A new histopathology scoring protocol reveals myopathy features in PSE-like pork.

Pale, Soft, and Exudative (PSE)-like pork defects are associated with fiber destruction and pale discoloration and have become a severe economic burden for the European meat sector. However, robust detection of PSE-like pork and its diverse features is challenging and makes studies into defect causation difficult. Implementation of histological examination may improve our knowledge about less-known features linked to PSE-like defects. Here we evaluate if a new histological protocol can reveal how myopathy in ham may be associated with visual and traditional physicochemical anomalies of PSE-like pork. We first created a list of pathological features, quantified them, and integrated them into a myodegeneration scoring scheme (MYO) for semimembranosus muscle sections. We then explored potential associations between overall MYO scoring and individual histology features with visual PSE-like defect scoring (DES) and with individual meat quality variables [pHu, color: L*, a*, b* (CIELAB), bioimpedance, and near-infrared spectroscopy (NIR)]. As the primary finding of this study, we show a significant association between overall myopathy (MYO) scoring and PSE-like defect (DES) scores. We also found associations of specific myopathy features with DES scores, and of overall MYO scoring with specific quality variables. In all, our data suggest links between signs of acute myodegeneration and PSE-like defects. Our data, hence, supports the implementation of semi-quantitative histopathological approaches for diagnosing PSE-like pork features and may help identify the underlying mechanisms behind these defects.

Clinical characteristic and survival outcomes of patients with advanced NSCLC according to KRAS mutational status in the French real-life ESME cohort.

PURPOSE: The RAS/MEK signaling pathway is essential in carcinogenesis and frequently altered in non-small-cell lung cancer (NSCLC), notably by KRAS mutations (KRASm) that affect 25%-30% of non-squamous NSCLC. This study aims to explore the impact of KRASm subtypes on disease phenotype and survival outcomes. PATIENTS AND METHODS: We conducted a retrospective analysis of the French Epidemiological Strategy and Medical Economics database for advanced or metastatic lung cancer from 2011 to 2021. Patient demographics, histology, KRASm status, treatment strategies, and outcomes were assessed. RESULTS: Of 10 177 assessable patients for KRAS status, 17.6% had KRAS p.G12C mutation, 22.6% had KRAS non-p.G12C mutation, and 59.8% were KRASwt. KRASm patients were more often smokers (96.3%) compared with KRASwt (85.8%). A higher proportion of programmed death-ligand 1 ≥50% was found for KRASm patients: 43.5% versus 38.0% (P < 0.01). KRASm correlated with poorer outcomes. First-line median progression-free survival was shorter in the KRASm than the KRASwt cohort: 4.0 months [95% confidence interval (CI) 3.7-4.3 months] versus 5.1 months (95% CI 4.8-5.3 months), P < 0.001. First-line overall survival was shorter for KRASm than KRASwt patients: 12.6 months (95% CI 11.6-13.6 months) versus 15.4 months (95% CI 14.6-16.2 months), P = 0.012. First-line chemoimmunotherapy offered better overall survival in KRAS p.G12C (48.8 months) compared with KRAS non-p.G12C (24.0 months) and KRASwt (22.5 months) patients. Second-line overall survival with immunotherapy was superior in the KRAS p.G12C subgroup: 12.6 months (95% CI 8.1-18.6 months) compared with 9.4 months (95% CI 8.0-11.4 months) for KRAS non-p.G12C and 9.6 months (8.4-11.0 months) for KRASwt patients. CONCLUSION: We highlighted distinct clinical profiles and survival outcomes according to KRASm subtypes. Notably KRAS p.G12C mutations may provide increased sensitivity to immunotherapy, suggesting potential therapeutic implications for sequencing or combination of therapies. Further research on the impact of emerging KRAS specific inhibitors are warranted in real-world cohorts.

Avoiding the use of long-term parenteral support in patients without intestinal failure: A position paper from the European Society of Clinical Nutrition & Metabolism, the European Society of Neurogastroenterology and Motility and the Rome Foundation for Disorders of Gut-Brain Interaction.

The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

TEMPUS-A microgravity electromagnetic levitation facility for parabolic flights.

During the ∼22 s lasting free fall phase in an aircraft flying a parabola, the aboard installed electromagnetic levitation facility "TEMPUS" is used to investigate contactless and undisturbed of gravity induced convection thermophysical properties and microstructure formations of hot and highly reactive metal or semiconductor melts. The completely contactless handling and measurement of a liquid by the levitation technique keeps the melt free of contamination and enables the extension of the accessible sample temperature range far into the undercooled liquid state below the melting point. Additionally, the state of reduced weight during parabolic flights allows us to considerably decrease the strongly disturbing electromagnetic levitation forces acting in ground-based facilities on the suspended liquids. The present paper explains in detail the basic principle and the technical realization of the TEMPUS levitation facility and its attached measurement devices. Furthermore, it presents some typical experiments performed in TEMPUS, which also show the advantages resulting from the combination of reduced weight, electromagnetic levitation, and contactless measurement techniques. The control and data recording, as well as the planning, preparation, and operation of the TEMPUS experiments within the parabolic flight campaign, are another aspect outlined in the following.

Immune checkpoint blockers in solid organ transplant recipients and cancer: the INNOVATED cohort.

BACKGROUND: Patients with solid organ transplant (SOT) and solid tumors are usually excluded from clinical trials testing immune checkpoint blockers (ICB). As transplant rates are increasing, we aimed to evaluate ICB outcomes in this population, with a special focus on lung cancer. METHODS: We conducted a multicenter retrospective cohort study collecting real data of ICB use in patients with SOT and solid tumors. Clinical data and treatment outcomes were assessed by using retrospective medical chart reviews in every participating center. Study endpoints were: overall response rate (ORR), 6-month progression-free survival (PFS), and grade ≥3 immune-related adverse events. RESULTS: From August 2016 to October 2022, 31 patients with SOT (98% kidney) and solid tumors were identified (36.0% lung cancer, 19.4% melanoma, 13.0% genitourinary cancer, 6.5% gastrointestinal cancer). Programmed death-ligand 1 expression was positive in 29% of tumors. Median age was 61 years, 69% were males, and 71% received ICB as first-line treatment. In the whole cohort the ORR was 45.2%, with a 6-month PFS of 56.8%. In the lung cancer cohort, the ORR was 45.5%, with a 6-month PFS of 32.7%, and median overall survival of 4.6 months. The grade 3 immune-related adverse events rate leading to ICB discontinuation was 12.9%. Allograft rejection rate was 25.8%, and risk of rejection was similar regardless of the type of ICB strategy (monotherapy or combination, 28% versus 33%, P = 1.0) or response to ICB treatment. CONCLUSIONS: ICB could be considered a feasible option for SOT recipients with some advanced solid malignancies and no alternative therapeutic options. Due to the risk of allograft rejection, multidisciplinary teams should be involved before ICB therapy.

Corrigendum: Echocardiography and extravascular lung water during 3 weeks of exposure to high altitude in otherwise healthy asthmatics.

[This corrects the article DOI: 10.3389/fphys.2023.1214887.].

Echocardiography and extravascular lung water during 3 weeks of exposure to high altitude in otherwise healthy asthmatics.

Background: Asthma rehabilitation at high altitude is common. Little is known about the acute and subacute cardiopulmonary acclimatization to high altitude in middle-aged asthmatics without other comorbidities. Methods: In this prospective study in lowlander subjects with mostly mild asthma who revealed an asthma control questionnaire score >0.75 and participated in a three-week rehabilitation program, we assessed systolic pulmonary artery pressure (sPAP), cardiac function, and extravascular lung water (EVLW) at 760 m (baseline) by Doppler-echocardiography and on the second (acute) and last day (subacute) at a high altitude clinic in Kyrgyzstan (3100 m). Results: The study included 22 patients (eight male) with a mean age of 44.3 ± 12.4 years, body mass index of 25.8 ± 4.7 kg/m2, a forced expiratory volume in 1 s of 92% ± 19% predicted (post-bronchodilator), and partially uncontrolled asthma. sPAP increased from 21.8 mmHg by mean difference by 7.5 [95% confidence interval 3.9 to 10.5] mmHg (p < 0.001) during acute exposure and by 4.8 [1.0 to 8.6] mmHg (p = 0.014) during subacute exposure. The right-ventricular-to-pulmonary-artery coupling expressed by TAPSE/sPAP decreased from 1.1 by -0.2 [-0.3 to -0.1] mm/mmHg (p < 0.001) during acute exposure and by -0.2 [-0.3 to -0.1] mm/mmHg (p = 0.002) during subacute exposure, accordingly. EVLW significantly increased from baseline (1.3 ± 1.8) to acute hypoxia (5.5 ± 3.5, p < 0.001) but showed no difference after 3 weeks (2.0 ± 1.8). Conclusion: In otherwise healthy asthmatics, acute exposure to hypoxia at high altitude increases pulmonary artery pressure (PAP) and EVLW. During subacute exposure, PAP remains increased, but EVLW returns to baseline values, suggesting compensatory mechanisms that contribute to EVLW homeostasis during acclimatization.

Efficacy and safety of switching between biologics in chronic rhinosinusitis with nasal polyps or N-ERD.

BACKGROUND AND OBJECTIVE: The effectiveness of biologics in chronic rhinosinusitis with nasal polyps (CRSwNP) is well-established. However, real-world experience on the effectiveness of transitioning between two monoclonal antibodies is scarce. Therefore, we aimed to analyze the safety and efficacy of antibody switching in treatment of chronic rhinosinusitis. METHODS: All patients with CRSwNP or nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD) requiring a switch between biologics were retrospectively studied. Analysis included changes in polyp size, quality of life parameters, asthma control, and side effects. RESULTS: Out of 195 patients treated with biologics for CRSwNP or N-ERD in our center, 23 (11.8%) required transition to a different monoclonal antibody. The majority switched from omalizumab to dupilumab (17/23, 73.9%), mostly due to inadequate symptom control. Nine out of these 17 patients (52.9%) were switched without a washout period. All patients showed significant improvement in nasal polyp score, asthma control test and sino-nasal outcome test-22 after changing to dupilumab. Keratoconjunctivitis sicca was the side-effect (4.3%) reported after the switch from omalizumab to dupilumab, which lead to termination of therapy in one patient. Due to limited sample size, other antibody transitions were reported in a descriptive manner. CONCLUSION: The transition to dupilumab is an effective option in patients with inadequate treatment response or side-effects of omalizumab in nasal polyposis. Our preliminary results indicate that a wash-out period may not be necessary when switching between biologics, however, these findings require further investigations. Other monoclonal antibody transitions also show promising results, but warrant validations in larger cohorts due to small patient samples in our study.

The JAK1/2 inhibitor ruxolitinib in patients with COVID-19 triggered hyperinflammation: the RuxCoFlam trial.

Dysregulated hyperinflammatory response is key in the pathogenesis in patients with severe COVID-19 leading to acute respiratory distress syndrome and multiorgan failure. Whilst immunosuppression has been proven to be effective, potential biological targets and optimal timing of treatment are still conflicting. We sought to evaluate efficacy and safety of the Janus Kinase 1/2 inhibitor ruxolitinib, employing the previously developed COVID-19 Inflammation Score (CIS) in a prospective multicenter open label phase II trial (NCT04338958). Primary objective was reversal of hyperinflammation (CIS reduction of ≥25% at day 7 in ≥20% of patients). In 184 patients with a CIS of ≥10 (median 12) ruxolitinib was commenced at an initial dose of 10 mg twice daily and applied over a median of 14 days (range, 2-31). On day 7, median CIS declined to 6 (range, 1-13); 71% of patients (CI 64-77%) achieved a ≥25% CIS reduction accompanied by a reduction of markers of inflammation. Median cumulative dose was 272.5 mg/d. Treatment was well tolerated without any grade 3-5 adverse events related to ruxolitinib. Forty-four patients (23.9%) died, all without reported association to study drug. In conclusion, ruxolitinib proved to be safe and effective in a cohort of COVID-19 patients with defined hyperinflammation.

Raster-scanning optoacoustic mesoscopy biomarkers for atopic dermatitis skin lesions.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease worldwide. Its severity is assessed using scores that rely on visual observation of the affected body surface area, the morphology of the lesions and subjective symptoms, like pruritus or insomnia. Ideally, such scores should be complemented by objective and accurate measurements of disease severity to standardize disease scoring in routine care and clinical trials. Recently, it was shown that raster-scanning optoacoustic mesoscopy (RSOM) can provide detailed three-dimensional images of skin inflammation processes that capture the most relevant features of their pathology. Moreover, precise RSOM biomarkers of inflammation have been identified for psoriasis. However, the objectivity and validity of such biomarkers in repeated measurements have not yet been assessed for AD. Here, we report the results of a study on the repeatability of RSOM inflammation biomarkers in AD to estimate their precision. Optoacoustic imaging analysis revealed morphological inflammation biomarkers with precision well beyond standard clinical severity metrics. Our findings suggest that optoacoustic mesoscopy may be a good choice for quantitative evaluations of AD that are inaccessible by other methods. This could potentially enable the optimization of disease scoring and drug development.

Generation of three CRISPR/Cas9 edited human induced pluripotent stem cell lines (DHMi005-A-5, DHMi005-A-6 and DHMi005-A-7) carrying a Holt-Oram Syndrome patient-specific TBX5 mutation with known cardiac phenotype and a FLAG-tag after exon 9 of the TBX5 gene.

TBX5 is a transcription factor (TF) playing essential role during cardiogenesis. It is well known that TF mutations possibly result in non- or additional binding of the DNA due to conformational changes of the protein. We introduced a Holt-Oram Syndrome (HOS) patient-specific TBX5 mutation c.920_C > A heterozygously in a healthy induced pluripotent stell cell (iPSC) line. This TBX5 mutation results in conformational changes of the protein and displayed ventricular septal defects in the patient itself. Additionally we introduced a FLAG-tag on the TBX5 mutation-carrying allele. The resulting heterozygous TBX5-FLAG iPSC lines are a powerful tool to investigate altered TF activity bonding.

Prevalence of scabies worldwide-An updated systematic literature review in 2022.

Scabies is a World Health Organization-defined neglected tropical disease, with continuously rising incidence worldwide in recent years. The aim of this study was to provide an update of the worldwide prevalence and new treatment approaches of scabies in population-based settings. MEDLINE (PubMed), Embase and LILACS databases were reviewed for English and German language population-based studies from October 2014 to March 2022. Two authors independently screened the records for eligibility, extracted all data and one critically appraised the quality of the studies and risk of bias. Systematic review registration: PROSPERO CRD42021247140. Overall, 1273 records were identified through database searching, of which 43 studies were included for the systematic review. Most of the studies (n = 31) examined the scabies prevalence in medium or low human development index countries. The highest prevalence of scabies reported in the general population (children and adults) was recorded in five randomly selected communities in Ghana (71.0%), whereas the highest scabies prevalence in studies, which only examined children (76.9%), was recorded in an Indonesian boarding school. The lowest prevalence was recorded in Uganda (0.18%). The systematic review highlights the prevalence of scabies worldwide, showing that scabies is still a serious, increasing disease that occurs globally and is clustered in developing countries. More transparent data on scabies prevalence are needed to identify risk factors to find new prevention measures.

Effect of 5 weeks of oral acetazolamide on patients with pulmonary vascular disease: A randomized, double-blind, cross-over trial.

BACKGROUND: The carbonic anhydrase inhibitor acetazolamide stimulates ventilation through metabolic acidosis mediated by renal bicarbonate excretion. In animal models, acetazolamide attenuates acute hypoxia-induced pulmonary hypertension (PH), but its efficacy in treating patients with PH due to pulmonary vascular disease (PVD) is unknown. METHODS: 28 PVD patients (15 pulmonary arterial hypertension, 13 distal chronic thromboembolic PH), 13 women, mean±SD age 61.6±15.0 years stable on PVD medications, were randomised in a double-blind crossover protocol to 5 weeks acetazolamide (250mg b.i.d) or placebo separated by a ≥2 week washout period. Primary endpoint was the change in 6-minute walk distance (6MWD) at 5 weeks. Additional endpoints included safety, tolerability, WHO functional class, quality of life, arterial blood gases, and hemodynamics (by echocardiography). RESULTS: Acetazolamide had no effect on 6MWD compared to placebo (treatment effect: mean change [95%CI] -18 [-40 to 4]m, p=0.102) but increased arterial blood oxygenation through hyperventilation induced by metabolic acidosis. Other measures including pulmonary hemodynamics were unchanged. No severe adverse effects occurred, side effects that occurred significantly more frequently with acetazolamide vs. placebo were change in taste (22/0%), paraesthesia (37/4%) and mild dyspnea (26/4%). CONCLUSIONS: In patients with PVD, acetazolamide did not change 6MWD compared to placebo despite improved blood oxygenation. Some patients reported a tolerable increase in dyspnoea during acetazolamide treatment, related to hyperventilation, induced by the mild drug-induced metabolic acidosis. Our findings do not support the use of acetazolamide to improve exercise in patients with PVD at this dosing. GOV IDENTIFIER: NCT02755298.

Generation of two CRISPR/Cas edited human induced pluripotent stem cell lines (DHMi005-A-3 and DHMi005-A-4) carrying a FLAG-tag after exon 9 of the TBX5 gene.

Although TBX5 plays a major role during human cardiogenesis and initiates and controls limb development, many of its interactions with genomic DNA and the resulting biological consequences are not well known. Existing anti-TBX5-antibodies work very inefficiently in certain applications such as ChIP-Seq analysis. To circumvent this drawback, we introduced a FLAG-tag sequence into the TBX5 locus at the end of exon 9 prior to the stop codon by CRISPR/Cas9. The expressed TBX5-FLAG fusion protein can effectively be precipitated by anti-FLAG antibodies. Therefore, these gene-edited iPSC lines represent powerful cellular in vitro tools to unravel TBX5:DNA interactions in detail.

[Rapid resolution of severe psoriasis vulgaris in an HIV-positive patient treated with antiretroviral therapy]. / Schnelle Abheilung einer schweren Psoriasis vulgaris bei einem HIV-positiven Patienten unter antiretroviraler Therapie.

Psoriasis exacerbation may occur in patients with human immunodeficiency virus (HIV). We present the case of a patient with severe psoriasis vulgaris (PASI 34.2) and an initial HIV diagnosis who showed rapid resolution of psoriasis upon initiation of antiretroviral therapy. Antiretroviral therapy is an effective treatment option for HIV-associated psoriasis. Especially in patients with a sudden psoriasis flare-up or resistance to therapy, HIV testing should be considered as knowledge of an underlying infection is elementary to treatment decision-making.

Nutrition education in medical schools (NEMS) project: Promoting clinical nutrition in medical schools - Perspectives from different actors.

BACKGROUND & AIMS: Nutrition education is not adequately represented in the medical curriculum, and this prompted the European Society for Clinical Nutrition and Metabolism (ESPEN) to launch the Nutrition Education in Medical Schools (NEMS) Project in 2017. The aim of this original paper was to describe the perspectives of different actors in the promotion of nutrition education in medical schools. METHODS: On 11 November 2021, an online meeting was held on this topic, where nine representatives from different backgrounds participated in the scientific programme. More than 640 participants registered to this webinar. RESULTS: The different models of Nutrition Education in Medical Schools were introduced by Prof. Cristina Cuerda (Spain) and Prof. Maurizio Muscaritoli (Italy). The students' perspective was given by Ms. Alexandra Archodoulakis (Germany) and Ms. Sila Gürbüz (Turkey), representing the European Medical Students' Association. The dietitian's perspective was given by Dr. Kirsten Berk (The Netherlands), whereas Dr. Matti Aapro (Switzerland) gave the medical doctor (oncology)'s perspective. Ms. Clare Farrand (Australia) gave the WHO perspective and Dr. Kristiina Patja (Finland) explained the healthy lifestyle teaching to medical students. Lastly, Prof. Michael Chourdakis (Greece) and Prof. Zeljko Krznaric (Croatia) hosted the round-table discussion. CONCLUSIONS: There was strong agreement among the representatives from different settings joining this ESPEN initiative that increasing nutritional knowledge and skills of young doctors is now possible and will launch a virtuous cycle that will proactively involve all the other healthcare professionals working in the nutritional field.

Visuomotor performance at high altitude in COPD patients. Randomized placebo-controlled trial of acetazolamide.

Introduction: We evaluated whether exposure to high altitude impairs visuomotor learning in lowlanders with chronic obstructive pulmonary disease (COPD) and whether this can be prevented by acetazolamide treatment. Methods: 45 patients with COPD, living <800 m, FEV1 ≥40 to <80%predicted, were randomized to acetazolamide (375 mg/d) or placebo, administered 24h before and during a 2-day stay in a clinic at 3100 m. Visuomotor performance was evaluated with a validated, computer-assisted test (Motor-Task-Manager) at 760 m above sea level (baseline, before starting the study drug), within 4h after arrival at 3100 m and in the morning after one night at 3100 m. Main outcome was the directional error (DE) of cursor movements controlled by the participant via mouse on a computer screen during a target tracking task. Effects of high altitude and acetazolamide on DE during an adaptation phase, immediate recall and post-sleep recall were evaluated by regression analyses. www.ClinicalTrials.gov NCT03165890. Results: In 22 patients receiving placebo, DE at 3100 m increased during adaptation by mean 2.5°, 95%CI 2.2° to 2.7° (p < 0.001), during immediate recall by 5.3°, 4.6° to 6.1° (p < 0.001), and post-sleep recall by 5.8°, 5.0 to 6.7° (p < 0.001), vs. corresponding values at 760 m. In 23 participants receiving acetazolamide, corresponding DE were reduced by -0.3° (-0.6° to 0.1°, p = 0.120), -2.7° (-3.7° to -1.6°, p < 0.001) and -3.1° (-4.3° to -2.0°, p < 0.001), compared to placebo at 3100 m. Conclusion: Lowlanders with COPD travelling to 3100 m experienced altitude-induced impairments in immediate and post-sleep recall of a visuomotor task. Preventive acetazolamide treatment mitigated these undesirable effects.

Local and diffusive dynamics of LiCl aqueous solutions in pristine and modified silica nanopores.

We use 1H, 2H, and 7Li nuclear magnetic resonance to investigate local and diffusive dynamics of LiCl-7H2O and LiCl-7D2O solutions in pristine and functionalized silica nanopores in a component-selective manner. Recently, we showed that the solution dynamics become slower when the diameter of the pristine pores is reduced. Here, we determine the effects of (aminopropyl)triethoxysilane and dye surface functionalizations on the motions of the water molecules and lithium ions from ambient temperatures down to the glass transition. The local and diffusive solution dynamics are similar in both functionalized pores but, on average, slower than in pristine pores with comparable diameters. When the exchange between different confinement regions is sufficiently slow at reduced temperatures, bimodal water and lithium dynamics may be observed. We attribute this bimodality to bulk-like motion in the pore centers and slowed-down motion at the pore walls. For the lithium ions, a bimodality observed in the pristine pores is absent in the functionalized ones. We conjecture that the steric hindrance and electrostatic interactions associated with the grafted functional groups interfere with the formation of a defined electric double layer, while the enhanced surface roughness and unequal charge distribution result in overall slower dynamics. Thus, the nature of the walls is an important parameter for the solution dynamics. Thereby, in situ measurements of the pH value inside the silica pores using the grafted dye molecules reveal that observed changes in the pH value in response to the surface functionalization are of limited relevance for the water reorientation.