Third whole-brain radiation therapy for multiple brain metastases. Should it be considered in selected patients?

Whole brain reirradiation for the treatment of multiple brain metastases has shown promising results. However, concerns remain over the possible neurotoxic effects of the cumulative dose as well as the questionable radiosensitivity of recurrent metastases. A second reirradiation of the whole brain is ordinarily performed in our department for palliative purposes in patients presenting with multiple metastatic brain progression. For this study, an investigational third whole brain reirradiation has been administered to highly selected patients to obtain disease control and delay progression. Clinical outcomes and neurological toxicity were also evaluated.

Review article: Functional dyspepsia-a gastric disorder, a duodenal disorder or a combination of both?

BACKGROUND: Functional dyspepsia (FD) is one of the most frequent conditions in gastroenterological outpatient health care. Most recent research in FD has shifted its focus to duodenal pathophysiological mechanisms, although current treatments still focus mainly the stomach. AIM: The aim of the study was to provide a comprehensive overview of the pathophysiology of FD focusing on a paradigm shift from gastric towards duodenal mechanisms. METHODS: We conducted a literature search in PubMed for studies describing mechanisms that could possibly cause FD. RESULTS: The pathophysiology of FD remains incompletely understood. Recent studies show that duodenal factors such as acid, bile salt exposure and eosinophil and mast cell activation correlate with symptom pattern and burden and can be associated with gastric sensorimotor dysfunction. The evolving data identify the duodenum an interesting target for new therapeutic approaches. Furthermore, the current first-line treatment, that is proton pump inhibitors, reduces duodenal low-grade inflammation and FD symptoms. CONCLUSION: Future research for the treatment of FD should focus on the inhibition of duodenal mast cell activation, eosinophilia and loss of mucosal integrity.

PCSK9 is associated with mortality in patients with septic shock: data from the ALBIOS study.

BACKGROUND: Pro-protein convertase subtilisin/kexin 9 (PCSK9) is a proenzyme primarily known to regulate low-density lipoprotein receptor re-uptake on hepatocytes. Whether PCSK9 can concurrently trigger inflammation or not remains unclear. Here, we investigated the potential association between circulating levels of PCSK9 and mortality in patients with severe sepsis or septic shock. METHODS: Plasma PCSK9 levels at days 1, 2 and 7 were measured in 958 patients with severe sepsis or septic shock previously enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial. Correlations between levels of PCSK9 and pentraxin 3 (PTX3), a biomarker of disease severity, were evaluated with ranked Spearman's coefficients. Cox proportional hazards models were used to assess the association of PCSK9 levels at day 1 with 28- and 90-day mortality. RESULTS: Median plasma PCSK9 levels were 278 [182-452] ng mL-1 on day 1. PCSK9 correlated positively with PTX3 at the three time-points, and patients with septic shock within the first quartile of PCSK9 showed higher levels of PTX3. Similar mortality rates were observed in patients with severe sepsis across PCSK9 quartiles. Patients with septic shock with lower PCSK9 levels on day 1 (within the first quartile) showed the highest 28- and 90-day mortality rate as compared to other quartiles. CONCLUSION: In our sub-analysis of the ALBIOS trial, we found that patients with septic shock presenting with lower plasma PCSK9 levels experienced higher mortality rate. Further studies are warranted to better evaluate the pathophysiological role of PCSK9 in sepsis.

Organ-specific isoform selection of fatty acid-binding proteins in tissue-resident lymphocytes.

Tissue-resident memory T (TRM) cells exist throughout the body, where they are poised to mediate local immune responses. Although studies have defined a common mechanism of residency independent of location, there is likely to be a level of specialization that adapts TRM cells to their given tissue of lodgment. It has been shown that TRM cells in the skin rely on the uptake of exogenous fatty acids for their survival and up-regulate fatty acid-binding protein 4 (FABP4) and FABP5 as part of their transcriptional program. However, FABPs exist as a larger family of isoforms, with different members selected in a tissue-specific fashion that is optimized for local fatty acid availability. Here, we show that although TRM cells in a range of tissue widely express FABPs, they are not restricted to FABP4 and FABP5. Instead, TRM cells show varying patterns of isoform usage that are determined by tissue-derived factors. These patterns are malleable because TRM cells relocated to different organs modify their FABP expression in line with their new location. As a consequence, these results argue for tissue-specific overlays to the TRM cell residency program, including FABP expression that is tailored to the particular tissue of TRM cell lodgment.

Resistin is associated with overall survival in non-small cell lung cancer patients during nivolumab treatment.

PURPOSE: Since the role of resistin was evaluated only in patients with non-small cell lung cancer (NSCLC) not treated with immunotherapy, we aimed to evaluate levels of resistin during immunotherapy (nivolumab) and its prognostic role with regard to OS. METHODS/PATIENTS: From a cohort of 78 patients with advanced NSCLC enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 43 patients have been considered for this sub-analysis because of the availability of samples. Before and during nivolumab administration, clinical information and blood samples were collected and resistin, matrix metalloproteinase (MMP)-8, MMP-9, and myeloperoxidase were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Median age was 71 with a prevalence of males and former smokers. Median resistin levels presented a peak at cycle 2 and then dropped down until the last cycle. Resistin correlated with all neutrophil degranulation products at cycle 1 (except for MMP-9) and at cycle 2 as well as with white blood cells and neutrophils. By a ROC curve analysis, a resistin value at cycle 2 of 19 ng/mL was tested as the best cut-off point for OS. Kaplan-Meier analysis demonstrated that patients above the resistin cut-off experienced a reduced OS (median OS 242.5 vs. 470 days, p = 0.0073), as confirmed by Cox proportional hazards regression analysis. CONCLUSIONS: Resistin levels > 19 ng/mL at the time of the second cycle of nivolumab treatment independently predict a reduced OS in patients with advanced NSCLC.

Current and emerging therapeutic options for the management of functional dyspepsia.

Introduction: Functional Dyspepsia (FD), defined as chronic symptoms originating from the gastroduodenal region in absence of readily identifiable organic disease, is one of the most common gastrointestinal disorders. FD is divided into two subgroups: Post-Prandial Distress Syndrome (PDS) or meal-related FD, characterized by postprandial fullness and early satiation, and Epigastric Pain Syndrome (EPS) or meal-unrelated FD, characterized by epigastric pain and burning.Areas covered: This review summarizes the existing and off-label therapeutic options for FD.Expert opinion: The identification of mechanisms, the Rome IV classification, the reduction of PDS/EPS overlap and pictograms for symptom identification allow a better diagnosis and a more targeted treatment choice. Acotiamide, a first-in-class prokinetic agent available only in Japan and India, is the only agent of proven efficacy for FD, but clinicians use acid-suppressive therapy, prokinetics, neuromodulators and herbal therapies for treating FD symptoms. New emerging targets are duodenal low-grade inflammation with eosinophils and duodenal or other modified luminal microbiota.

Analysis of Postprandial Symptom Patterns in Subgroups of Patients With Rome III or Rome IV Functional Dyspepsia.

BACKGROUND & AIMS: Among patients with functional dyspepsia (FD), there is overlap in symptoms between those in the Rome III subgroups of postprandial distress syndrome (PDS) and those with epigastric pain syndrome (EPS). The Rome IV consensus proposed to incorporate all patients with postprandial symptoms into the PDS group. We aimed to evaluate the assessment of meal-related dyspepsia symptoms in patients with FD according to the Rome III vs Rome IV subdivisions. METHODS: Consecutive patients with FD referred for a gastric emptying test (n = 96) were asked to fill out the Rome III gastroduodenal questionnaire, with questions on meal-related occurrence. Study participants underwent a gastric emptying breath test, during which the intensity of dyspeptic symptoms (fullness, bloating, belching, nausea, epigastric pain, and burning) was scored before and up to 4 hours after a meal. We analyzed the association between the Rome subdivision and symptom severity and pattern during the breath test. RESULTS: According to Rome III, 10% had EPS alone, 29% PDS alone, and 61% overlapping EPS and PDS. The frequency of the symptoms reported in the Rome questionnaire associated with the intensity of the symptoms during the breath test in the PDS group and in the groups with PDS and EPS overlap, but not in the group with EPS. We adapted the definition of the PDS subgroup to include patients with meal-related non-PDS symptoms (Rome IV); this reduced the proportion of patients with overlap of EPS and PDS symptoms from 61% to 18% and in this group the association of symptoms with the meal was reduced. CONCLUSIONS: In an analysis of patients with FD, a meal induced or exacerbated symptoms in most patients. The Rome IV criteria for PDS reduce the proportions categorized as having both PDS and EPS and identify a patient group whose symptoms are associated with the meals. University hospital of Leuven study no: S55426.

Holographic imaging of electromagnetic fields via electron-light quantum interference.

Holography relies on the interference between a known reference and a signal of interest to reconstruct both the amplitude and the phase of that signal. With electrons, the extension of holography to the ultrafast time domain remains a challenge, although it would yield the highest possible combined spatiotemporal resolution. Here, we show that holograms of local electromagnetic fields can be obtained with combined attosecond/nanometer resolution in an ultrafast transmission electron microscope (UEM). Unlike conventional holography, where signal and reference are spatially separated and then recombined to interfere, our method relies on electromagnetic fields to split an electron wave function in a quantum coherent superposition of different energy states. In the image plane, spatial modulation of the electron energy distribution reflects the phase relation between reference and signal fields. Beyond imaging applications, this approach allows implementing quantum measurements in parallel, providing an efficient and versatile tool for electron quantum optics.

Ultrafast generation and control of an electron vortex beam via chiral plasmonic near fields.

Vortex-carrying matter waves, such as chiral electron beams, are of significant interest in both applied and fundamental science. Continuous-wave electron vortex beams are commonly prepared via passive phase masks imprinting a transverse phase modulation on the electron's wavefunction. Here, we show that femtosecond chiral plasmonic near fields enable the generation and dynamic control on the ultrafast timescale of an electron vortex beam. The vortex structure of the resulting electron wavepacket is probed in both real and reciprocal space using ultrafast transmission electron microscopy. This method offers a high degree of scalability to small length scales and a highly efficient manipulation of the electron vorticity with attosecond precision. Besides the direct implications in the investigation of nanoscale ultrafast processes in which chirality plays a major role, we further discuss the perspectives of using this technique to shape the wavefunction of charged composite particles, such as protons, and how it can be used to probe their internal structure.

Prevalence and impact of self-reported irritable bowel symptoms in the general population.

Background and aims: The symptom-based diagnostic criteria for irritable bowel syndrome (IBS) have recently been revised in the Rome IV consensus. On the other hand, with rising public awareness of IBS, self-diagnosis and self-management is also increasing. We compared the prevalence and impact of Rome IV-based IBS vs self-diagnosed IBS in the general population. Methods: An internet panel filled out an online survey on bowel symptoms and their impact on health care utilization and daily activities. Results: A representative internet panel of 1012 individuals completed the online survey. Bowel symptoms were present in 68.6% of the population. Of these, 21% consulted a physician for these symptoms in the last year and 42% earlier. Rome IV IBS criteria were fulfilled by 5.5%, and these were younger and more likely to be female. In this subset, 37% had consulted a physician for IBS symptoms in the preceding year and 29% had done so earlier. A colonoscopy had been performed in 22%. Based on a brief description, 17.6% of the population self-identified as suffering from IBS (p < 0.001 compared to Rome IV IBS prevalence), and these were more likely to be female. Concordance with the Rome IV criteria was only 25%, but except for a lower reporting of pain, the symptom pattern, severity, impact on daily life, inability to work and health care utilization were similar to the Rome IV group. A total of 134 days of absence from work were attributed to bowel symptoms in those self-reporting with IBS. Conclusion: In the general population, bowel symptoms are highly prevalent, and the self-reported "IBS" is three times more prevalent than according to Rome IV criteria. Self-reported IBS is associated with a similar impact on health care utilization and quality of life but a higher impact on absence from work.

Author Correction: Attosecond coherent control of free-electron wave functions using semi-infinite light fields.

The authors became aware of a mistake in the original version of this Article. Specifically, an extra factor γ was incorrectly included in a number of mathematical equations and expressions. As a result of this, a number of changes have been made to both the PDF and the HTML versions of the Article. A full list of these changes is available online.

Serum levels of osteopontin predict diabetes remission after bariatric surgery.

AIM: Bariatric surgery has been shown to effectively improve glycaemic control in morbidly obese subjects. However, the molecular bases of this association are still elusive and may act independently of weight loss. Here, our retrospective study has investigated the inflammatory molecule osteopontin (OPN) as a potential predictor of type 2 diabetes mellitus (T2DM) remission. METHODS: Baseline serum levels of OPN were analyzed in 41 T2DM patients who underwent bariatric surgery. Anthropometric measures and biochemical variables, including insulin sensitivity indices (HOMA2), were assessed at baseline and at 1 and 3 years after surgery. RESULTS: At baseline, patients who experienced T2DM remission had increased waist circumference, body weight and BMI, and higher serum OPN, compared with non-remitters. Patients with and without T2DM remission improved their lipid and glucose profiles, although insulin resistance indices were only improved in the T2DM remission group. In the overall cohort of both T2DM remission and non-remission patients, baseline circulating levels of OPN significantly correlated with reductions of body weight and BMI over time, and insulin sensitivity improved as well. However, only the HOMA2-%S remained independently associated with serum OPN on multivariate linear regression analysis (B: 0.227, 95% CI: 0.067-0.387, ß = 0.831; P = 0.010). Baseline values of OPN predicted 3-year T2DM remission independently of body weight loss, lower BMI and duration of diabetes (OR: 1.046, 95% CI: 1.004-1.090; P = 0.033). CONCLUSION: Although larger studies are still needed to confirm our preliminary results, pre-operative OPN serum levels might be useful for predicting 3-year T2DM remission independently of weight loss in patients undergoing bariatric surgery.

The superstatistical nature and interoccurrence time of atmospheric mercury concentration fluctuations.

The probability density function (PDF) of the time intervals between subsequent extreme events in atmospheric Hg0 concentration data series from different latitudes has been investigated. The Hg0 dynamic possesses a long-term memory autocorrelation function. Above a fixed threshold Q in the data, the PDFs of the interoccurrence time of the Hg0 data are well described by a Tsallis q-Exponential function. This PDF behavior has been explained in the framework of superstatistics, where the competition between multiple mesoscopic processes affects the macroscopic dynamics. An extensive parameter µ, encompassing all possible fluctuations related to mesoscopic phenomena, has been identified. It follows a χ 2-distribution, indicative of the superstatistical nature of the overall process. Shuffling the data series destroys the long-term memory, the distributions become independent of Q, and the PDFs collapse on to the same exponential distribution. The possible central role of atmospheric turbulence on extreme events in the Hg0 data is highlighted.

The effect of sildenafil on gastric motility and satiation in healthy controls.

Sildenafil induces relaxation of smooth muscle cells by blocking PDE5. Dyspepsia is one of sildenafil's most frequently reported adverse events, suggesting its effect on gastric motility. Our aim was to study the effect of sildenafil on gastric accommodation (GA) and gastric emptying (GE) in healthy volunteers (HVs). METHODS: Sildenafil (50 mg) or placebo was randomly administered to 16 blinded HVs. After a manometry probe and an infusion catheter were positioned in the proximal stomach, the intragastric pressure (IGP) was measured before and during nutrient drink infusion (ND, 60 ml/min). HVs were asked to score their hunger, satiation and six epigastric symptoms at five-minute intervals. The experiment ended when the HVs scored maximal satiation during ND infusion at one-minute intervals. To assess GE, breath samples were collected every 15 minutes for six hours after the meal (244 kcal). RESULTS: ND infusion induced a drop in proximal stomach IGP, which was suppressed by sildenafil (average area under the curve for sildenafil: -33.6 ± 8.8 mmHg; placebo: -60.8 ± 11.3 mmHg, p = 0.005). Sildenafil-treated volunteers reached earlier maximal satiation compared to placebo (678 ± 70 ml vs. 836 ± 82.6 ml, p = 0.019). Finally, GE was significantly slower after sildenafil (90.6 ± 5.9 min vs. 76.6 ± 7.1 min, p = 0.04). CONCLUSION: Sildenafil inhibits GA, leading to significantly decreased nutrient tolerance, and slightly delays the GE rate in humans.

Attosecond coherent control of free-electron wave functions using semi-infinite light fields.

Light-electron interaction is the seminal ingredient in free-electron lasers and dynamical investigation of matter. Pushing the coherent control of electrons by light to the attosecond timescale and below would enable unprecedented applications in quantum circuits and exploration of electronic motions and nuclear phenomena. Here we demonstrate attosecond coherent manipulation of a free-electron wave function, and show that it can be pushed down to the zeptosecond regime. We make a relativistic single-electron wavepacket interact in free-space with a semi-infinite light field generated by two light pulses reflected from a mirror and delayed by fractions of the optical cycle. The amplitude and phase of the resulting electron-state coherent oscillations are mapped in energy-momentum space via momentum-resolved ultrafast electron spectroscopy. The experimental results are in full agreement with our analytical theory, which predicts access to the zeptosecond timescale by adopting semi-infinite X-ray pulses.

Three-trocar laparoscopic cholecystectomy under spinal anesthesia in a patient with asthma.

INTRODUCTION: Laparoscopy is perceived as the state-of-the-art technique for a wide variety of operations but is contraindicated by comorbidities such as respiratory diseases. We present the case of a patient affected by asthma who underwent a successful three-trocar low-pressure pneumoperitoneum under spinal anesthesia. CASE REPORT: A 58 year-old male with symptomatic gallstones had partly-controlled asthma and respiratory allergies. Potential bronchospasm was avoided by a less invasive laparoscopic technique. Under spinal anesthesia open pneumoperitoneum was achieved at the umbilicus. Two more trocars were inserted. A cholecystectomy was performed in 90 minutes keeping the patient in a supine position and the pneumopneumoperitoneum at 8 mmHg. The post-operative course was uneventful. Discharge to home occurred on day two. DISCUSSION: Laparoscopy is contraindicated in the presence of hemodynamic instability and inability of the patient to tolerate laparoscopic surgery. Asthma is caused by bronchoconstriction from a myriad possible stimuli requiring a specific anesthetic plan. Spinal anesthesia under low pressure pneumoperitoneum is a safe alternative to general anesthesia in high risk candidates. In experienced hand, a three-trocar cholecystectomy is safe and feasible. CONCLUSION: Our patient represented a challenging case due to a partly-controlled asthma. Bronchospasm under general anesthesia was prevented by spinal anesthesia to keep a spontaneous physiologic respiration, irrigation of the right subdiaphragmatic surface with lidocaine to control right shoulder pain, safe dissection by three trocars, a pneumoperitoneum at 8 mmHg, the supine position to prevent significant physiologic changes and minimize diaphragmatic irritation.

Laser-Induced Skyrmion Writing and Erasing in an Ultrafast Cryo-Lorentz Transmission Electron Microscope.

We demonstrate that light-induced heat pulses of different duration and energy can write Skyrmions in a broad range of temperatures and magnetic field in FeGe. Using a combination of camera-rate and pump-probe cryo-Lorentz transmission electron microscopy, we directly resolve the spatiotemporal evolution of the magnetization ensuing optical excitation. The Skyrmion lattice was found to maintain its structural properties during the laser-induced demagnetization, and its recovery to the initial state happened in the sub-µs to µs range, depending on the cooling rate of the system.

High serum levels of C-reactive protein (CRP) predict beneficial decrease of visceral fat in obese females after sleeve gastrectomy.

BACKGROUND & AIMS: Gender-related differences represent an emerging investigation field to better understand obesity heterogeneity and paradoxically associated cardiovascular (CV) risk. Here, we investigated if high-sensitivity C-reactive protein (hs-CRP) might differently affect adiposity and predict the clinical response to bariatric surgery in obese males and females. METHODS AND RESULTS: In 110 morbidly obese patients undergoing laparoscopic sleeve gastrectomy, hs-CRP as well as anthropometric assessment of adiposity, completed by electric bioimpedance and ultrasonography quantification of visceral fat area (VFA), were measured before and one year after surgery. As compared to males, obese female showed less severe overweight and prevalent subcutaneous fat deposition, but higher circulating hs-CRP. In obese females, hs-CRP was associated with VFA at baseline, independently of body mass index (BMI) and visceral adiposity index (OR 1.022 [95% CI 1.001-1.044]; p = 0.039). Based on decreases and increases in hs-CRP levels after surgery, two distinct subgroups of females were identified. Post-surgery decreases in hs-CRP was predominantly observed in patients with higher baseline levels of hs-CRP and associated with greater reduction of weight, BMI, fat and lean mass, VFA and visceral to subcutaneous fat ratio. Finally, we observed that high baseline values of hs-CRP were able to predict VFA reduction one-year after surgery, independently of BMI and visceral adiposity index (VAI) loss (OR 1.031 [95% CI 1.009-1.053]; p = 0.005). CONCLUSION: In obese females, hs-CRP levels might be a promising biomarker of visceral fat amount and dysfunction, in addition to predict the effectiveness of bariatric surgery in terms of loss of VFA one-year after surgery.

Real-Time Observation of Phonon-Mediated σ-π Interband Scattering in MgB_{2}.

In systems having an anisotropic electronic structure, such as the layered materials graphite, graphene, and cuprates, impulsive light excitation can coherently stimulate specific bosonic modes, with exotic consequences for the emergent electronic properties. Here we show that the population of E_{2g} phonons in the multiband superconductor MgB_{2} can be selectively enhanced by femtosecond laser pulses, leading to a transient control of the number of carriers in the σ-electronic subsystem. The nonequilibrium evolution of the material optical constants is followed in the spectral region sensitive to both the a- and c-axis plasma frequencies and modeled theoretically, revealing the details of the σ-π interband scattering mechanism in MgB_{2}.

The effect of mirtazapine on gastric accommodation, gastric sensitivity to distention, and nutrient tolerance in healthy subjects.

BACKGROUND: Disturbances of gastric motor function of functional dyspepsia (FD) have been implicated in the pathogenesis of the symptoms, and hence, motility modifying agents are considered for its treatment. Mirtazapine was recently shown to improve symptoms and increase nutrient tolerance in FD patients with weight loss. We aim to evaluate the effect of mirtazapine on gastric sensorimotor function in healthy volunteers (HV). METHODS: Thirty-one HV underwent an intragastric pressure (IGP) and barostat measurements on separate days before and after 3 weeks of placebo or mirtazapine (15 mg). Gastric compliance, sensitivity and accommodation (GA) measured by the barostat. GA was quantitated as the difference (delta) in intra-balloon volume before and after ingestion of 200 mL of a nutrient drink (ND). GA measured by IGP was quantitated as the drop of IGP from baseline during the intragastric infusion of ND until maximal satiation. KEY RESULTS: Mirtazapine significantly increased the bodyweight of subjects (67.8±3.7 to 69.1±3.7 kg; P=.01). Barostat results showed no effect on gastric compliance, sensitivity, and GA. Nutrient tolerance was not affected after treatment (1170±129.4 vs 1104±133.6 kcal; P=.4), and mirtazapine was associated with lower symptom ratings. The IGP drop during meal ingestion was significantly suppressed (area under the curve: -43.3±4.5 mm Hg vs -28.9±3.1 mm Hg; P=.005). CONCLUSIONS & INFERENCES: In HVs, the occurrence of weight gain and decreased meal-induced symptoms in spite of a suppressed meal-induced IGP drop, point towards a central mode of action. Mirtazapine does not display changes in gastric sensorimotor function that could explain its beneficial effects on symptoms and nutrient tolerance in FD.