Transoral Incisionless Fundoplication Leads to Esophageal Mucosa Healing in Responder Patients Followed up to 2 Years, as Documented by Esophageal Mean Nocturnal Baseline Impedance.

Background/Aims: Decrease of esophageal mean nocturnal baseline impedance reflects loss of mucosal integrity. It can predict response to anti-reflux therapy. Mean nocturnal baseline impedance after transoral incisionless fundoplication for gastroesophageal reflux disease has never been assessed. The aim of the study is to investigate mean nocturnal baseline impedance and conventional pathophysiological parameters following transoral incisionless fundoplication. Methods: Patients prospectively treated by transoral incisionless fundoplication in a single center were retrospectively reviewed regarding 1- and 2-year 24-hour pH-metry and multichannel intraluminal impedance with calculation of mean nocturnal baseline impedance, gastroesophageal reflux disease-health related quality of life and reflux symptom index scores. Results: Thirty-eight and 17/38 patients with 1- and 2-year 24-hour pH-multichannel intraluminal impedance assessment and mean nocturnal baseline impedance's calculation after transoral incisionless fundoplication, respectively, were identified. Mean nocturnal baseline impedance significantly increased up to 2-year follow-up (P = 0.033), along with significant decrease in % of acid exposure time (P = 0.003), gastroesophageal reflux disease-health related quality of life score (P < 0.001), and reflux symptom index (P = 0.008), compared with baseline. The longest orthostatic reflux decreased too, approaching statistical significance (P = 0.054). These significant changes occurred in patients experiencing ≥ 50% reduction of symptom questionnaires' scores ("responders"). Conversely, mean nocturnal baseline impedance worsened and no significant changes of 24-hour pH-multichannel intraluminal impedance metrics were observed in "non-responder" patients (symptom questionnaires' scores decrease < 50%).ConclusionIn patients who responded a significant improvement of mean nocturnal baseline impedance and % acid exposure time was observed up to 2-year follow-up, suggesting that transoral incisionless fundoplication achieves an effective esophageal mucosa healing besides symptom improvement.

Role of the Binding Energy on Nondipole Effects in Single-Photon Ionization.

We experimentally study the influence of the binding energy on nondipole effects in K-shell single-photon ionization of atoms at high photon energies. We find that for each ionization event, as expected by momentum conservation, the photon momentum is transferred almost fully to the recoiling ion. The momentum distribution of the electrons becomes asymmetrically deformed along the photon propagation direction with a mean value of 8/(5c)(E_{γ}-I_{P}) confirming an almost 100 year old prediction by Sommerfeld and Schur [Ann. Phys. (N.Y.) 396, 409 (1930)10.1002/andp.19303960402]. The emission direction of the photoions results from competition between the forward-directed photon momentum and the backward-directed recoil imparted by the photoelectron. Which of the two counteracting effects prevails depends on the binding energy of the emitted electron. As an example, we show that at 20 keV photon energy, Ne^{+} and Ar^{+} photoions are pushed backward towards the radiation source, while Kr^{+} photoions are emitted forward along the light propagation direction.

Tracing Photoinduced Hydrogen Migration in Alcohol Dications from Time-Resolved Molecular-Frame Photoelectron Angular Distributions.

The recent implementation of attosecond and few-femtosecond X-ray pump/X-ray probe schemes in large-scale free-electron laser facilities has opened the way to visualize fast nuclear dynamics in molecules with unprecedented temporal and spatial resolution. Here, we present the results of theoretical calculations showing how polarization-averaged molecular-frame photoelectron angular distributions (PA-MFPADs) can be used to visualize the dynamics of hydrogen migration in methanol, ethanol, propanol, and isopropyl alcohol dications generated by X-ray irradiation of the corresponding neutral species. We show that changes in the PA-MFPADs with the pump-probe delay as a result of intramolecular photoelectron diffraction carry information on the dynamics of hydrogen migration in real space. Although visualization of this dynamics is more straightforward in the smaller systems, methanol and ethanol, one can still recognize the signature of that motion in propanol and isopropyl alcohol and assign a tentative path to it. A possible pathway for a corresponding experiment requires an angularly resolved detection of photoelectrons in coincidence with molecular fragment ions used to define a molecular frame of reference. Such studies have become, in principle, possible since the first XFELs with sufficiently high repetition rates have emerged. To further support our findings, we provide experimental evidence of H migration in ethanol-OD from ion-ion coincidence measurements performed with synchrotron radiation.

Effect of General Anesthesia Versus Conscious Sedation/Local Anesthesia on the Outcome of Patients with Minor Stroke and Isolated M2 Occlusion Undergoing Immediate Thrombectomy: A Retrospective Multicenter Matched Analysis.

BACKGROUND: This study investigates the impact of general anesthesia (GA) versus conscious sedation/local anesthesia (CS/LA) on the outcome of patients with minor stroke and isolated M2 occlusion undergoing immediate mechanical thrombectomy (iMT). METHODS: The databases of 16 comprehensive stroke centers were retrospectively screened for consecutive patients with isolated M2 occlusion and a baseline National Institutes of Health Stroke Scale score ≤5 who received iMT. Propensity score matching was used to estimate the effect of GA versus CS/LA on clinical outcomes and procedure-related adverse events. The primary outcome measure was a 90-day modified Rankin Scale (mRS) score of 0-1. Secondary outcome measures were a 90-day mRS score of 0-2 and all-cause mortality, successful reperfusion, procedural-related symptomatic subarachnoid hemorrhage, intraprocedural dissections, and new territory embolism. RESULTS: Of the 172 patients who were selected, 55 received GA and 117 CS/LA. After propensity score matching, 47 pairs of patients were available for analysis. We found no significant differences in clinical outcome, rates of efficient reperfusion, and procedural-related complications between patients receiving GA or LA/CS (mRS score 0-1, P = 0.815; mRS score 0-2, P = 0.401; all-cause mortality, P = 0.408; modified Treatment in Cerebral Infarction score 2b-3, P = 0.374; symptomatic subarachnoid hemorrhage, P = 0.082; intraprocedural dissection, P = 0.408; new territory embolism, P = 0.462). CONCLUSIONS: In patients with minor stroke and isolated M2 occlusion undergoing iMT, the type of anesthesia does not affect clinical outcome or the rate of procedural-related complications. Our results agree with recent data showing no benefit of one specific anesthesiologic procedure over the other and confirm their generalizability also to patients with minor baseline symptoms.

Student insights towards animal welfare science and law. Survey results from Sassari University, Italy.

In this paper, we describe the results of an online survey consisting of 23 questions created to evaluate the knowledge and interest on animal welfare by students attending 15 different scientific, medical, and biomedical courses at University of Sassari, Italy. The survey collected students' demographic data, level of knowledge both on animal welfare and 3Rs, as well as their opinions on animal experimentation. The majority of the cohort was female and over 24 years of age. About a third of the students responded that their graduate programme included subjects that taught science, ethics, and animal welfare legislation. Just 21.2% of respondents had heard about the concept of 3Rs. About a quarter of the students believed that animal models can be replaced by in vitro and in silico methods while half believed that both are needed. However, 70% of the participants did not know the existence of an Ethics and Animal Welfare Committee. The result showed the importance of an Animal Welfare Course for the professional future of a larger number of students and underlined the key role of veterinary medicine in promoting ethics and animal experimentation.

Gastric peroral endoscopic myotomy (G-POEM) for refractory gastroparesis.

Gastroparesis is a chronic functional disorder characterized by severe symptoms and objective documentation of delayed gastric emptying, in the absence of any mechanical obstruction. The pathogenesis of gastroparesis comprises abnormalities of gastric motility (corpus and fundus dysmotility and antral hypomotility), pyloric resistance to gastric outflow (pyloric lower compliance or hypertone), and lack of antroduodenal motor coordination. Several conditions have been correlated to gastroparesis: diabetes, post-surgical sequelae, medications, neurological/muscular disorders and collagen vascular diseases. Diabetes is the most frequent condition associated with gastroparesis, which has been reported in up to 50% of patients suffering from long-lasting disease. The therapy of gastroparesis is primarily medical, with prokinetic or antiemetic drugs, but response may be limited, and side effects can arise; if medical therapy fails, pyloromyotomy remains the main option, either surgical or endoscopic. Gastric peroral endoscopic myotomy (G-POEM) may be considered nowadays an effective potential therapeutic intervention in alternative to surgery, relatively easy to perform in experienced hands, with a technical success of 100%, a favorable safety profile, and positive outcomes in the short-term as documented in three meta-analyses. However, to date, the definition of clinical success in gastroparesis is still not standardized, the correlation between symptom improvement and the objective documentation of an improvement in gastric emptying remains in some cases uncertain, reliable data to help in predicting which categories of gastroparesis and which symptoms could benefit most from the intervention, and long-term outcomes are still lacking.

Investigating charge-up and fragmentation dynamics of oxygen molecules after interaction with strong X-ray free-electron laser pulses.

During the last decade, X-ray free-electron lasers (XFELs) have enabled the study of light-matter interaction under extreme conditions. Atoms which are subject to XFEL radiation are charged by a complex interplay of (several subsequent) photoionization events and electronic decay processes within a few femtoseconds. The interaction with molecules is even more intriguing, since intricate nuclear dynamics occur as the molecules start to dissociate during the charge-up process. Here, we demonstrate that by analyzing photoelectron angular emission distributions and kinetic energy release of charge states of ionic molecular fragments, we can obtain a detailed understanding of the charge-up and fragmentation dynamics. Our novel approach allows for gathering such information without the need of complex ab initio modeling. As an example, we provide a detailed view on the processes happening on a femtosecond time scale in oxygen molecules exposed to intense XFEL pulses.

Observation of Nondipole-Induced Asymmetry in the Angular Emission Distribution of Photoelectrons from Fixed-in-Space CO Molecules.

We investigate experimentally and theoretically the C and O 1s photoionization of fixed-in-space CO molecules at a photon energy of 905 eV. We find a significant dependence of the photoelectron angular distributions on the direction of propagation of the ionizing radiation. It results from an interplay of nondipole effects, on one hand, and molecular effects, on the other. The nondipole effects lead to an increase of the emission probability in the forward direction along the light propagation, and the photoelectron wave being scattered by the molecular potential gives rise to a strong peak in the direction of the atom neighboring the emitter site. These effects can either conspire or extenuate each other, depending on the photoelectron emission direction and molecular orientation in space.

A2A Adenosine Receptor Antagonists in Neurodegenerative Diseases.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia worldwide, with approximately 6 million cases reported in America in 2020. The clinical signs of AD include cognitive dysfunction, apathy, anxiety and neuropsychiatric signs, and pathogenetic mechanisms that involve amyloid peptide-ß extracellular accumulation and tau hyperphosphorylation. Unfortunately, current drugs to treat AD can provide only symptomatic relief but are not disease-modifying molecules able to revert AD progression. The endogenous modulator adenosine, through A2A receptor activation, plays a role in synaptic loss and neuroinflammation, which are crucial for cognitive impairment and memory damage. OBJECTIVE: In this review, recent advances covering A2A adenosine receptor antagonists will be extensively reviewed, providing a basis for the rational design of future A2A inhibitors. METHODS: Herein, the literature on A2A adenosine receptors and their role in synaptic plasticity and neuroinflammation, as well as the effects of A2A antagonism in animal models of AD and in humans, are reviewed. Furthermore, current chemical and structure-based strategies are presented. RESULTS: Caffeine, the most widely consumed natural product stimulant and an A2A antagonist, improves human memory. Similarly, synthetic A2A receptor antagonists, as described in this review, may provide a means to fight AD. CONCLUSION: This review highlights the clinical potential of A2A adenosine receptor antagonists as a novel approach to treat patients with AD.

Targeting CXCR1/2 in the first multicenter, double-blinded, randomized trial in autologous islet transplant recipients.

Several cytokines and chemokines are elevated after islet infusion in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT), including CXCL8 (also known as interleukin-8), leading to islet loss. We investigated whether use of reparixin for blockade of the CXCL8 pathway would improve islet engraftment and insulin independence after TPIAT. Adults without diabetes scheduled for TPIAT at nine academic centers were randomized to a continuous infusion of reparixin or placebo (double-blinded) for 7 days in the peri-transplant period. Efficacy measures included insulin independence (primary), insulin dose, hemoglobin A1c (HbA1c ), and mixed meal tolerance testing. The intent-to-treat population included 102 participants (age 39.5 ± 12.2 years, 69% female), n = 50 reparixin-treated, n = 52 placebo-treated. The proportion insulin-independent at Day 365 was similar in reparixin and placebo: 20% vs. 21% (p = .542). Twenty-seven of 42 (64.3%) in the reparixin group and 28/45 (62.2%) in the placebo group maintained HbA1c ≤6.5% (p = .842, Day 365). Area under the curve C-peptide from mixed meal testing was similar between groups, as were adverse events. In conclusion, reparixin infusion did not improve diabetes outcomes. CXCL8 inhibition alone may be insufficient to prevent islet damage from innate inflammation in islet autotransplantation. This first multicenter clinical trial in TPIAT highlights the potential for future multicenter collaborations.

Risk factors and clinical characteristics of early-onset colorectal cancer vs. late-onset colorectal cancer: a case-case study.

BACKGROUND AND OBJECTIVES: Early-onset colorectal cancer (eoCRC), defined as colorectal cancer (CRC) before the age of 50 is increasing in incidence. We evaluated exogenous and endogenous risk factors, and clinical features of eoCRC, compared to late-onset CRC (loCRC). METHODS: In this retrospective case-case study, patients were prospectively enrolled from 2015 to 2018. We collected clinical features (age, sex, time from symptom onset to diagnosis, symptoms, family history, smoking and alcohol habits, diabetes, BMI, and genetic analysis) and tumor characteristics. Independent risk factors for eoCRC and odds ratios (ORs) were identified. RESULTS: Fifty-four eoCRCs and 494 loCRCs were enrolled. Patients with eoCRC experienced longer delay time from symptom onset to diagnosis: 40.7% were diagnosed within 6 months from symptoms onset, compared to 85.6% of patients with loCRC (P < 0.0001). They differed for sex, presence of symptoms, family history, smoking habit, alcohol intake, and BMI. Rectal localization was more closely associated with eoCRC (64.8%) than loCRC (34.5%, P < 0.0001). Family history of CRC was associated with eoCRC (OR = 8.8). When family history occurred with hereditary cancer syndromes, the OR for eoCRC increased to 21. CONCLUSION: In young adults with alarming symptoms, CRC must be suspected to avoid delay time from symptom onset to diagnosis and genetic risk assessment has to be evaluated. Smoking habits, alcohol intake, and BMI are not associated with eoCRC.

Protein-altering germline mutations implicate novel genes related to lung cancer development.

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

Cross-Sectional Analysis of University Students' Health Using a Digitised Health Survey.

University student years are a particularly influential period, during which time students may adopt negative behaviours that set the precedent for health outcomes in later years. This study utilised a newly digitised health survey implemented during health screening at a university in Singapore to capture student health data. The aim of this study was to analyze the health status of this Asian university student population. A total of 535 students were included in the cohort, and a cross-sectional analysis of student health was completed. Areas of concern were highlighted in student's body weight, visual acuity, and binge drinking. A large proportion of students were underweight (body mass index (BMI) < 18.5)-18.9% of females and 10.6% of males-and 7% of males were obese (BMI > 30). Although the overall prevalence of alcohol use was low in this study population, 9% of females and 8% of males who consumed alcohol had hazardous drinking habits. Around 16% of these students (male and female combined) typically drank 3-4 alcoholic drinks each occasion. The prevalence of mental health conditions reported was very low (<1%). This study evaluated the results from a digitised health survey implemented into student health screening to capture a comprehensive health history. The results reveal potential student health concerns and offer the opportunity to provide more targeted student health campaigns to address these.

Maternal peri-conceptional undernourishment perturbs offspring sperm methylome.

The genotype of an organism is stable throughout its life; however, its epigenome is dynamic and can be altered in response to environmental factors, such as diet. Inheritance of acquired epigenetic modifications by the next generation occurs through the germline, although the precise mechanisms remain to be elucidated. Here, we used a sheep model to evaluate if modification of the maternal diet (CTR; control, UND: undernutrition; FA: undernutrition and folic acid supplementation) during the peri-conceptional period affects the genome-wide methylation status of the gametes of male offspring. Sperm DNA methylation, measured by Reduced Representation Bisulfite Sequencing (RRBS), identified Differentially Methylated Regions (DMR) in offspring that experienced in utero undernutrition, both in UND (244) and FA (240), compared with CTR. Gene ontology (GO) analysis identified DMRs in categories related to sperm function, therefore we investigated whether the fertilizing capacity of the semen from the three groups differed in an in vitro fertilization assay. Spermatozoa from the undernourished groups showed lower motility and sperm chromatin structure abnormalities, represented by a higher percentage of DNA fragmentation and an increased number of immature cells, compared with CTR. While good quality blastocysts were obtained from all three groups, the proportion of embryos reaching the blastocyst stage was reduced in the UND vs CTR, an effect partially rescued by the FA treatment. The data reported here show that nutritional stress during early pregnancy leads to epigenetic modifications in the semen of the resulting offspring, the effects of which in next generation remain to be elucidated.

MSH6 gene pathogenic variant identified in familial pancreatic cancer in the absence of colon cancer.

OBJECTIVES: Lynch syndrome is characterized by pathogenetic variants in the mismatch repair genes and autosomal dominant inheritance with incomplete penetrance. Lynch syndrome is characterized by colorectal and, with lesser and variable extent, extracolonic cancers. We describe a family with MSH6-dependent Lynch syndrome and familial pancreatic cancer and other tumours (gastric and endometrial), in the absence of colorectal neoplasia. METHODS: Patients were analysed by sequencing, Next Generation or Sanger, to identify germinal pathogenic variants in hereditary cancer genes. RESULTS: We identified the MSH6 gene pathogenic variant c.2194C>T, p.(Arg732Ter) in a family with hereditary pancreatic cancer without diagnosed cases of colorectal adenocarcinoma. Seven family members were affected by the MSH6 pathogenic variant. Three had pancreatic adenocarcinoma at 65, 57 and 44 years; one had endometrial cancer at 36 years. None of the remaining three subjects (75, 45 and 17 years old) had developed any cancer yet. CONCLUSIONS: Lynch syndrome should be suspected in families with familial pancreatic cancer, even in the absence of colon cancers. Specifically, our observation supports the association between the MSH6 c.2194C>T pathogenic variant and extracolonic tumours and it suggests that MSH6 pathogenic variants are associated with familial pancreatic cancer more frequently than assumed.

The epidemic spreading of basal cell carcinoma: incidence trend, demographic features, characteristics and risk factors in a retrospective study of 8557 lesions in Bologna. A 25-year analysis in a Dermatology referral center.

BACKGROUND: The aim of this study was to retrospectively analyze all the cases of BCC histologically diagnosed in the Cutaneous Tumor Center of Dermatology of Bologna University, in a period between 1990 and 2014. METHODS: All the consecutive histopathologically diagnosed BCCs at the Dermatology of the Bologna University from 1990 to 2014 were retrospectively reviewed. We evaluated the absolute number of basal cell carcinoma (BCCs), the demographic features of patients and the characteristics of BCCs with statistically significant correlations. RESULTS: During the investigated 25 years, 8557 BCCs were collected in 7297 patients. We observed that the incidence of this cancer, after stabilizing around a plateau of 400 cases/year in 2005, progressively increased onwards reaching a maximum of cases (821) in 2014 (+105.25%), with an 8.32% mean increase per year in those last 9 years. Moreover, we found a significant correlation (P<0.01%) between gender and the onset of BCC, between the anatomic location and the occurrence of the tumor, between the onset of recurrent or new BCCs and sun exposure. CONCLUSIONS: The present study collects the largest series in the Italian literature focused on demographic features and characteristics of BCC, highlights its higher increasing incidence in Bologna and the need to improve preventive strategies to stem the epidemic diagnosis of BCC.

Safety profile of chronic leg ulcer biopsy: a monocentric retrospective series.

BACKGROUND: Skin biopsy is an important tool for various skin conditions. However, in the case of leg ulcers, some Authors still consider it highly risky and mandatory only in selected cases. METHODS: The aim of this study was to evaluate the rate of adverse events after leg ulcers biopsy in 866 consecutive patients referring to our Wound Care Unit in Bologna from January 2008 to December 2016. Two biopsies were performed (from the border and the centre) by the same dermatologist following a standardized structured protocol. RESULTS: A total of 329 males and 537 females (ratio of 1:1.6), mean age 72 years (range 50-97 years) underwent a skin biopsy. Up to 70% of all analyses revealed a vascular ulcer (614 patients; 70.9%) while other conditions (252 patients; 29.1%) included inflammatory dermatitis, vasculitis, ulcerated neoplasms, infective lesions, post-traumatic and pressure sores, erosive pustular, dermatitis and pyoderma gangrenosum. Adverse events occurred in 322 patients (38.43% of all biopsies), mostly a dull pain (320 patients, 37%) that resolved within some hours. Five patients with vasculitis (0.6%) experienced a worsening of the lesion and another five patients (0.6%) developed erysipelas. Only two patients, on double antithrombotic therapy (0.23%), had intraoperative bleeding. No allergic reactions were detected. CONCLUSIONS: According to our experience, skin biopsy should be mandatory for non-healing wounds. It is safe and involves only a low rate of adverse events.