source for additional context surrounding unintentional nonfatal shooting incidents. Findings suggest two policy implications: requiring a gun safety course as part of the permitting process and treating gun safety as a life skill by advocating for gun safety courses in schools. Further research is needed to determine why some victims choose not to engage public safety or emergency services prior to arriving at emergency departments.

Introduction: Traumatic brain injury (TBI) has become the signature wound of recent military operations and training over the past two decades. A treatment that would protect against secondary brain injury in TBI and improve the long-term functional outcomes of traumatic brain injury on service personnel is therefore of great interest. One agent that has shown promise in modifying the post-traumatic neuroinflammatory response in murine closed-head injury models of TBI is a novel, small 5 amino acid apolipoprotein E (ApoE) mimetic peptide, CN-105. The goal of this study was to determine whether CN-105 would maintain its neuroprotective effects if administered prior to closed-head injury in a clinically relevant murine model.Materials and Methods: CN-105 was synthesized by Polypeptide Inc. (San Diego, CA) to > 99% purity. We examined the efficacy of prophylactic administration of CN-105 in a well-established closed head injury model associated with reproducible vestibulomotor deficits. CN-105 was dissolved in sterile 0.9% saline and administered to male 12 week old C57-BL/6 mice intravenously (IV) through a tail vein and/or by intraperitoneal (IP) injection in a volume of 100 microliters at various time points prior to injury. Vehicle treated animals received IV and/or IP injection of 100 microliters of normal saline at the same time points. Animals were randomly assigned to treatment groups immediately following injury and all behavioral observations were conducted by investigators blinded to treatment. Vestibulomotor function was assessed using an automated Rotarod (Ugo Basile, Comerio, Italy). An in vivo assessment of the pharmacokinetics of CN-105 following IV or IP administration in healthy fed adult male CD-1 mice was conducted by Charles River (Worcester, MA). Mouse brains were harvested and sectioned 7 days post TBI with 25 ml phosphate buffered saline (PBS) and fixed overnight in 4% paraformaldehyde in PBS. Brains were left in sucrose 30% prior to being sectioned in 40 µm sections by microtome. Microglial activation in rat hippocampi was assessed in 5 vehicle and 5 CN-105 treated rats who had been received CN-105 three hours prior to injury using F4/80 immunohistochemical staining.Results: Intravenous (IV) administration of CN-105 up to thirty minutes prior to closed head injury significantly improved durable vestibulomotor function compared to vehicle control-treated animals. In pharmacokinetic studies in uninjured CD-1 mice, IP administration of CN-105 resulted in an ~ 3-fold increase in the time to reach maximal plasma concentration (Tmax) and an ~1.5-fold increase in mean plasma residence time (MRT) compared to IV administration although the terminal elimination half-lives (T1/2) were similar. When CN-105 was co-administered by IP and IV dosing 6 hours prior to injury, a durable improvement in vestibulomotor function was observed up to 28 days following injury. Microglial counted in CN-105 treated specimens were significantly less (p = 0.0327) than those counted in vehicle specimens. Conclusion: CN-105 improves functional outcomes and reduces hippocampal microglial activation when administered prior to injury. This may be adaptable in the future as a means of preventing or reducing TBI-related secondary brain injury and improving clinical outcomes in service members who are identified as high-risk for TBI, are pre-treated, and subsequently suffer a TBI in the line of duty.

Programmed cell death (PCD) is an important pathologic process after spinal cord injury (SCI), and as a newly type of PCD, ferroptosis is also involved in the secondary SCI, however, the underlying molecular mechanisms remain unclear. Integrating animal experiment and bioinformatics, we validated the ferroptotic phenotype in SCI first, and then bioinformatic analyses, including Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, gene set enrichment analysis and protein-protein interaction analysis were performed to investigate the ferroptotic genes at 1 day, 3 days, 7 days, 14 days and 56 days post-SCI, finally, the ferroptotic genes in SCI were identified and expression of 5 key genes were validated by western blot. The ferroptotic symbols including iron overload, lipid peroxidation, shrunken mitochondria and ROS accumulation were detected in the acute and sub-acute phase of SCI. The outcomes of bioinformatics suggested that mTOR signaling pathway, HIF-1 signaling pathway, VEGF signaling pathway, Protein processing in endoplasmic reticulum were involved in ferroptotic regulation and ATF-3, XBP-1, HO-1, DDIT-3 and CHAC-1 were selected as the ferroptotic key genes in SCI. Besides, response to oxidative stress, amide metabolic process, cation transport and cytokine production were showed as the essential biological process in ferroptosis after SCI. The ferroptotic phenotype following SCI was validated and the ferroptotic genes and signaling pathways were identified. The results contribute to exploring the ferroptotic mechanism underlying secondary SCI and to providing potential target for clinical treatment.

Purpose: The aim of this study was to describe the anatomical outcomes of Brilliant Blue G (BBG)–assisted extensive internal limiting membrane peeling (eILMp) for proliferative vitreoretinopathy (PVR) under three-dimensional (3D) visualization. Methods: This study constitutes a retrospective case series conducted in a private retina practice, of 14 consecutive patients (14 eyes) with rhegmatogenous retinal detachment (RRD) complicated by PVR who underwent pars plana vitrectomy between January 2019 and January 2020. The internal limiting membrane (ILM) was selectively stained with BBG, and perspectives were enhanced with a 3D visualization system. We peeled off the ILM beyond the vascular arcades up to the periphery. The main outcome was anatomical success, defined as persistent retinal reattachment after removal of the silicone oil tamponade.Results: Anatomic success was achieved with a single surgery in 11 of 14 (78.6%) eyes, and eventual success was achieved in all eyes. The mean patient follow-up time was 12.3 months (range, 7–16 months). The mean preoperative logMAR BCVA was 2.09 (range, 2.8–1.3), which decreased to 1.54 (range, 2.8–0.6) at the last follow-up. Conclusion: This technique allowed the creation of a cleavage plane underlying the PVR membranes that facilitated its complete ILM removal, thereby reducing the risk of recurrence of retinal detachment.

Aims To assess lipid trajectories throughout pregnancy in relation to early postpartum glucose intolerance in women with gestational diabetes mellitus (GDM). Methods This prospective cohort study included 221 Chinese women with GDM who completed plasma lipid test in each trimester of pregnancy and oral glucose tolerance test at 6–9 weeks postdelivery between January 1, 2018 and January 8, 2020. Using the group-based trajectory modeling, total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-c), and high-density lipoprotein-cholesterol(HDL-c) were identified separately as three trajectories: low, moderate, and high trajectory. The associations between lipid trajectories and early postpartum glucose intolerance were all evaluated. Results Seventy-three participants developed postpartum glucose intolerance. For patients in low, moderate and high trajectory, the incidence of postpartum glucose intolerance was 38.4%, 34.9%, and 17.9%, respectively. GDM women with lower LDL-c trajectories presented a higher risk of postpartum glucose intolerance. The adjusted odds ratio (95% CI) for glucose intolerance was 3.14 (1.17–8.39) in low LDL-c trajectory and 2.68 (1.05–6.85) in moderate trajectory when compared with the high one. However, TC trajectory was not associated with the risk of postpartum glucose intolerance, nor were TG trajectory and HDL-c trajectory. Moreover, a significant difference of insulin sensitivity was observed in participants with different LDL-c trajectories; participants in high LDL-c trajectory had the highest insulin sensitivity, whereas the women in low LDL-c trajectory had the lowest insulin sensitivity (P = 0.02). Conclusions The high trajectory of LDL-c during pregnancy may play a protective role on postpartum glucose intolerance in women with GDM. Further studies are warranted to explore the underlying mechanism. Trial registration The study was reviewed and approved by the Institutional Review Board of The First Affiliated Hospital of Sun Yat-sen University (reference number: [2014]No. 93). All participants provided written informed consent forms, and the ethics committee approved this consent procedure.

Background. Esophageal cancer (EC) is the 7th most common neoplasm and the 6th most common cause of cancer-related death worldwide. Immunotherapy is an effective treatment for EC patients. However, there are no dependable markers for predicting prognosis and immunotherapy responses in EC. Our study aims to explore prognostic models and markers in EC as well as predictors for immunotherapy. Methods. The expression profiles of EC were obtained from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and International Cancer Genome Consortium (ICGC) databases. Cox regression analysis was performed to construct a prognostic model. Overall survival and receiver operating characteristic curve analyses were applied to verify the accuracy of the model. The CIBERSORT algorithm was conducted to quantify the infiltration of different immune cells, and EC was grouped into three immune cell infiltration (ICI) clusters. PD-1 and PD-L1 expressions were compared between the ICI clusters. Overall survival analysis between ICI score and tumor mutation burden was conducted. The immunotherapy response of patients in different ICI score clusters was also compared. The copy number variations, somatic mutations, and single nucleotide polymorphisms were analyzed. Enrichment analyses were also performed. Results. A prognostic model was successfully constructed. Three ICI clusters were identified, and the clusters with high immune and stromal scores tended to have more immune-activated phenotypes and higher expressions of PD-1 and PDL1. The ICI score may be used as a predictor independent of tumor mutation burden. Patients with higher ICI score tended to have better immunotherapeutic responses than those with lower scores. Enrichment analyses showed that the differentially expressed genes were mostly enriched in microvillus and the KRAS and IL6/JAK/STAT3 pathways. The top eight genes with the highest mutation frequencies in EC were identified and all related to the prognosis of EC patients. Conclusions. Our study established an effective prognostic model and identified markers for predicting the prognosis and immunotherapy response of EC patients.

Deep learning techniques are playing an important role in the classification and prediction of diseases. Undoubtedly deep learning has a promising future in the health sector, especially in medical imaging. The popularity of deep learning approaches is because of their ability to handle a large amount of data related to the patients with accuracy, reliability in a short span of time. However, the practitioners may take time in analyzing and generating reports. In this paper, we have proposed a Deep Neural Network-based classification model for Parkinson’s disease. Our proposed method is one such good example giving faster and more accurate results for the classification of Parkinson’s disease patients with excellent accuracy of 94.87%. Based on the attributes of the dataset of the patient, the model can be used for the identification of Parkinsonism's. We have also compared the results with other existing approaches like Linear Discriminant Analysis, Support Vector Machine, K-Nearest Neighbor, Decision Tree, Classification and Regression Trees, Random Forest, Linear Regression, Logistic Regression, Multi-Layer Perceptron, and Naive Bayes.

Thyroid disorder affects the regulation of various metabolic processes throughout the human body. The structural and functional disorders can affect the body as well as the brain. The computer-aided diagnosis system can identify the kind of Thyroid disease. One such machine learning framework is presented in this paper to recognize disease existence and type. In this paper, a fuzzy adaptive feature filtration, expansion, and again filtration based model is presented for generating the most relevant and contributing features. This two-level filtration model is processed in a controlled fuzzy-based multi-measure evaluation. At the first level, the composite-fuzzy measures are combined with expert’s recommendations for identifying the ranked and relevant features. At the second level, the statistical computation based distance measure is applied for expanding the featureset. The fuzzification is applied to expanded featureset for transiting the continuous values to fuzzy-values. At this level, the fuzzy-based composite-measure is applied for selecting the most contributing and relevant features over the expanded dataset. This processing featureset is processed by the ELM classifier to predict the disease existence and class. Five experiments are conducted on two datasets for validating the performance and reliability of the proposed framework. The comparative analysis is conducted against the NaiveBayes, Decision Tree, Decision Forest, Random Tree, Multilevel Perceptron, and RBF Networks. The analysis outcome is taken in terms of accuracy, error, and relevancy based parameters. The proposed framework clams the significant gain in accuracy, relevancy, and reduction in the error rate.

Infectious bursal disease virus (IBDV) can cause a highly contagious immunosuppressive disease in young chickens, resulting in considerable economic losses to the poultry industry. MicroRNAs (miRNAs) are crucial regulators of gene expression and are involved in the pathogenesis of IBDV infection. To investigate the roles of miRNA in chicken bursae of Fabricius in response to very virulent IBDV (vvIBDV) infection, RNA sequencing was performed. For this, we established an IBDV infection model as observed using histopathology, transmission electron microscopy (TEM), viral load detection, and cytokine expression levels. In total, 77 differentially expressed (DE) miRNAs were identified, of which 42 were upregulated and 35 were downregulated. A gene ontology analysis showed that genes associated with cellular processes, cells, and binding were enriched, and pathway analyses suggested that axon guidance, tight junctions, and endocytosis may be activated following vvIBDV infection. Moreover, we predicted the target genes of DE miRNAs and constructed an miRNA-mRNA regulatory network. In total, 189 pairs of miRNA-target genes were identified, comprising 67 DE miRNAs and 73 mRNAs. In this network, gga-miR-1684b-3p was identified with the highest fold change, and gga-miR-1788-3p and gga-miR-3530-5p showed a high degree of change, suggesting that they play vital roles in vvIBDV-host interactions. This study is the first to perform a comprehensive analysis of DE miRNAs in the bursa of Fabricius in response to vvIBDV infection, and it provides new insights into the molecular mechanisms underlying vvIBDV infection and pathogenesis.

Background Immune checkpoint inhibitors (ICPIs) have revolutionized cancer therapy, although immune-related adverse events (irAEs) remain a severe issue. The clinical characteristics of colitis induced by ICPIs are very similar to inflammatory bowel disease. Recently, CD8+ lymphocyte infiltration into organs has been associated with the onset of irAEs. The present study compared the histological infiltration of CD8+ lymphocytes in irAE colitis with that in other colitis. Methods Among 102 newly diagnosed and untreated patients, 12 with irAE colitis, 37 with ulcerative colitis (UC), 22 with Crohn's disease (CD), and 31 with ischemic colitis (IC) were retrospectively enrolled. Biopsy specimens were obtained from endoscopic areas of high inflammation for immunohistochemical analysis of the number of CD4+ and CD8+ lymphocytes in the most inflamed high-powered microscopic field. Results In irAE colitis, CD8+ lymphocyte infiltration was significantly greater than that of CD4+ lymphocytes (p < 0.01). The amount of CD8+ lymphocyte infiltration was significantly higher in irAE colitis than in UC (p < 0.05), CD (p < 0.05), and IC (p < 0.01). The CD8+/CD4+ ratio was also significantly higher in irAE colitis (p < 0.01 vs. UC, CD, and IC, respectively). The optimal cut-off CD8+/CD4+ ratio for diagnosing irAE colitis was 1.17 (sensitivity: 83%, specificity: 84%). The optimal cut-off the number of CD8+ lymphocytes for diagnosing irAE colitis was 102 cells/high-power field (sensitivity: 75%, specificity: 81%). Conclusions Greater CD8+ lymphocyte infiltration and a higher CD8+/CD4+ ratio may be simple and useful biomarkers to distinguish irAE colitis from other forms of colitis.

Purpose In patients with esophageal cancer, skeletal muscle mass has been reported to decrease progressively after surgery and be independently associated with a poor prognosis. The purpose of this study was to investigate perioperative changes in dysphagia, oral intake status, and nutritional status and identify factors related to sarcopenia 6 months after esophagectomy. Methods A total of 134 patients who underwent radical resection for thoracic esophageal cancer between March 2016 and July 2019 were analyzed retrospectively. The diagnosis of sarcopenia was made by CT taken 6 months postoperatively using the cut-off criteria of skeletal muscle index (SMI) 2/m2 for male and SMI 2/m2 for female patients. As factors related to postoperative sarcopenia, dysphagia, oral intake status, nutritional status, and physical function were extracted from the medical records. Multivariate logistic regression analysis was performed to identify perioperative risk factors related to sarcopenia 6 months after surgery. Results Of the 134 patients, 34.3% were judged to be unable to start oral intake on swallowing assessment. At discharge, 30.6% received tube feeding with or without oral intake. In the non-oral intake group on swallowing assessment, a significantly higher proportion of patients received tube feeding at discharge (p = 0.014). Preoperative BMI, postoperative handgrip strength, and tube feeding at discharge were independent risk factors for sarcopenia 6 months after esophagectomy in male patients. Conclusion Tube feeding at discharge is significantly related to postoperative sarcopenia in patients with esophageal cancer. Identifying high-risk groups might allow early detection of malnutrition and provision of appropriate care.

Purpose: Mammographic breast density (BD) is strongly associated to breast cancer (BC) risk; however, its association with survival is unclear.Methods: Using data from the Piedmont Cancer Registry (Registro Tumori Piemonte), we identified 693 women diagnosed with primary invasive BC between 2009-2014. We applied the Kaplan-Meier method to estimate overall survival in strata of BD and the log-rank test to assess survival differences. We evaluated the hazard ratios (HRs) of death using Cox proportional hazards model and HRs of BC-related and other causes of death using the cause-specific hazards regression model. Models included terms for BD (assessed according to the Breast Imaging Reporting and Data System [BI-RADS] density classification) and were adjusted for selected patient and tumour characteristics.Results: There were102 deaths, of which 49 were from BC. After 5 years, the overall survival was 70% in women with BI-RADS 1, 85% in those with BI-RADS 2, about 95% in those with BI-RADS 3-4 (p Conclusion: In women with BC, low BD has a negative prognostic impact.

Background Scientists have been facing numerous challenges in the development of an effective therapeutic strategy for the treatment of COVID-19 pneumonia. Several studies have suggested that improving patient immunity and reducing lung injury induced by SARS-CoV-2 may be effective for treating patients with COVID-19. Methods A pilot trial of nebulization therapy with exosomes of mesenchymal stem cells (MSCs) was performed on seven patients with COVID-19 pneumonia. Exosomes secreted from MSCs were collected and purified using multiple ultrafiltration steps. All patients were treated with nebulization of MSC-derived exosomes, and primary safety and efficacy outcomes were evaluated. Results Our clinical study demonstrated that nebulization of MSC-derived exosomes is a novel method that might be utilized in the treatment of COVID-19 pneumonia. Nebulization of MSC-derived exosomes did not induce acute allergic or secondary allergic reactions but did promote the absorption of pulmonary lesions and reduce the duration of hospitalization for mild cases of COVID-19 pneumonia. Conclusions Nebulization of MSC-derived exosomes is a safe, effective, and simple method, and their application at the beginning of treatment may be more beneficial. Trial Registration Chinese Clinical Trial Registry, ChiCTR2000030261. Registered on 26 February 2020. Graphical Abstract

Background Over the past twenty years, progress of cardiac surgery has been such that actual life expectancy of a patient with congenital heart disease (CHD) approaches that of the average for the general population. The current challenge is no longer to decrease cardiac surgery's mortality rate, but rather to manage morbidity and a child's overall development regarding nutrition and neurodevelopment. Malnutrition is a common cause of morbidity in infants with CHD, especially before the age of one. It can easily be explained by an increased metabolic demand linked to cardiac failure, hypoxemia or pulmonary hypertension. Secondly, food intake is frequently not optimal in this population and the infant's growth is insufficiently examined by paediatric cardiologists. Another factor is that much needed therapeutics such as diuretic drugs for example, often lead to weight loss. Ultimately, malnutrition in infants with CHD increases surgical risk, morbidity (infections, …), hospital stay, and alters long-term cognitive development. This study reports prevalence and associated factors of malnutrition on short and long-term follow-up of a large cohort of patients with various CHD, and who underwent cardiac surgery before the age of one. Method We conducted a retrospective and multicentre study that included infants from the North of France with CHD who underwent cardiac surgery before the age of one, between 2013 and 2017. To determine malnutrition, anthropometric measures (weight and height) were collected on the day of the surgery and during follow-up until 3 years after surgery to calculate Z-score for weight, height and weight/height. To test the statistical significance of the association between nutritional status and risk variables, univariate analysis was done applying Chi-square test. All variables significant at 0.1 in univariate analysis were included in the multivariate logistic regression analysis. The study was approved by French national ethic committee Commission national de l’informatique et des libertes (CNIL) and by the GFHGNP ethic committee (Groupe francophone d’hepatologie–gastro-enterologie et nutrition pediatrique). The author declares that he has no competing of interest. Result In total, 331 patients with CHD who underwent their first cardiac surgery (palliation or repair) before the age of one were included. Table 1 lists the cardiac diagnosis of patients included in the study. Demographic and clinical characteristics are summarised in Table 2 . Caesarean section was performed in 23.5% of cases. Only 38% infants were breastfed after maternity stay. An important part of our population was treated with diuretic drugs before surgery for congestive heart failure (38.5%). 69 (21%) infants needed a gastric tube before surgery. Feeding difficulties (including need for dietary enrichment and/or presence of a gastric tube) represented 35% of our population at the day of surgery. Only 39 (12%) were specifically assessed by speech therapist for feeding problems. Concerning surgery, 246 (74.5%) infants had undergone a biventricular repair, 51 (15.5%) infants had undergone a palliative intervention before a biventricular repair and 33 (10%) had a palliative intervention before a univentricular repair. 84 (26%) were cyanotic after their first surgery, 104 (32%) needed at least a second intervention. 49 (15%) infants had postoperative complications and 84 (26%) infants were treated by diuretics for congestive heart failure one month after surgery. 19 (5.9%) infants needed intravenous (IV) nutrition for more than 7 days. There were 19 (6%) deaths. Regarding nutritional status, at the time of the surgery, 14% of the infants presented moderate to severe growth failure (with a Z score weight for age During follow-up, between six months and 12 months after surgery, moderate to severe growth failure persisted in 16% of the study population and minor growth failure in 24%. In other terms, 40% of our cohort presented a persistent minor to severe growth failure. Fig. 1 , Fig. 2 summarize evolution of growth failure and malnutrition respectively during follow-up from 15 days to 3 years after surgery. Nineteen patients died during follow-up. A significant proportion of patients had impaired somatic growth or malnutrition at the end of the follow-up. Several associated factors of persistent growth failure 6 to 12 months after surgery were identified in univariate analysis: prenatal diagnosis, presence of genetic syndrome, birth weight ≤ 3 kg, complex CHD (CHD with 2 or more significative lesions or double outlet right ventricule or single ventricule physiology), surgery after 30 days from birth, and diuretic therapy before surgery and/or still necessary one month after surgery. The results of multivariate logistic regression analysis are summarized in Table 3 . CHD types were divided in 4 groups regarding anatomy and complexity, using TGA, Fallot and coarctation of Aorta as referent CHD with low impact on infant growth away from the day of surgery. The presence of a feeding tube at the day of surgery was not associated with growth failure 6 to 12 months after. Conclusion Growth failure in infants with CHD who undergo cardiac surgery before the age of one persists between 6 and 12 months after surgery. This should be taken into account as it can have serious consequences on children's health and development. Highlighting predictive factors will allow medical staff to identify vulnerable infants at birth and during the period of surgery and therefore increase nutritional care to combat malnutrition and growth failure.

Background We investigated the safety and efficacy of bendamustine-rituximab (BR) in previously untreated symptomatic and advanced CLL patients, as there is no data available on BR from Indian subcontinent. Methods This retrospective study included 120 consecutive treatment naive patients with CLL without del (17p), who were registered at Department of Medical Oncology, AIIMS between January 2010 and to July 2018. Bendamustine was given at a dose of 90 mg/m2on day 1 and 2, combined with rituximab 375 mg/m2 rituximab on day 1, every 28 days for up to 6 courses. Event free survival (EFS) was defined as date of treatment to date of relapse, disease progression or death due to any cause. Results The median age was 57 years (range: 30-75 years). As per clinical Rai stage 30(25%) patients were in stage II, 42(35%) were in stage III and 48(40%)were in stage IV. ZAP-70 was positive (>20%) in 50%, CD 38 was positive (>30%) in 33%, and CD49d was positive (>30%) in 49% of cases. Beta-2 microglobulin (B2M) was elevated (≥3.5 mg/L) in 80% of cases. Fifty five cases (50%, n = 110) were IGHV mutated. The mean number of cycles was 5 (1-6). Overall response rate (ORR) seen with BR was 90% and complete response was 45%. Median event free survival was 24 months with a median follow up period of 29 months. Haemoglobin ( Conclusions This is the first study of Asia to demonstrate safety and efficacy of BR in symptomatic CLL patients. BR is effective and safe regimen in the first-line treatment of CLL. Unmutaed- CLL patients have inferior EFS than mutated - CLL patients. Skin toxicity was the most common adverse effect seen in our population which was observed in around one third of cases. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Purpose: To compare the success rates of balloon dacryocystoplasty (BDP) and probing as a primary procedure in congenital nasolacrimal duct obstruction (CNLDO) and investigate the effect of age on both procedures.Methods: A total of 135 patients (171 eyes) with simple or incomplete complex CNLDO were included in this retrospective study; complete complex CNLDO cases were excluded. The success rates for primary BDP (118 eyes) and for probing (53 eyes) were compared as overall and among the age groups; Group 1 (12–24 months old), Group 2 (25–36 months old), and Group 3 (> 36 months old).Results: Mean age of the patients was 41.5±27.2 months for primary BDP, and 21.8±10.8 months for probing (pConclusion: Probing success decreased to a point where different treatment options such as primary BDP can be discussed with the patient’s parents after 18 months of age. The success of BDP decreased after 36 months, while it maintained a high success rate between 24-36 months as primary treatment.