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19 Pág., This research was funded by Biotechnology and Biological Sciences Research Council, grant number BBS/E/I/00007039/7031/7034 with support by the Pirbright flow cytometry and sequencing facilities. Some parts of the quoted research were funded in part by UK Aid from the UK Government through Global Alliance for Livestock Veterinary Medicines (GALVmed) (grant number and FCDO. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of GALVmed.

Aims: Long noncoding RNAs (lncRNAs) play key roles in the pathophysiology of DKD involving actions of microRNAs (miRNAs). The aims of the study were to establish the involvement of selected lncRNAs in the epigenetic mechanisms of podocyte damage and tubular injury in DKD of type 2 diabetes mellitus (DM) patients in relation to a particular miRNAs profile. Methods: A total of 136 patients with type 2 DM and 25 healthy subjects were assessed in a cross-sectional study concerning urinary albumin: creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (synaptopodin, podocalyxin) and of proximal tubule (PT) dysfunction (Kidney injury molecule-1-KIM-1, N-acetyl-D-glucosaminidase-NAG), urinary lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), nuclear-enriched abundant transcript 1 (NEAT1), myocardial infarction-associated transcript (MIAT), taurine-upregulated gene 1 (TUG1), urinary miRNA21, 124, 93, 29a. Results: Multivariable regression analysis showed that urinary lncMALAT1 correlated directly with urinary synaptopodin, podocalyxin, KIM-1, NAG, miRNA21, 124, UACR, and negatively with eGFR, miRNA93, 29a (p

Objectives To provide a consensus statement describing best practices and evidence regarding head and neck cancer survivorship. Methods Key topics regarding head and neck cancer survivorship were identified by the multidisciplinary membership of the American Head and Neck Society Survivorship, Supportive Care & Rehabilitation Service. Guidelines were generated by combining expert opinion and a review of the literature and categorized by level of evidence. Results Several areas regarding survivorship including dysphonia, dysphagia, fatigue, chronic pain, intimacy, the ability to return to work, financial toxicity, lymphedema, psycho‐oncology, physical activity, and substance abuse were identified and discussed. Additionally, the group identified and described the role of key clinicians in survivorship including surgical, medical and radiation oncologists; dentists; primary care physicians; psychotherapists; as well as physical, occupational, speech, and respiratory therapists. Conclusion Head and neck cancer survivorship is complex and requires a multidisciplinary approach centered around patients and their caregivers. As survival related to head and neck cancer treatment improves, addressing post‐treatment concerns appropriately is critically important to our patient's quality of life. There continues to be a need to define effective and efficient programs that can coordinate this multidisciplinary effort toward survivorship.

Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks., Joshi, Gomes et al. employ a chemical modulation approach of the cellular interactome to a hyperconnectivity state and show association with the increased response of pancreatic cancer cell lines to specific drugs, including those that target the MAPK-pathways and PI3K-mTOR pathway. To achieve this, the authors employ chemical modulation of the interactome via epichaperome inhibition with the small molecule PU-H71.

Objectives\udThe aim of this study was to define the variability of maximal wall thickness (MWT) measurements across modalities and predict its impact on care in patients with hypertrophic cardiomyopathy (HCM).\ud\udBackground\udLeft ventricular MWT measured by echocardiography or cardiovascular magnetic resonance (CMR) contributes to the diagnosis of HCM, stratifies risk, and guides key decisions, including whether to place an implantable cardioverter-defibrillator (ICD).\ud\udMethods\udA 20-center global network provided paired echocardiographic and CMR data sets from patients with HCM, from which 17 paired data sets of the highest quality were selected. These were presented as 7 randomly ordered pairs (at 6 cardiac conferences) to experienced readers who report HCM imaging in their daily practice, and their MWT caliper measurements were captured. The impact of measurement variability on ICD insertion decisions was estimated in 769 separately recruited multicenter patients with HCM using the European Society of Cardiology algorithm for 5-year risk for sudden cardiac death.\ud\udResults\udMWT analysis was completed by 70 readers (from 6 continents; 91% with >5 years’ experience). Seventy-nine percent and 68% scored echocardiographic and CMR image quality as excellent. For both modalities (echocardiographic and then CMR results), intramodality inter-reader MWT percentage variability was large (range –59% to 117% [SD ±20%] and –61% to 52% [SD ±11%], respectively). Agreement between modalities was low (SE of measurement 4.8 mm; 95% CI 4.3 mm-5.2 mm; r = 0.56 [modest correlation]). In the multicenter HCM cohort, this estimated echocardiographic MWT percentage variability (±20%) applied to the European Society of Cardiology algorithm reclassified risk in 19.5% of patients, which would have led to inappropriate ICD decision making in 1 in 7 patients with HCM (8.7% would have had ICD placement recommended despite potential low risk, and 6.8% would not have had ICD placement recommended despite intermediate or high risk).\ud\udConclusions\udUsing the best available images and experienced readers, MWT as a biomarker in HCM has a high degree of inter-reader variability and should be applied with caution as part of decision making for ICD insertion. Better standardization efforts in HCM recommendations by current governing societies are needed to improve clinical decision making in patients with HCM.

Summary Background AMP kinase (AMPK) is an energy sensor implicated in regulation of lipid metabolism, inflammation, and insulin sensitivity. We aimed to assess efficacy and safety of PXL770, a novel direct AMPK activator, in patients with non-alcoholic fatty liver disease (NAFLD). Methods STAMP-NAFLD, a randomised, double-blind, placebo-controlled phase 2a study, was done across 15 US clinical sites. Patients aged 18–75 years with liver fat content of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned (1:1:1:1), via an interactive web response system, to receive oral PXL770 250 mg once daily, 250 mg twice daily, or 500 mg once daily, or matched placebo. Patients were stratified according to type 2 diabetes status and study site. The primary endpoint was relative change in liver fat content from baseline compared with placebo at week 12, assessed by MRI-PDFF. The primary endpoint was analysed in an ANCOVA model with treatment and stratification criteria as factors and baseline liver fat content as a covariate in the modified intention-to-treat population, defined as all as-randomised patients who received at least one dose of study treatment. Safety was analysed in the safety population, defined as all as-treated patients receiving at least one dose of the study treatment. The trial has been completed and the final results are reported. The trial is registered with ClinicalTrials.gov , NCT03763877 . Findings Between March 29, 2019, and March 13, 2020, 387 patients were screened, of whom 120 were included in the modified intention-to-treat and safety analyses (30 in the 250 mg once daily group, 30 in the 250 mg twice daily group, 29 in the 500 mg once daily group, and 31 in the placebo group). The mean relative change from baseline in liver fat content at week 12 was −1·1% in the placebo group, −1·0% in the 250 mg once daily group (mean difference versus placebo 0·1% [95% CI −15·4 to 15·7], p=0·99), −14·3% in the 250 mg twice daily group (−13·1% [–28·1 to 1·8], p=0·084), and −14·7% in the 500 mg once daily group (−13·5% [–28·5 to 1·4], p=0·076). At least one treatment-emergent adverse event occurred in 23 (77%) of 30 patients in the 250 mg once daily group, 20 (67%) of 30 patients in the 250 mg twice daily group, 21 (72%) of 29 patients in the 500 mg once daily group, and 21 (68%) of 31 patients in the placebo group. The most common treatment-emergent adverse event was diarrhoea (five [17%] of patients in the 250 mg once daily group, seven [23%] in the 250 mg twice daily group, six [21%] in the 500 mg once daily group, and none in the placebo group). No life-threatening events or treatment-related deaths occurred. Interpretation PXL770 treatment did not meet the primary outcome of liver fat improvement compared with placebo. Treatment was well tolerated. Given indications that metabolic features improved with PXL770 treatment, AMPK activation might be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further assessment in patients with non-alcoholic steatohepatitis. Funding Poxel.

Congenital epulis is a rare benign tumor of the newborn that could be detected in the prenatal period. Females are more often affected than males and the premaxillary region is usually the predilection site for this oral mass. Excision is the treatment of choice and no recurrences have been reported so far. We present our experience with two cases of congenital epulis, detected in the second trimester of gestation and treated shortly after birth with no further complications. Histopathology should differentiate between congenital epulis and other congenital oral tumors even if its clinical appearance is usually enough to make a tentative diagnosis. A multidisciplinary assessment in the management of this tumor can avoid unwanted complications such as airway obstruction or bleeding.

The gastrointestinal microbiome contains at least 100 trillion microorganisms (bacteria, viruses, fungi), whose distribution varies from the mouth to the rectum spatially and temporally throughout one's lifetime. The microbiome benefits from advancing research due to its major role in human health. Studies indicate that its functions are immunity, metabolic processes and mucosal barrier. The disturbances of these functions, dysbiosis, influence physiology, lead to diabetes, inflammatory bowel disease, obesity and colon tumorigenesis. The third most common form of cancer, colorectal cancer, is the result of many factors and genes, and although the link between dysbiosis and this type of cancer is poorly characterized, it has been shown that some bacterial species and their metabolites have a critical role in developing colorectal cancer. Also, gut microbiota plays a role in the inflammatory response and immune process perturbations during the progression of colorectal cancer. Some new technologies, such as metagenome sequencing, facilitated the progress by analyzing the metabolic and genetic profile of microbiota, revealing details about the bacterial composition, host interactions, and taxonomic alterations. This review summarizes the studies regarding the link between gut microbiota and colorectal cancer, targeting new therapeutic strategies.

Neuroendocrine breast carcinomas represent a rare subtype of breast cancer. Their definition, prevalence and prognosis remain controversial in the literature. Regarding the presentation, there are no differences from other breast carcinomas and clinical syndromes related to hormone production are extremely rare. Refinement of the classification of neuroendocrine neoplasms of the breast is needed in order to improve the reproducibility of their diagnostic criteria and to define their clinical significance. This article presents the case of a 44-year-old female patient diagnosed with invasive breast carcinoma with neuroendocrine features, according to the 2012 World Health Organization (WHO) definition, with focus on presentation, clinical manifestations, diagnostic approach and differential diagnosis.

Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (−3.1, 95% confidence interval (CI) −6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was −29.1 IU l−1 (95% CI = −41.6 to −16.5). Early termination due to adverse events (AEs) was

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

This paper presents the case of a 58-year-old heavy smoker female who came to our clinic with acute pain, as well as mastication and feeding difficulties. The macroscopic examination revealed oral erosive lesions and ulcerations. The polymorphic aspect of the lesions required the differential diagnosis of oral erythroplakia or carcinoma, which were excluded by biopsy. At the same time, we assessed the expression of S100 protein, Ki67 and the cluster of differentiation (CD) 4, CD8 (T-cell) and CD20 (B-cell) immune cell markers by immunohistochemical analysis. As a result, after the clinical and pathological assessment, the diagnosis of oral lichen planus was established, and a therapy plan was conducted. We observed a favorable clinical evolution after the administration of corticosteroids and immunomodulatory agents.

Treatment for inflammatory bowel disease (IBD) often requires specialized care. While much of IBD care has shifted to the outpatient setting, hospitalizations remain a major site of healthcare utilization and a sizable proportion of patients with inflammatory bowel disease require hospitalization or surgery during their lifetime. In this review, we approach IBD care from the population-level with a specific focus on hospitalization for IBD, including the shifts from inpatient to outpatient care, the balance of emergency and elective hospitalizations, regionalization of specialty IBD care, and contribution of surgery and endoscopy to hospitalized care.

Introduction. Osteoporosis has a major influence on the quality of life because of its impact on bone strength. Osteoporosis and fractures are frequent in patients with multiple sclerosis, decreased mobility being an important risk factor in these patients. Objectives. This paper presents a case of severe osteoporosis in a patient with multiple sclerosis, to emphasize a correlation between this two pathologies. Material and Methods. We present the case of a female Caucasian patient, aged 65 years, known with progressive multiple sclerosis, on long-term use of glucocorticoids, and severe osteoporosis, who is investigated for mechanical pain and functional deficiency in the lumbar spine and the right hip, motor deficit, predominantly on right limbs and walking disorders. The patient was diagnosed with severe osteoporosis treated with raloxifene and bisphosphonates, with multiple vertebral fractures and vitamin D deficiency. During hospitalization the patient followed myorelaxant therapy and an individualized rehabilitation program. Results and discussion. During follow-up, there was a significant increase followed by a recent decrease in bone mass density in the lumbar spine and hip. The patient was recommended a loading dose of cholecalciferol for three months and initiation of teriparatide therapy after restoring 25-hydroxy vitamin D levels. Conclusion. In patients with multiple sclerosis,screening and early management of osteoporosis and osteopenia are essential. Keywords: multiple sclerosis, glucocorticoid therapy, osteoporosis

Objective To identify the diagnoses and outcomes associated with elevated high sensitivity cardiac troponin T (hs-cTnT) compared with the 4th-generation troponin T and to validate the Mayo Clinic hs-cTnT myocardial infarction algorithm cutoff values. Patients and Methods Consecutive blood samples of patients presenting to the emergency department between July 2017 and August 2017, who had 4th-generation troponin T, were also analyzed using the hs-cTnT assay. Troponin T values, discharge diagnoses, comorbidities, and outcomes were assessed. In addition, analyses of sex-specific and hs-cTnT cutoff values were assessed. Results Of 830 patients, 32% had an elevated 4th-generation troponin T, whereas 64% had elevated hs-cTnT. With serial sampling, 4th-generation troponin missed a chronic myocardial injury pattern and acute myocardial injury pattern in 64% and 16% of patients identified with hs-cTnT, respectively. Many of these “missed” patients had discharge diagnoses associated with cardiovascular disease, infection, or were postoperative. Five of the 6 patients with unstable angina ruled in for myocardial infarction. Conclusion There were many increases in hs-cTnT that were missed by the 4th-generation cTnT assay. Most new increases are not related to acute cardiac causes. They were more consistent with chronic myocardial injury. High-sensitivity cTnT did reclassify most patients with unstable angina as having non–ST-elevation myocardial infarction. Older age, more comorbidities, and lower hemoglobin were associated with elevated hs-cTnT. Our data also support the use of our sex-specific cutoff values.

There is an urgent need for anti-viral agents that treat SARS-CoV-2 infection. The shortest path to clinical use is repurposing of drugs that have an established safety profile in humans. Here, we first screened a library of 1,900 clinically safe drugs for inhibiting replication of OC43, a human beta-coronavirus that causes the common-cold and is a relative of SARS-CoV-2, and identified 108 effective drugs. We further evaluated the top 26 hits and determined their ability to inhibit SARS-CoV-2, as well as other pathogenic RNA viruses. 20 of the 26 drugs significantly inhibited SARS-CoV-2 replication in human lung cells (A549 epithelial cell line), with EC50 values ranging from 0.1 to 8 micromolar. We investigated the mechanism of action for these and found that masitinib, a drug originally developed as a tyrosine-kinase inhibitor for cancer treatment, strongly inhibited the activity of the SARS-CoV-2 main protease 3CLpro. X-ray crystallography revealed that masitinib directly binds to the active site of 3CLpro, thereby blocking its enzymatic activity. Mastinib also inhibited the related viral protease of picornaviruses and blocked picornaviruses replication. Thus, our results show that masitinib has broad anti-viral activity against two distinct beta-coronaviruses and multiple picornaviruses that cause human disease and is a strong candidate for clinical trials to treat SARS-CoV-2 infection.

Gastroschisis is a malformation of the closure of the anterior abdominal wall which has had a growing incidence in recent years. It is a borderline pathology between several specialties such as: obstetrics, neonatology, pediatric surgery, family medicine and requires many resources. In general, the chance of survival of newborns with gastroschisis is high. However, complex cases with complications are more likely to have an unfavorable prognosis. The therapeutic plan should start from the intra-embryonic period, from the time of the ultrasound diagnosis and it should extend over a long period of time, which can vary depending on the case, and on the surgical options. When it comes to the management of the cases, there is no valid protocol for all the cases, and there is a great variability starting with the choice of birth time, birth pathway, the option of reintegrating the intestinal loops and closing the abdominal defect. Because of this, the cases of gastroschisis represent a challenge for modern medicine, when also taking into account the fact that the etiopathogenesis of this malformation is not clearly established and that there is a large variety of therapeutic options.

Congenital diaphragmatic hernia is a severe condition with an etiology and pathogenesis still been developed; also, the involvement of genetic and environmental factors in the occurrence of this malformation is under study. Morbi-mortality in these patients is high, and quality of life is diminished. Under these circumstances, careful follow-up of the pregnancy and multidisciplinary management after birth is needed to diagnose the malformation as early as possible and adapt the therapeutic plan to the particularities of each case. In conclusion, despite several research data in the literature concerning this topic, the management of newborn babies with congenital diaphragmatic hernia remains a severe challenge. The treatment of congenital diaphragmatic hernia remains the prerogative of overqualified teams.

Cantrell’s pentalogy is a congenital syndrome that includes multiple defects which predispose the fetus to a high mortality rate. Over time, the association of malformations defining this syndrome has changed accepting incomplete forms, or forms that associate other anomalies. The therapeutic strategy in Cantrell's pentalogy is an intensely debated one as it deals with newborns having a low survival rate and multiple malformations. Once treatment is started for certain malformations it can lead to the aggravation of others. In conclusion, a conservative approach is recommended, with the initiation of surgical treatment after the stabilization of the newborn. A multidisciplinary approach is needed to achieve optimal results in these difficult cases.

Background The association between a slower physical growth and poorer neurodevelopment has been established in infants born preterm or small for gestational age. However, this association is inconsistent in term-born infants, and detailed investigations in infancy, when intervention is most beneficial for improving outcomes, are lacking. We therefore examined this association separately by sex during the first year of life in term-born infants. Methods Using data collected until children reached 12 months old in an ongoing prospective cohort of the Japan Environment and Children’s Study, we analyzed 44,264 boys and 42,541 girls with singleton term-birth. The exposure variables were conditional variables that disentangle linear growth from weight gain relative to linear growth, calculated from the length and weight at birth and 4, 7 and 10 months old. Neurodevelopmental delay was identified using the Japanese-translated version of Ages & Stages Questionnaires, third edition. Results A reduced risk of neurodevelopmental delay at 6 months old was observed in children with a higher birth weight (adjusted relative risks [aRRs]: 0.91 and 0.93, 95 % confidence intervals [95 % CIs]: 0.87–0.96 and 0.88–0.98 in boys and girls, respectively) and increased linear growth between 0 and 4 months old (aRRs: 0.85 and 0.87, 95 % CIs: 0.82–0.88 and 0.83–0.91 in boys and girls, respectively). A reduced risk at 12 months was found in children with an increased linear growth between 0 and 4 months (aRRs: 0.92 and 0.90, 95 % CIs: 0.87–0.98 and 0.84–0.96 in boys and girls, respectively), boys with an increased relative weight gain between 0 and 4 months (aRR: 0.90, 95 % CI: 0.84–0.97), and girls with a higher birth weight (aRR: 0.89, 95 % CI: 0.83–0.96). Conclusions These results suggest that a slow physical growth by four months old may be a predictor of neurodevelopmental delay during infancy.

Recent studies suggest that lymph node ratio (LNR) has significantly better prognostic power than N-status in patients with colorectal cancer, in particular when the number of evaluated lymph nodes (LNs) was insufficient. The aim of this study was to assess the prognostic value of LNR in patients with resected synchronous colorectal liver metastases (SCLMs) and less than 12 examined LNs. A prospectively maintained database of patients with resected SCLMs was queried for patients with less than 12 LNs evaluated at the time of surgery. X-tile software was used to determine the LNR cutoff value able to divide the patients in two subgroups with distinct prognosis. Overall survival (OS) and disease-free survival (DFS) rates were compared by log-rank test. A multivariate Cox regression analysis identified independent prognostic factors. A cutoff LNR value of 0.22 divided patients into Low-LNR group (35 patients) and High-LNR group (36 patients). Both OS and DFS rates were significantly higher in Low-LNR group than those in High-LNR group. Independent predictors of poor OS were High-LNR (HR: 2.841, 95% CI: 1.480–5.453, p value = 0.002), bilobar SCLMs (HR: 2.253, 95% CI: 1.144–4.437, p value = 0.019) and lack of adjuvant chemotherapy (HR: 2.702, 95% CI: 1.448–5.043, p value = 0.002), while the only independent predictor of poor DFS was High-LNR (HR: 2.531, 95% CI: 1.259–5.090, p value = 0.009). LNR > 0.22 was independently associated with poor OS and DFS in patients with resected SCLMs and less than 12 evaluated LNs.

The aim of this prospective cohort study was: to identify the association between different biomarkers [proprotein convertase subtilisin/kexin 9-PCSK9, lipoprotein(a)-Lp(a) and high-sensitivity C-reactive protein-hsCRP] and the cardiovascular events; to evaluate the relationship between the 3 biomarkers mentioned above and the renal outcomes that contributed to end-stage renal disease (ESRD).We studied 110 patients with chronic kidney disease (CKD) stages 2 to 4. The identification of the new cardiovascular events and the renal outcomes were performed by clinical and paraclinical explorations.350 patients were examined and 110 (31.4%) were included in this study. The mean age was 55.6 ± 10.9 years, with a higher number of men compared to women. The CKD patients with de novo cardiovascular events and new renal outcome during the study, had significantly increased values of total cholesterol (TC), low density cholesterol lipoprotein (LDL-C) at 6 and 12 months and higher levels of Lp(a), PCSK9, hsCRP and low ankle-brachial index (ABI) and ejection fraction (EF) values compared to patients without cardiovascular and renal events. In CKD patients, PCSK9 220 ng/mL was a predictor of cardiovascular events, while the EF 50% was a predictor for renal outcomes. For CKD patients with PCSK9 220 ng/mL and hsCRP 3 mg/L levels, the time-interval for the new cardiovascular and renal events occurrence were significantly decreased compared to patients displaying low values of these biomarkers.The results of this study show that PCSK9 220 ng/mL was predictor for cardiovascular events, while EF 50% was predictor for CKD progression to ESRD. PCSK9 220 ng/mL and hsCRP 3 mg/L were associated with the occurrence of renal and cardiovascular events earlier.

George Gershwin (1898-1937) was one of the most influential American composers of the 20th century. Likewise his swift, comet-like, career progress from a high school dropout to an iconic composer of the 20th century: "The man who said he had more notes in his head than he could write down in a hundred years died suddenly ... in Hollywood". His malignant glioma presented symptoms only in his last year of life and even then, the symptoms were masked by other hectic events in his personal life, which typical accompany the life of a famous and handsome composer from Hollywood. Considering new, emerging studies regarding the relationship between gliomas and brain activity, the authors explore the following questions: (i) Is intense neuronal, intellectual activity a cause that can trigger the development of a malignant brain tumor, especially a glioblastoma? (ii) Is glioblastoma and its connections with normal nerve cells, with noble tissue (a fact demonstrated in recent years), a cause that can trigger geniality, a different thought process from most people with a normal-functioning brain?

We describe an uncommon clinical presentation of caudal duplication syndrome and features of caudal regression syndrome in a female infant with complex urogenital and colorectal duplication associated with lipomyleomeningocele and left lower limb hypoplasia. A staged surgical treatment plan was carried out to maintain fecal and urine continence, potential fertility, and cosmetic appearance.

The resistance of cancer cells to radiation-based treatment is a major clinical challenge confounding standard of care in cancer. This problem is particularly notable in many solid tumors where cancer cells are only partially responsive to radiation therapy. Combination of radiation with radiosensitizers is able to enhance tumor cell killing. However, currently available radiosensitizers are associated with significant normal tissue toxicity. Accordingly, there is an unmet need to develop safer and more effective radiosensitizers to improve tumor control. Here, we evaluated the radiosensitizing effect of the FDA-approved drug esomeprazole in normal and radioresistant human head and neck squamous cell carcinoma (HNSCC) cells in vitro, and in a mouse model of HNSCC. For the in vitro studies, we used cancer cell colony formation (clonogenicity) assay to compare cancer cell growth in the absence or presence of esomeprazole. To determine mechanism(s) of action, we assessed cell proliferation and profiled cell cycle regulatory proteins. In addition, we performed reverse phase protein array (RPPA) study to understand the global effect of esomeprazole on over 200 cancer-related proteins. For the in vivo study, we engrafted HNSCC in a mouse model and compared tumor growth in animals treated with radiation, esomeprazole, and combination of radiation with esomeprazole. We found that esomeprazole inhibits tumor growth and dose-dependently enhances the cell killing effect of ionizing radiation in wildtype and p53-mutant radioresistant cancer cells. Mechanistic studies demonstrate that esomeprazole arrests cancer cells in the G1 phase of the cell cycle through upregulation of p21 protein and inhibition of cyclin-dependent kinases (Cdks) type 1 (Cdk1) and type 2 (Cdk2). In vivo data showed greater tumor control in animals treated with combination of radiation and esomeprazole compared to either treatment alone, and that this was associated with inhibition of cell proliferation in vivo. In addition, combination of esomeprazole with radiation significantly impaired repair following radiation-induced DNA damage. Our studies indicate that esomeprazole sensitizes cancer cells to ionizing radiation, and is associated with upregulation of p21 to arrest cells in the G1 phase of the cell cycle. Our findings have significant therapeutic implications for the repurposing of esomeprazole as a radiosensitizer in HNSCC and other solid tumors.

Background & aims Porto-sinusoidal vascular liver disease (PSVD) is a rare cause of portal hypertension. PSVD is still often misdiagnosed as cirrhosis, emphasizing the need to improve PSVD diagnosis strategies. Data on liver stiffness measurement (TE-LSM) using transient elastography, in PSVD are limited. The aim of this study was to evaluate the accuracy of TE-LSM to discriminate PSVD from cirrhosis in patients with signs of portal hypertension. Approach & results Retrospective multicenter study comparing TE-LSM in patients with PSVD, according to VALDIG criteria, to patients with compensated biopsy-proven cirrhosis related to alcohol (n=117), hepatitis C virus (HCV) infection (n=110) or non-alcoholic fatty liver disease (NAFLD) (n=46). All patients had at least one sign of portal hypertension among gastroesophageal varices, splenomegaly, porto-systemic collaterals, history of ascites or platelet count Conclusions This study including a total of 155 patients with PSVD and 273 patients with cirrhosis demonstrates that TE-LSM 20 kPa, PSVD is highly unlikely.

BACKGROUND Atherosclerosis represents the main cause of myocardial infarction (MI); other causes such as coronary embolism, vasospasm, coronary-dissection or drug use are much rarely encountered, but should be considered in less common clinical scenarios. In young individuals without cardiovascular risk factors, the identification of the cause of MI can sometimes be found in the medical history and previous treatments undertaken. CASE SUMMARY We present the case of a 34-year-old man presenting acute inferior ST-elevation MI without classic cardiac risk factors. Seven years ago, he suffered from orchidopexy for bilateral cryptorchidism, and was recently diagnosed with right testicular seminoma for which he had to undergo surgical resection and chemotherapy with bleomycin, etoposide and cisplatin. Shortly after the first chemotherapy treatment, namely on day five, he suffered an acute MI. Angiography revealed a mild stenotic lesion at the level of the right coronary artery with suprajacent thrombus and vasospasm, with no other significant lesions on the other coronary arteries. A conservative treatment was decided upon by the cardiac team, including dual antiplatelets therapy and anticoagulants with good further evolution. The patient continued the chemotherapy treatment according to the initial plan without other cardiovascular events. CONCLUSION In young individuals with no cardiovascular risk factors undergoing aggressive chemotherapy, an acute MI can be caused by vascular toxicity of several anti-cancer drugs.

INTRODUCTION: Thrombocytopenia is common in SARS-COV-2 infection, and about a quarter of cases have moderate thrombocytopenia. Severe thrombocytopenia is less common and is associated with severe forms of COVID-19. The pathogenesis of this thrombocytopenia appears to be complex, the immune mechanism being incriminated. Immune thrombocytopenic purpura (ITP) is one of the severe complications of COVID-19 and has an increased risk of mucosal or cutaneous bleeding. CASE REPORT: We present the case of a 72-year-old woman admitted to the hospital with moderate COVID-19 who developed severe thrombocytopenia 13 days after the onset of COVID symptoms. Nine days after admission, her platelets decreased from 149×10(9)/L to 3×10(9)/L and numerous patches appeared on the skin and mucous membranes. She was responsive to corticosteroids and platelet transfusion, after five days, the platelet level returned to normal. CONCLUSIONS: Close hematological monitoring of patients with COVID is necessary to prevent severe complications. Even if this patient did not receive immunoglobulins, corticosteroid therapy and platelet administration led to a favorable outcome.

Introduction. Gum hyperplasia is clinically translated by growth in gum size, edema and bleeding (over-normal bags). The gum may be thin or fibrous, firm (in pseudotumor forms). In the absence of proper treatment, it will be associated with the bone resorption of the alveolar process, leading to different degrees of dental mobility. Purpose. Through this clinical-statistical study, we aim to analyze patients diagnosed with gum hyperplasia by age, gender, type of gum hyperplasia, etiology and localization. Also, by observing in surgical practice more and more cases of gum hyperplasia in patients with orthodontic treatment, through this clinical-statistical study, we aim to quantify the incidence of gingival hyperplasia in orthodontic treatments carriers and its distribution by gender. Material and method. The study is retrospective type, performed on 172 patients with the diagnosis of gum hyperplasia (K06.1), treated in the Oro-maxillo-facial surgery Clinic in Targu Mures, during Jan.2015-march 2021. Hypocrate concept 3 was used to access patient observation sheets. Results and discussions. Analyzing the descriptive statistical data of this retrospective clinical-statistical study, it is observed that the average age of the subjects is 58 years, the distribution by sex favors the female gender (59%), generally occurs in adults, has affinity for the right hemimaxilla, approx. 25% of patients have gingival hyperplastic lesions caused by orthodontic appliances and mobile/mobilizable prostheses. These types of lesions represent a ratio of 2/1 in favor of females, which indicates that the aesthetic requirements for females are much higher compared to males. Also, interpreting, from a medical point of view, the statistical conclusions of this study, we find that the patient's gender does not influence the location and appearance of the hyperplasic lesion, instead the age of the patients influences the occurrence of the hyperplastic lesion. Conclusion. Orthodontic therapy should be indicated after a correct evaluation of periodontal tissues, quantification of periodontal indices and detection of risk factors.

Background Patients with obesity are at higher risk for community-acquired and nosocomial infections. However, no study has specifically evaluated the relationship between obesity and ventilator-associated pneumonia (VAP). Research Question Is obesity associated with an increased incidence of VAP? Study Design and Methods This study was a post hoc analysis of the Impact of Early Enteral vs Parenteral Nutrition on Mortality in Patients Requiring Mechanical Ventilation and Catecholamines (NUTRIREA2) open-label, randomized controlled trial performed in 44 French ICUs. Adults receiving invasive mechanical ventilation and vasopressor support for shock and parenteral nutrition or enteral nutrition were included. Obesity was defined as BMI ≥ 30 kg/m2 at ICU admission. VAP diagnosis was adjudicated by an independent blinded committee, based on all available clinical, radiologic, and microbiologic data. Only first VAP episodes were taken into account. Incidence of VAP was analyzed by using the Fine and Gray model, with extubation and death as competing risks. Results A total of 699 (30%) of the 2,325 included patients had obesity; 224 first VAP episodes were diagnosed (60 and 164 in obese and nonobese groups, respectively). The incidence of VAP at day 28 was 8.6% vs 10.1% in the two groups (hazard ratio, 0.85; 95% CI 0.63-1.14; P = .26). After adjustment on sex, McCabe score, age, antiulcer treatment, and Sequential Organ Failure Assessment at randomization, the incidence of VAP remained nonsignificant between obese and nonobese patients (hazard ratio, 0.893; 95% CI, 0.66-1.2; P = .46). Although no significant difference was found in duration of mechanical ventilation and ICU length of stay, 90-day mortality was significantly lower in obese than in nonobese patients (272 of 692 [39.3%] patients vs 718 of 1,605 [44.7%]; P = .02). In a subgroup of patients (n = 123) with available pepsin and alpha-amylase measurements, no significant difference was found in rate of abundant microaspiration of gastric contents, or oropharyngeal secretions between obese and nonobese patients. Interpretation Our results suggest that obesity has no significant impact on the incidence of VAP.

Operating on obese patients can increase case complexity and result in worse outcomes. We described the incremental impact of BMI on morbidity and outcomes of colorectal operations and whether laparoscopic and robotic(MIS) approaches mitigate this morbidity differently.A retrospective cohort of patients undergoing elective colorectal operations in SCOAP was created to examine the association of increasing BMI on surgical outcomes. Additionally, multivariable logistic regression models were constructed.From 2011 to 2019, 22,863 elective colorectal operations (mean age 62, 55% female) were performed at 42 hospitals. Patients had BMI≥30 in 7576(33%) and BMI≥40 in 1180(5%) of operations. After risk adjustment, BMI≥40 was associated with increased conversions(OR1.57,95%CI1.26-1.96), increased combined adverse events(CAE)(OR1.32,95%CI1.15-1.52), and death(OR2.24, 95%CI1.41-3.55)(all p 0.01). MIS approaches were each associated with lower CAE(lap OR0.49,95%CI0.46-0.53; robot OR0.42,95%CI0.37-0.47), and death(lap OR0.24,95%CI0.18-0.33; robot OR0.18,95%CI0.10-0.35)(all p 0.01).Severe obesity is associated with increased conversion rates and worse short-term outcomes after colorectal surgery, though this trend is partially mitigated with a minimally invasive approach. These findings support the broad application of MIS for colorectal operations in obese patients.

Summary Background Haematopoietic stem cells expressing the CD34 surface marker have been posited as a niche for Mycobacterium tuberculosis complex bacilli during latent tuberculosis infection. Our aim was to determine whether M tuberculosis complex DNA is detectable in CD34-positive peripheral blood mononuclear cells (PBMCs) isolated from asymptomatic adults living in a setting with a high tuberculosis burden. Methods We did a cross-sectional study in Ethiopia between Nov 22, 2017, and Jan 10, 2019. Digital PCR (dPCR) was used to determine whether M tuberculosis complex DNA was detectable in PBMCs isolated from 100 mL blood taken from asymptomatic adults with HIV infection or a history of recent household or occupational exposure to an index case of human or bovine tuberculosis. Participants were recruited from HIV clinics, tuberculosis clinics, and cattle farms in and around Addis Ababa. A nested prospective study was done in a subset of HIV-infected individuals to evaluate whether administration of isoniazid preventive therapy was effective in clearing M tuberculosis complex DNA from PBMCs. Follow-up was done between July 20, 2018, and Feb 13, 2019. QuantiFERON-TB Gold assays were also done on all baseline and follow-up samples. Findings Valid dPCR data (ie, droplet counts >10 000 per well) were available for paired CD34-positive and CD34-negative PBMC fractions from 197 (70%) of 284 participants who contributed data to cross-sectional analyses. M tuberculosis complex DNA was detected in PBMCs of 156 of 197 participants with valid dPCR data (79%, 95% CI 74–85). It was more commonly present in CD34-positive than in CD34-negative fractions (154 [73%] of 197 vs 46 [23%] of 197; p

Background This report presents 5-year outcomes of the rapid-deployment Edwards Intuity valve in a prospective, single-center study. Methods All patients who underwent an aortic valve replacement (AVR) with an Edwards Intuity bioprosthesis at La Timone Hospital, Marseille, France, from July 2012 to June 2015 were assessed over a 5-year follow-up period. The primary outcome was overall mortality at 5 years. Secondary outcomes were reoperation, overall mortality and stroke, cardiovascular mortality, composite endpoints defined by the updated Valve Academic Research Consortium-2 (VARC-2), periprosthetic regurgitation, prosthesis-patient mismatch, and the need for new pacemaker implantation. Results In total, 170 consecutive patients were assessed, of which 67.1% were males. The mean age was 76 years, mean EuroSCORE II was 3.5% and 5-year overall mortality was 12.4%. At 5 years, reoperation was 2.9%, overall mortality and stroke was 4.1% per patient-year, and cardiovascular mortality was 4.7%. VARC clinical efficacy and VARC time-related valve safety were achieved in 46.0% and 59.9% of patients, respectively. At one month VARC device success was 71.2% and VARC early safety was 87.1%. At one year, mild and moderate periprosthetic regurgitation were 2.4% and 0.6%, respectively, and moderate and severe prosthesis-patient mismatch were 18.8% and 4.8%, respectively. Conduction disturbances needing new PPI occurred in 3.5% patients. Conclusion The 5-year outcomes of AVR with the Edwards Intuity valve system demonstrate satisfactory midterm safety and excellent haemodynamic performance.

The aim of this retrospective study was: to analyze the epidemiological patterns of the kidney disease based on clinical and histological features in a single-center in the N-E region of Romania, between 2011 and 2019 and to compare the biopsy results with the others periods, as well as the results from other countries. We studied 442 renal biopsies. The indications for renal biopsy were represented by the clinical features: nephrotic syndrome, nephritic syndrome, asymptomatic urinary abnormalities, acute kidney injury, and chronic kidney disease of unknown etiology. During the past 8 years, the annual incidence of renal biopsies was constant, albeit this incidence remained lower than in other countries. Nephrotic syndrome was the most common indication for renal biopsy (47.6%). Primary glomerulonephritis (GN) was the most common diagnosis in each of the three periods, followed by secondary GN. Vascular nephropathy and TIN were constant as a proportion from the overall biopsies in each of the three periods. The membranoproliferative GN (24.4%) and membranous nephropathy (MN) (21.9%) were the most prevalent primary GN, while lupus nephritis (LN) was the most common secondary glomerular disease in young female patients (7.5%). Compared to 1994–2004 period, we observed a significant decrease of incidence of focal segmental glomerulosclerosis (FSGS) and mesangial proliferative GN, and a significant increases in the frequency of MN. The results of this study show that the GN distribution model was constant in N-E Romania and became similar to that observed in many countries with high socio-economic status.

Struma ovarii is a rare dermoid tumor of the ovary (1% of all ovarian tumors and 2,7% of ovarian teratomas), with more than 50% of the overall tissue being thyroid. Approximately one third of the cases present ascites. Pseudo-Meigs syndrome has been reported in fewer than 10 cases and 5-8% present thyroid hyperfunction. However, only 26 cases reported the association of ascites or pseudoMeigs’ syndrome, elevated cancer antigen 125 and benign struma ovarii in the literature. The authors submit a case of benign struma ovarii that presented as a pelvic mass with ascites and highly elevated CA 125 serum levels and an extensive literature survey on this topic.

Prostate cancer represents the leading malignant tumor in men over 50 years of age with 400,000 new cases being diagnosed yearly in Europe. Even if the incidence rate is higher than the mortality rate, still there is an increasing trend when speaking of its mortality. The increasing incidence of the metabolic syndrome, the unhealthy lifestyle, the high lipid and Calcium intake, the high spread of infections with Human Papilloma Virus, Human Herpes Virus, the excess of androgen consumption and the longer life expectancy, are few of the main causes of prostate cancer increasing incidence. The new systemic therapies such as immunotherapy with Checkpoint Inhibitors or Poly, ADP-Ribose Polymerase inhibitors and local experimental procedures addressing tumor destruction, such as High- Intensity Focused Ultrasound, the Cryo and Focal Laser Ablation, provide good outcomes and become new promising tools for prostate cancer therapy. Physicians consider these methods worth using; the efficacy of some specific categories of patients being arguments for their use in the current protocols even though solid data regarding the improvement of global mortality rates are not yet published. The current article focuses on the newest systemic and local experimental treatment tools highlighting their benefits, especially for hormone-resistant prostate cancer.

The acute development and the accumulation of chyle into the peritoneal space is a rare condition and one needs to be able to distinguish it from chylous ascites, which is most commonly chronic and associated with related diseases. It is frequently idiopathic and additionally, clinical and imaging findings are nonspecific. In almost all cases, the diagnosis is made intraoperatively during laparoscopy or laparotomy, most diagnostic procedures being indicated by acute complaints pertaining to the abdomen. A 23-year-old man was admitted to the Emergency Department with abdominal pain, with right iliac fossa tenderness and peritonism. Laparoscopy was performed due to acute abdomen findings. Further exploration revealed chylous effusion with milky-like fluid. The peritoneal lavage and the insertion of drains were subsequent to the careful inspection of the cavity. The biochemical analysis of the peritoneal fluid was an important aid which provided the diagnosis of chylous peritonitis due to acute pancreatitis.

Tudor Parvanescu,1 Andrei Vitel,1 Ioan Sporea,2 Ruxandra Mare,2 Bogdan Buz,1 Diana Aurora Bordejevic,1 Mirela Cleopatra Tomescu,1 Sergiu Florin Arnautu,3 Vlad Ioan Morariu,1 Ioana Mihaela Citu1 1Cardiology Department, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania; 2Department of Gastroenterology and Hepatology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania; 3Department of Neurology, Victor Babes University of Medicine and Pharmacy, Timisoara, RomaniaCorrespondence: Diana Aurora BordejevicCardiology Department, Victor Babe” University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, Timisoara, RomaniaTel +40 734600550Fax +40 256220636Email aurora.bordejevic@umft.roBogdan BuzCardiology Department, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Square, Timisoara, RomaniaTel +40 756346910Email buzbogdan93@gmail.comPurpose: The constitutive elements of the metabolic syndrome (MetS) are linked with both non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease. Controlled attenuation parameter (CAP), and vibration controlled transient elastography (VCTE), are able to detect and quantify NAFLD, while conventional and two-dimensional speckle tracking echocardiography (2D-STE) is capable to identify subclinical changes in cardiac function. We wanted to evaluate whether there is any correspondence between left ventricular (LV) diastolic dysfunction and different degrees of liver steatosis and fibrosis in MetS subjects with NAFLD.Patients and Methods: A total of 150 adult subjects having MetS and a normal left ventricular (LV) systolic function were recorded in the study, while 150 age- and sex- matched adults without MetS were enrolled as controls. NAFLD was established by VCTE and CAP. The left heart systolic and diastolic function was evaluated by conventional and 2D-ST echocardiography. Left atrial (LA) stiffness was calculated as the ratio between the E/A ratio and the LA reservoir-strain.Results: In univariate regression analysis, the variables associated with LV diastolic dysfunction in MetS patients were: liver steatosis grade ≥ 2, liver fibrosis grade ≥ 2, the longitudinal LA peak strain during the reservoir phase, the LA strain rate during ventricular contraction and the LA stiffness. In multivariate logistic regression, two variables were selected as independent predictors of LV diastolic dysfunction, namely the liver stiffness (P=0.0003) and the LA stiffness (P< 0.0001). LA stiffness predicted subclinical LV diastolic dysfunction in MetS patients with a sensitivity of 45% and a specificity of 96% when using a cut-off value > 0.38, and was significantly correlated with liver steatosis stage ≥ 2 and liver fibrosis stage ≥ 2.Conclusion: The present study confirms the association between liver stiffness, LA stiffness and LV diastolic dysfunction in MetS patients. Our study suggests that liver elastography and 2D-STE should become habitual assessments in MetS patients.Keywords: metabolic syndrome, strain and strain‑rate imaging, left atrial stiffness, left ventricular diastolic dysfunction, liver elastography, liver steatosis and fibrosis

Objective:Cardiovascular disease remains a leading cause of mortality worldwide. Ceramide scores have been associated with adverse outcomes in patients with established coronary artery disease. The prognostic value of ceramide score has not been assessed in the general population. We tested the hypothesis that ceramide scores are associated with major adverse cardiac events (MACE) in a community-based cohort with average coronary artery disease burden at enrollment.Approach and results:In a prospective community-based cohort, we performed passive follow-up using a record linkage system to ascertain the composite outcome of MACE, defined as acute myocardial infarction, coronary revascularization (bypass grafting or percutaneous intervention), stroke, or death. Ceramides were analyzed as log-transformed continuous variables, ratios or scores, and quartiles with adjustment for confounders. We analyzed 1131 subjects, 52% females, mean age±(SD) 64±9 years. After a median follow-up of 13.3 years (Q1, 12.7; Q3, 14.4), 486 patients experienced a MACE: myocardial infarction (80), coronary artery bypass surgery (34), percutaneous coronary intervention (62), stroke (94), and all-cause death (362). Ceramide ratios were significantly associated with MACE independently of LDL-c (low-density lipoprotein cholesterol) and conventional coronary artery disease risk factors. Those in the highest quartile of ceramide score had nearly 1.5-fold risk of MACE, hazard ratio, 1.47 (95% CI, 1.12–1.92). There was a dose-response association across quartiles of ceramide ratios and MACE.Conclusions:Elevated ceramide score is a robust predictor of cardiovascular disease and MACE in the community. The risk conferred by the ceramide score has a dose-response behavior and is independent of conventional risk factors.

Background The coronavirus disease 2019 pandemic restricted movement of individuals and altered provision of health care, abruptly transforming health care-use behaviors. It serves as a natural experiment to explore changes in presentations for surgical diseases including acute appendicitis. The objective was to determine if the pandemic was associated with changes in incidence of acute appendicitis compared to a historical control and to determine if there were associated changes in disease severity. Methods The study is a retrospective, multicenter cohort study of adults (N = 956) presenting with appendicitis in nonpandemic versus pandemic time periods (December 1, 2019–March 10, 2020 versus March 11, 2020–May 16, 2020). Corresponding time periods in 2018 and 2019 composed the historical control. Primary outcome was mean biweekly counts of all appendicitis presentations, then stratified by complicated (n = 209) and uncomplicated (n = 747) disease. Trends in presentations were compared using difference-in-differences methodology. Changes in odds of presenting with complicated disease were assessed via clustered multivariable logistic regression. Results There was a 29% decrease in mean biweekly appendicitis presentations from 5.4 to 3.8 (rate ratio = 0.71 [0.51, 0.98]) after the pandemic declaration, with a significant difference in differences compared with historical control (P = .003). Stratified by severity, the decrease was significant for uncomplicated appendicitis (rate ratio = 0.65 [95% confidence interval 0.47–0.91]) when compared with historical control (P = .03) but not for complicated appendicitis (rate ratio = 0.89 [95% confidence interval 0.52–1.52]); (P = .49). The odds of presenting with complicated disease did not change (adjusted odds ratio 1.36 [95% confidence interval 0.83–2.25]). Conclusion The pandemic was associated with decreased incidence of uncomplicated appendicitis without an accompanying increase in complicated disease. Changes in individual health care–use behaviors may underlie these differences, suggesting that some cases of uncomplicated appendicitis may resolve without progression to complicated disease.

Esophageal tumors are uncommon in pediatric population and most of them are benign. Esophageal hamartomas have been reported extremely rare in children. These can present as intramural tumors of the esophageal wall or as polyps. Dysphagia is the main symptom described in their case, but other specific symptoms are also reported. Such symptoms encountered in clinical practice are represented by obstructive apnea episodes and bradycardia, poor weight gain, epigastric or retrosternal pain, hematemesis or melena, dysphonia or tracheal sounds. Diagnosis can be delayed due to the insidious onset and non-specific symptoms, therefore patient’s compliance to follow-up and broad, careful evaluation are mandatory. Preoperative imagistic assessment is extremely important for a precise definition of the tumor’s anatomical relations, especially when facing large tumors located in the posterior mediastinum. Herein we report a case of a large chondromatous polypoid hamartoma of the esophagus in a 9 years old boy, emphasizing over the diagnosis and surgical challenges we have met, along with comments on illustrative similar cases reported in the literature.

The authors report a unique recurrent septated cystic hygroma (CH), on two successive pregnancies, at five years interval. The chromosome analysis of the first fetus showed an increase in length of heterochromatin on the long arm of chromosome 1 - 1qh+, a chromosomal polymorphism inherited from mother, 46XX,1qh+,14ps+,21ps+. The karyotype of the second CH, with more severe ultrasound (US) imaging, showed a 69XXX triploidy. The patient took no risk and underwent each time a termination of pregnancy (TOP). The first karyotype is generally considered "normal", although there are few reports linking 1qh+ with low fertility, but this was not the case, the patient having, from a previous marriage, a healthy boy and two TOPs. So, this "particular", but "healthy" karyotype was not a cause for the first CH. The second karyotype highlights a possible causality between the 69XXX triploidy, usually associated with partial hydatidiform mole, and a more severe septated CH in the last fetus. Neither the CHs' appearance nor their recurrence seemed to be family linked, as the two CHs had distinct genetic profiles. We recommend that, once CH is diagnosed, a careful US examination is compulsory for the determination of subcutaneous edema, ascites, pleural and pericardial effusions and cardiac or renal abnormalities; an early genetic work-up is mandatory, by chorionic villus sampling or amniocentesis. However, a "healthy" karyotype does not exclude a severe form, as in our first case of CH. Due to the very poor outcome of fetuses with CH, the patient must be thoroughly informed about the short and the long-term fetal prognosis.

Background: Visual estimation (VE) of coronary stenoses is the first step during invasive coronary angiography. The aim of this study was to evaluate the accuracy of VE together with invasive functional assessment (IFA) in defining the functional significance (FS) of coronary stenoses based on the opinion of multiple operators. Methods: Fourteen independent operators visually evaluated 133 coronary lesions which had a previous FFR measurement, indicating the degree of stenosis (DS), FS and IFA intention. We determined the accuracy of FS prediction using several scenarios combining individual and group decision, considering IFA as deemed necessary by the operator or only in intermediate lesions. Results: The accuracy of VE in predicting FS was largely variable between operators (average 66.1%); it improved significantly when IFA was used either as per operator’s opinion (86.3%; p < 0.0001) or only in intermediate DS (82.9; p < 0.0001). There was no significant difference between using IFA per observer’s opinion or only in intermediate DS lesions (p = 0.166). The poorest accuracy of VE for FS was obtained in intermediate DS lesions (59.1%). Conclusions: There are significant inter-observer differences in reporting the degree of DS, while the accuracy of VE prediction of FS is also largely dependent on the operator, and the worst performance is obtained in the evaluation of intermediate DS.

Aim: This paper aims to emphasize the importance of nuclear imaging for cancer patients evolution and personalized treatment. Material and method: A retrospective study comprising 5,670 patients, who performed bone scans, between 2003-2015, at the “Sf. Spiridon” County Clinical Emergency Hospital Iași Nuclear Medicine Laboratory. Studied parameters were demographic data, referral diagnosis, staging, tumor markers, bone metastases and patient follow-up. Results: Of all, 3,960 were oncological patients. They performed in evolution 3,846 bone scans, between two (21.01%) and 11 (0.05%) explorations. Patients’ age varied between 2 and 97 years (with two peaks, at 55 and 65). Gender distribution showed female (61.73%) over male (38.27%) predominance, especially in multiple scans (73.32%). For half of the patients the bone scan showed evolution (worsening), meaning the treatment was only partially effective and required modifications. Ethically, for these patients bone scan was irreplaceable. Its absence would have meant undergoing a partially/inefficient treatment, a reserved prognosis and a shorter survival period. The benefits outweigh the risks in terms of radiation exposure. Conclusions: Ethics in oncological nuclear medicine is complex, following the balance between risk and benefit, in the interest of a personalized management. As a result, ethically it is equivalent to maximizing the benefits of this minimally invasive functional investigation, scintigraphy, which is essential for treatment modulation, in order to improve the disease prognosis and increase the patients’ survival rate, for precision medicine in cancer.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.METHODS: We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.RESULTS: In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (PCONCLUSIONS: This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).

"Background: Cancer patients represent one of the most challenging group to care for during the Covid-19 pandemic. In this study, we aim to present the experience of our Oncology Department during the ongoing Covid-19 pandemic. Methods: The activity of our Oncology Department was retrospectively analyzed from 16th March to 15th December 2020 to investigate how the organizational changes related to Covid-19 pandemic influenced the oncological activity in comparison with the same period in 2019. We also assessed the cases of SARS-CoV-2 infections observed among patients and oncology health professionals from our department. Results: We report an important shift of the oncology activity at our department. The number of inpatients decreased by 50% while the number of treatments administered in the outpatient treatment unit decreased by 13%. We performed 4775 swabbing tests to detect SARS-CoV-2 infection in 1147 symptomatic and asymptomatic patients before receiving treatment or undergoing imaging examinations. SARS-CoV-2 infection was detected in 68 (5.9%) patients. Most of the patients were asymptomatic at the moment of the diagnosis (60%). Two patients were admitted to the intensive therapy unit; 12 had severe pneumonia and were hospitalized. All the other patients had a mild form of Covid-19 and were referred to home-based management, according to the local practice and clinical indications. Four patients died of Covid-19 related complications and 32 patients have already resumed their oncological treatment. Conclusion: Our experience demonstrates that timely adoption of protective measures and coordinated efforts of all medical staff can lead to effective protection of Journal of Medical and Radiation Oncology Journal homepage: www.jmedradonc.org Original research 36 patients with cancer and healthcare professionals, while minimally disrupting adequate cancer care. Methods: The activity of our Oncology Department was retrospectively analyzed from 16th March to 15th December 2020 to investigate how the organizational changes related to Covid-19 pandemic influenced the oncological activity in comparison with the same period in 2019. We also assessed the cases of SARS-CoV-2 infections observed among patients and oncology health professionals from our department. Results: We report an important shift of the oncology activity at our department. The number of inpatients decreased by 50% while the number of treatments administered in the outpatient treatment unit decreased by 13%. We performed 4775 swabbing tests to detect SARS-CoV-2 infection in 1147 symptomatic and asymptomatic patients before receiving treatment or undergoing imaging examinations. SARS-CoV-2 infection was detected in 68 (5.9%) patients. Most of the patients were asymptomatic at the moment of the diagnosis (60%). Two patients were admitted to the intensive therapy unit; 12 had severe pneumonia and were hospitalized. All the other patients had a mild form of Covid-19 and were referred to home-based management, according to the local practice and clinical indications. Four patients died of Covid-19 related complications and 32 patients have already resumed their oncological treatment. Conclusion: Our experience demonstrates that timely adoption of protective measures and coordinated efforts of all medical staff can lead to effective protection of Journal of Medical and Radiation Oncology Journal homepage: www.jmedradonc.org Original research 36 patients with cancer and healthcare professionals, while minimally disrupting adequate cancer care."

BACKGROUND: Lactate dehydrogenase (LDH) is a critical metabolic enzyme. LDH A (LDHA) overexpression is a hallmark of aggressive malignancies and has been linked to tumour initiation, reprogramming and progression in multiple tumour types. However, successful LDHA inhibition strategies have not materialised in the translational and clinical space. We sought to develop a rational strategy for LDHA suppression in the context of solid tumour treatment. METHODS: We utilised a doxycycline-inducible short hairpin RNA (shRNA) system to generate LDHA suppression. Lactate and LDH activity levels were measured biochemically and kinetically using hyperpolarised (13)C-pyruvate nuclear magnetic resonance spectroscopy. We evaluated effects of LDHA suppression on cellular proliferation and clonogenic survival, as well as on tumour growth, in orthotopic models of anaplastic thyroid carcinoma (ATC) and head and neck squamous cell carcinoma (HNSCC), alone or in combination with radiation. RESULTS: shRNA suppression of LDHA generated a time-dependent decrease in LDH activity with transient shifts in intracellular lactate levels, a decrease in carbon flux from pyruvate into lactate and compensatory shifts in metabolic flux in glycolysis and the Krebs cycle. LDHA suppression decreased cellular proliferation and temporarily stunted tumour growth in ATC and HNSCC xenografts but did not by itself result in tumour cure, owing to the maintenance of residual viable cells. Only when chronic LDHA suppression was combined with radiation was a functional cure achieved. CONCLUSIONS: Successful targeting of LDHA requires exquisite dose and temporal control without significant concomitant off-target toxicity. Combinatorial strategies with conventional radiation are feasible as long as the suppression is targeted, prolonged and non-toxic.