We prove that the uniform radius of spatial analyticity $\sigma(t)$ of solution at time $t$ to the one-dimensional fourth order nonlinear Schr\”odinger equation $$ i\partial_tu-\partial_x^4u =|u |^2u $$ cannot decay faster than $1/ \sqrt{t}$ for large $t$, given initial data that is analytic with fixed radius $\sigma_0$. The main ingredients in the proof are a modified Gevrey space, a method of approximate conservation law and a Strichartz estimate for free wave associated with the equation.

BACKGROUND: Initially identified in December 2019 in China, the 2019 Coronavirus disease (COVID-19) is now affecting more than 200 countries and territories around the world. Given the current unavailability of an effective medical cure for COVID-19, a public health strategy of reduced social contact and shelter in place has been adopted worldwide. Nonetheless, social distancing and isolation could also represent risk factors for mental disorders, determining loneliness, reduced social support and under-detection of mental health needs. Along with this, social distancing determines an insurmountable obstacle for direct access to psychiatric care services. The pandemic generates the urgent need for integrating technology into innovative models of mental healthcare. AIMS: In this paper we discuss the potential role of telepsychiatry and other cutting-edge technologies in the management of mental health assistance. We narratively review the literature to examine advantages and risks related to the massive application of these new therapeutic settings, along with the possible limitations and ethical concerns. RESULTS: Telemental health services are particularly feasible and appropriate for the support of patients, family members and health-care providers during this COVID-19 pandemic. The integration of telepsychiatry with other technological innovations (e.g., mobile apps, virtual reality, big data and artificial intelligence) opens up interesting future perspectives for the improvement of mental health assistance. CONCLUSION: The COVID-19 pandemic situation shows us how vast the amount of untreated mental illnesses can be. The pandemic crisis can contribute to spread, among numerous mental health professionals, the knowledge of the possibilities offered by the digital era.

Free light chains (FLC), considered a biomarker of B cell activity, are frequently elevated in different systemic inflammatory-autoimmune diseases. As systemic sclerosis (SSc) clinical course may be variable, this study aimed to assess FLCs levels in serum and urine of affected individuals, as biomarkers of disease activity. We assessed FLC levels in serum and urine of 72 SSc patients and 30 healthy controls (HC). Results were analyzed in comparison with overall clinical and laboratory findings, disease activity index (DAI) and disease severity scale (DSS). SSc patients displayed increased levels of k and λ FLC in serum, significantly higher than HC (p=0.0001) alongside with the mean levels of free k/λ ratio and of the k+λ sum (p=0.0001). In addition, SSc patients had significant higher levels in the urine of free k and of k/λ ratio than HC (p=0.0001). SSc patients with increased k+λ sum in serum showed a statistically higher levels of erythro-sedimentation rate (p=0.034), C-reactive protein (p=0.003), higher DAI (p=0.024) and DSS (p=0.015) than SSc patients with normal levels of FLC. A positive linear correlation was found between serum levels of free k and DAI (r=0.29, p=0.014). SSc patients with increased free k in urine had statistically higher DAI (p=0.048) than SSc patients with normal level of free k. The significant increased levels of FLC correlated with disease activity in SSc patients. Our results strengthen the role of FLC as useful biomarkers in clinical practice to early diagnosis and monitor disease activity with an improvement of SSc patients’ management.

Body fat has regulatory functions through producing cytokines and adipokines whose role in the pathogenesis of Systemic Sclerosis (SSc) is currently emerging. Changes in body mass, either overweight or underweight status, entail a dysregulation of the cytokines/adipokines network that may impact on SSc disease activity. We evaluated serum levels of adipokines and cytokines in SSc patients and correlated them to clinical features and body mass index (BMI) categories. The study included 89 SSc patients and 26 healthy donors (HD). Serum levels of adiponectin, leptin, resistin, visfatin, TNFα, IFNγ, IL-2, IL-10, and IL-17A were measured by Multiplex Immunoassay, and correlated to BMI, waist to hip ratio, and disease specific features. Mann-Whitney U-test or t-Student for unpaired data, Kruskal-Wallis test or ANOVA, were used for comparisons between groups. Spearman’s or Pearson’s test were used for correlation analysis. Serum levels of TNFα, IL-2, leptin, and resistin, were significantly higher in SSc than in HD. The highest levels of IL-17A, IL-2, IL-10, leptin and visfatin were detected in obese SSc patients (p <0.01). Conversely, underweight SSc patients showed the highest TNFα levels (p<0.05), which were negatively correlated with BMI (p=0.05). No correlation between adipokines/cytokines and clinical characteristics was found. Adipokines, IL-2, IL-10 and IL-17A were found to be increased in obese SSc patients, but whether they play a role in the pathogenesis of the disease remains to be investigated. Intriguingly, underweight patients had higher TNFα levels, suggesting a potential role of TNFα in inducing the cachexia observed in long-lasting disease.

Objective: SARS-CoV-2 has caused nearly 4 million confirmed cases of COVID-19 worldwide in the approximately 4 months since it emerged in Wuhan, China in December 2019. Comorbidities increase morbidity and mortality in COVID-19, and many laboratory parameters have been associated with mortality. The aim of the present study was to identify the relationship between endogenous carboxyhemoglobin (COHb) level and the clinical course and prognosis of COVID-19. Methods: The study included 48 non-smokers or ex-smokers aged 18 years or older who presented to the emergency department, were diagnosed with COVID-19 by real-time PCR analysis of nasopharyngeal swab sample, and were treated in the pulmonary diseases ward of the Atatürk University hospital after between March 24, 2020 and April 15, 2020. The patients’ laboratory parameters and demographic data were analyzed retrospectively. Results: Prothrombin time and C-reactive protein (CRP), troponin-I, and D-dimer levels decreased in COVID-19 patients during follow-up (p=0.024, p=0.001, p=0.001, p=0.001), while PaO2/FiO2 ratio and COHb increased (p=0.002, p=0.001). COHb level at admission was significantly lower in patients who developed macrophage activation syndrome (MAS), acute respiratory distress syndrome (ARDS), and those who died compared to the other patients (p=0.002, p=0.001). COHb level on day 5 of treatment was significantly higher in patients with ARDS and patients who died (p=0.001, p=0.001).Significant correlations were detected between COHb level and CRP (r=-0.425, p=0.001), ferritin (r=-0.395, p=0.001) and PaO2/FiO2 ratio (r=0.431, p=0.001). Conclusions: COHb level may be an easily accessible biomarker that guides early follow-up and treatment planning to avoid ARDS, MAS, and mortality in COVID-19.

Abdominal wall endometrioma is an extremely rare entity with a precise incidence of 0.07%–0.47% remaining an insidious cause of usually delayed diagnosis. Differential diagnosis should include that rare condition and ultrasonography remains a pivotal tool to unravel that enigma as well.

RP7214 is a potent and selective inhibitor of human mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). This paper describes the results from a Phase 1 study that evaluated safety and pharmacokinetics of single and multiple ascending doses (SAD and MAD) and the food effect of RP7214 in healthy subjects. Target engagement of DHODH was also evaluated. A randomized, double-blind, placebo-controlled trial of single-dose (100, 200, and 400 mg QD) and multiple doses (200 and 400 mg BID for 7 days) followed by food effect at a single dose of 200 mg was conducted. A total of 18 healthy volunteers (HVs) (6 subjects in each of three cohorts) in the SAD part, 12 (6 subjects each in two cohorts) in the MAD part, and 12 in the food effect study were enrolled. RP7214 was well tolerated at all dose levels. None of the subjects reported any RP7214-related adverse events. RP7214 showed dose-proportional pharmacokinetics after single and multiple dosing. Steady-state concentrations were reached within about 3–6 days. The mean plasma half-life of RP724 at steady-state was approximately 13h. RP7214 showed accumulation on multiple dosing.. Food did not impact the absorption of RP7214. RP7214 showed dose-dependent inhibition of DHODH as measured by analyzing accumulating DHO levels, confirming target engagement. The rapid absorption and high systemic exposure of RP724 with a favorable safety profile shows the potential for the development of RP7214 in SARS-CoV-2 infection and acute myeloid leukemia. (NCT04680429). Keywords: RP7214, dihydroorotate dehydrogenase, SAD, MAD, HV

Abstract Aim: To evaluate the respiratory functions of children with nephrotic syndrome (NS) by IOS and its correlation with spirometry. Methods: Fifty-five NS patients aged 3–18 years were included as the study group and 40 healthy children of the same age formed the control group. Patients were divided into nephrotic phase (first attack and relapse) and remission. Demographic, anthropometric and laboratory data of the children were recorded. Respiratory functions were evaluated by IOS and spirometry. Children over 6 years old performed both IOS and spirometry while children under 6 years performed only IOS. Results: The R (R5%, R10%, R5-20) and AX and Z5% values of IOS in patients with nephrotic phase were higher than remission patients and control group while spirometry indices of FEV1%, FEV1/FVC, PEF% and MEF25-75% were lower. FEV1% showed negative correlation with R5%, R10%, R15%, X10% and X15% results, FEV1/FVC% showed negative correlation with R5%, R5-20 and X15% results, FVC showed negative correlation with X10% results, MEF25-75% showed negative correlation with, R5%, R10%, R5-20, X15%, F res, Z5% and AX results. Conclusion: Our study demonstrated that respiratory functions measured by IOS and spirometry were affected at the time of nephrotic phase in NS patients. And IOS, a novel method easily applicable even in small children, is a valuable and reliable tool to detect this condition; given its good correlation with spirometry. Keywords Nephrotic syndrome, Respiratory functions, Spirometry, Impulse Oscillometry

Recently, Large-scale Language Models (LLMs) such as Chat Generative Pre-trained Transformer (ChatGPT) and Generative Pre-trained Transformer 4 (GPT-4) have demonstrated remarkable performance in the general domain. However, Inadaptability in a particular domain have led to hallucination for these LLMs when responding in specific domain contexts. The issue has attracted widespread attention, existing domain-centered fine-tuning efforts have predominantly focused on sectors like medical, financial, and legal, leaving critical areas such as power energy relatively unexplored. To bridge this gap, this paper introduces a novel power energy chat model called PowerPulse. Built upon the open and efficient foundation language models (LLaMA) architecture, PowerPulse is fine-tuned specifically on Chinese Power Sector Domain Knowledge. This work marks the inaugural application of the LLaMA model in the field of power energy. By leveraging pertinent pre-training data and instruction fine-tuning datasets tailored for the power energy domain, the PowerPulse model showcases exceptional performance in tasks such as text generation, summary extraction, and topic classification. Experimental results validate the efficacy of the PowerPulse model, making significant contributions to the advancement of specialized language models in specific domains.

Viral vectors for gene therapy, such as recombinant Adeno-Associated Viruses (rAAV), are produced in Human Embryonic Kidney (HEK) 293 cells. However, the presence of the SV40 T-antigen-encoding CDS SV40GP6 and SV40GP7 in the HEK293T genome raises safety issues when these cells are used in manufacturing for clinical purposes. We developed a new T-antigen-negative HEK cell line from ExcellGene’s proprietary HEKExpress®, using the CRISPR-Cas9 strategy. We obtained a high number of clonally-derived cell populations and all of them were demonstrated T-antigen negative. Stability study and AAV production evaluation showed that the deletion of the T-antigen-encoding locus did not impact neither cell growth nor viability nor productivity. The resulting CMC-compliant cell line, named HEKzeroT®, is able to produce high AAV titers, from small to large scale.

Cerebrovascular accident (CVA) is one of the commonest neurological deficits. There is a well-known association between COVID-19 and stroke. We present a case series of Sudanese patients who developed CVA after receiving the AstraZeneca COVID-19 vaccine suggesting a relationship between the vaccine and CVA.

Background: Desmoid tumor (DT) is rare and challenging, often affects head neck (HN) region in children, and its appropriate treatments are under discussed. This study aimed to retrospectively evaluate long-term effectiveness and safety of 125I seed brachytherapy for pediatric DT in HN. Procedure: Seven pediatric patients with median age of 3 years old suffered from DT in HN treated with 125I brachytherapy from January 2008 to June 2018 were included. Among which, 5 underwent sole brachytherapy and the others combined with surgery under a prescription doses ranging from 10 000 cGy to 12 000 cGy. The rate of local control (LC), complete response (CR) and partial response (PR) were calculated after evaluation by radiological and pathological means. The radiation-associated toxicities were also evaluated Results: The LC rate was 7/7 during the follow-up time ranging from 43 to 135 months and with a mean of 57 months. No recurrent lesion was found in the patients receiving surgery combined with brachytherapy. In patients treated with sole brachytherapy, the radiological PR rate and CR rate were 4/5 and 1/5, respectively. In those reaching radiological PR, 3/4 were pathological CR. Slight acute radiation-associated toxicities were observed in all patients, and no late or severe acute toxicity was observed. Conclusion: 125I brachytherapy is effective and safe in the management of pediatric DT in HN as sole modality or combined with surgery in long term.

Background: Initial clinical evaluation (ICE) is traditionally considered a useful screening tool to identify frail patients during the pre-operative assessment. However, emerging evidence supports the more objective assessment of cardiorespiratory fitness (CRF) via cardiopulmonary exercise testing (CPET) to improve surgical risk stratification. Herein, we compared both subjective and objective assessment approaches to highlight the interpretive idiosyncrasies. Methods: As part of routine pre-operative patient contact, patients scheduled for major surgery were prospectively ‘eyeballed’ (ICE) by two experienced clinicians prior to more detailed history taking that also included American Society of Anaesthesiologists score classification. Each patient was subjectively judged to be either ‘frail’ or ‘not frail’ by ICE and ‘fit’ or ‘unfit’ from thorough review of the medical notes. Subjective data were compared against the more objective validated assessment of post-operative outcomes using established CPET ‘cut-off’ metrics incorporating peak pulmonary oxygen uptake ( V̇O 2PEAK), V̇O 2 at the anaerobic threshold ( V̇O 2-AT) and ventilatory equivalent for carbon dioxide that collectively informed risk stratification. These data were retrospectively extracted from a single-centre prospective National Health Service database. Data were analysed using the Chi-square automatic interaction detection decision tree method. Results: A total of 127 patients examined that comprised 58 % male and 42 % female patients aged 69 ± 10 y with a BMI of 29 ± 7 kg/m 2. Patients were poorly conditioned with a peak pulmonary oxygen uptake almost 20 % lower than that predicted for age, sex-matched healthy controls with 35 % exhibiting a V̇O 2-AT <11 mL/kg/min. Disagreement existed between the subjective assessments of risk with ~34 % of patients classified not frail on ICE were considered unfit by notes review ( P < 0.0001). Furthermore, ~35 % of patients considered not frail on ICE and ~31 % of patients considered fit by notes review exhibited a V̇O 2-AT <11 mL/kg/min and of these, ~28 % and ~19 % were classified as intermediate-to-high risk. Conclusions: These findings highlight the interpretive limitations associated with the subjective assessment of patient frailty with surgical risk classification underestimated in up to a third of patients compared to the validated assessment of CRF. They reinforce the benefits of a more objective and integrated approach offered by CPET that may help improve perioperative risk assessment and better direct critical care provision in patients scheduled for ‘high-stakes’ surgery including open TAAA repair.

The rise of deepfakes and AI-generated images has raised concerns regarding their potential misuse in society. However, this commentary highlights the valuable opportunities these technologies offer for neuroscience research. Deepfakes provide accessible, realistic, and customisable dynamic face stimuli, while generative adversarial networks (GANs) can generate and modify diverse and high-quality static content. These advancements enhance the variability and ecological validity of research methods, and enable the creation of previously unattainable stimuli. When AI-generated images are informed by brain responses, they provide unique insights into the structure and function of visual systems. The authors encourage experimental psychologists and cognitive neuroscientists to stay informed about these emerging tools and embrace their potential to advance visual neuroscience.

Tropical forests are experiencing unprecedented high temperature conditions due to climate change that could limit their photosynthetic functions. We studied the high temperature sensitivity of photosynthesis in a rainforest site in southern Amazonia, where some of the highest temperatures and most rapid warming in the Tropics have been recorded. The quantum yield (Fv/Fm) of photosystem II was measured in seven dominant tree species using leaf discs exposed to varying levels of heat stress. T50 was calculated as the temperature at which Fv/Fm) was half the maximum value. T5 is defined as the breakpoint temperature, at which Fv/Fm) decline was initiated. Leaf thermotolerance in the rapidly warming Southern Amazonia was the highest recorded for forest tree species globally. T50 and T5 varied between species, with one mid storey species, Amaioua guianensis, exhibiting particularly high T50 and T5 values. While the T50 values of the species sampled were several degrees above the maximum air temperatures experienced in southern Amazonia, the T5 values of several species are now exceeded under present-day maximum air temperatures.

Benzoic acid is one of the most commonly used food preservatives, but currently exclusively produced in petrochemical processes. In this study, we describe a bio-based production pathway using an engineered strain of Pseudomonas taiwanensis. In a phenylalanine-overproducing strain, we heterologously expressed bacterial, yeast, and plant genes to achieve production of benzoate via a β-oxidation pathway. Strategic disruption of the native Pseudomonas benzoate degradation pathway further allowed the production of catechol and cis,cis-muconate. Taken together, this work demonstrates new routes for the microbial production of these industrially relevant chemicals from renewable resources.

Solving the world’s health challenges requires multidisciplinary collaborations that bring together the talents, experiences, resources, and ideas from multiple sectors in low and middle-income countries (LMIC) and high -income countries (HIC). Cystic Fibrosis (CF) was thought to be a disease of Caucasian populations from European decent. However, it has been shown to affect people from all ethnic backgrounds. CF care varies significantly for people with CF (pw CF) from HIC with median survival approaching 50 years of age, to LMIC with pw CF dying in infancy or early childhood. To address the discrepancy in quality of care and outcomes, we report on a collaboration between our team at the University of Michigan cystic fibrosis center (UoM CFC), through support from the Middle East CF Association (MECFA) and the CF Foundation (CFF), and a CF center in Turkey (Marmara University CF Center, Istanbul) to address deficiencies and improve quality of care in that center. The collaboration has been successful in improving Ma CFC data and patient care. This partnership can be viewed as a model of collaboration to be duplicated in other Middle East Countries and LMIC to deliver optimal CF care.

Schizophrenia remains a sizable socioeconomic burden that continues to be treated with therapeutics based on 70-year old science. All currently approved therapeutics primarily target the dopamine D2 receptor to achieve their efficacy. Whilst dopaminergic dysregulation is a key feature in this disorder, the targeting of dopaminergic machinery has yielded limited efficacy and an appreciable side effect burden. Over the recent decades, numerous drugs that engage non-dopaminergic GPCRs have yielded a promise of efficacy without the deleterious side effect profile, yet none have successfully completed clinical studies and progressed to the market. More recently, there has been increased attention around non-dopaminergic GPCR-targeting drugs, notably KarXT, which demonstrated efficacy in some schizophrenia symptom domains. This provides renewed hope that effective schizophrenia may lay outside of the dopaminergic space. Despite the potential for muscarinic receptor- (and other well-characterised GPCR families) targeting drugs to treat schizophrenia, they are often plagued with complications such as lack of receptor subtype selectivity and peripheral on-target side-effects. Orphan GPCR studies have opened a new avenue of exploration with many demonstrating schizophrenia-relevant mechanisms and a favourable expression profile, thus offering potential for novel drug development. This review discusses centrally-expressed orphan G protein-coupled receptors: GPR3, GPR6, GPR12, GPR52, GPR85, GPR88 and GPR139 and their relationship to schizophrenia. We review their expression, signalling mechanisms and cellular function, in conjunction with small molecule development and structural insights. We seek to provide a snapshot of the growing evidence and development potential of new classes of schizophrenia therapeutics.