Search

Aim: We investigated how to use Internet user searches to gauge the impact of a celebrity illness on global public interest. Methods: The study design is cross-sectional. Data on Internet searches were obtained from Google Trends (GT) for the period between 2017–2022 using the search words “Ramsay Hunt syndrome” (RHS), “Ramsay Hunt syndrome type 2,” “Herpes zoster,” and “Justin Bieber.” The frequency of specific page views for “Ramsay Hunt syndrome,” “Ramsay Hunt syndrome type 1,” Ramsay Hunt syndrome type 2,” Ramsay Hunt syndrome type 3,” “Herpes zoster,” and “Justin Bieber” were collected via a Wikipedia analysis tool that shows the number of times a specific page is viewed. Statistical analyses were performed using the Pearson (r) and Spearman’s rank correlation coefficient (rho). Results: GT data, in 2022, show a strong correlation for Justin Bieber and RHS or RHS type 2 (r = 0.75); similarly, Wikipedia data show a strong correlation for Justin Bieber and the others explored terms (r > 0.75). Furthermore, the correlation was strong between GT and Wikipedia for RHS (rho = 0.89) and RHS type 2 (rho = 0.88). Conclusions: The peak search times for the GT and Wikipedia pages were during the same period. Useful new tools and analyses of Internet traffic data may be effective in assessing the impact of announced celebrity uncommon illnesses on global public interest.

In the last 3 decades, laparoscopic Heller myotomy (LHM) has represented the treatment of choice for esophageal achalasia, solving symptoms in most patients. Little is known about the fate of patients relapsing after LHM or their treatment. In this study, we aimed at evaluating the results of complementary pneumatic dilations (CPDs) after ineffective LHM.

This study aimed to evaluate epilepsy outcome and antiseizure medication (ASM) discontinuation after lesionectomies as first surgical approach in pediatric population diagnosed with low‐grade epilepsy‐associated neuroepithelial tumors (LEATs). We conducted a retrospective study. Thirty‐six consecutive patients with histological diagnoses of LEATs who underwent surgery between 2018 and 2021 at our institution were included. The clinical and surgical data were retrospectively analyzed. Thirty (83.3%) of 36 patients are free of disabling seizures (Engel class I) and 19 (63,4%) of them are classified as Engel Ia. In 17 (47.2%) patients, ASM could be discontinued. The mean age at surgery was 8.6 years (±4.04) and the mean age at onset of epilepsy was 7.2 years (±3.8), whereas the mean duration of epilepsy in months at the time of surgery was 21.3 months (±23.7). The epileptogenic tumor was in the temporal lobe in 20 (55.5%) patients. Because of seizure persistence, a second or a third surgery was necessary for six patients (16.7%) and four of them had residual lesions (three in temporal and one in extratemporal site). No perioperative complications were recorded, including acute seizures, with a median hospitalization time of 7 days. Shorter epilepsy duration at time of surgery as long as a single ASM was significantly correlated with an Engel class I outcome (p‐value = .01 and p‐value = .016, respectively). Focal seizure semeiology was associated with an increased probability of antiseizure medication discontinuation (p‐value = .042). Our findings confirm that shorter epilepsy disease duration, monotherapy before surgery, and seizure semeiology are determinant factors for a positive seizure outcome and medication discontinuation, also with less invasive surgical approaches such as lesionectomies. However, considering the intrinsic multifactorial epileptogenic nature of LEATs, a tailored surgical approach should be considered to optimize clinical and seizure outcome, especially for lesions located in the temporal lobe.

The pathophysiological and clinical value of performing High‐Resolution Manometry (HRM) after laparoscopic fundoplication (LF) for gastroesophageal reflux disease (GERD) is still unclear and debated. We sought to establish the HRM parameters indicative of functioning fundoplications, and whether HRM could distinguish them from tight or defective ones. The study involved patients with GERD who underwent laparoscopic Nissen (LN) or Toupet (LT) fundoplication between 2010 and 2022. HRM and 24‐h pH monitoring were performed before and 6 months after surgery. The study population was divided into 5 groups: LN and LT patients with normal 24h‐pH findings (LNpH‐ and LTpH‐, respectively); LN and LT patients with pathological 24h‐pH findings (LNpH+ and LTpH + groups, respectively); and patients with a postoperative dysphagia intensity score >2 (Dysphagia group). The novel Hiatal Morphology (HM) classification was applied, envisaging 3 different subtypes: HM1 (normal), HM2 (intrathoracic fundoplication), and HM3 (slipped fundoplication). Among the 132 patients recruited during the study period, 46 were in the LNpH‐ group, 51 in the LTpH‐ group, 15 in the LNpH + group, 7 in the LTpH + group, and 5 in the Dysphagia group. In multivariate analysis, postoperative abdominal lower esophageal sphincter length (p= 0.001) and HM2 (p< 0.001) were both independently associated with surgical failure. Integrated relaxation pressure was significantly higher in the Dysphagia group than in the LNpH‐ group. This study generated reference HRM values for an effective LF, and confirms that using HRM to assess the neo‐sphincter and HM improves the clinical assessment in cases of symptom recurrence.

ABSTRACTBackgroundContagious exanthematous diseases are becoming a major public health problem. The purpose of this study was to evaluate the potential epidemiological trend of four infectious exanthematous diseases in Italy through the searches on the internet.MethodsWe used the following Italian search term: ‘Sesta malattia’ (Sixth Disease, in English), ‘Eritema Infettivo’ (also knows ‘Quinta malattia’ in Italian; Fifth Disease in English), ‘Quarta malattia’ (Fourth Disease in English) and ‘Scarlattina’ (Scarlet fever in English). We overlapped Google Trends and Wikipedia data to perform a linear regression and correlation analysis. Statistical analyses were performed using the Spearman’s rank correlation coefficient (rho). The study period is between July 2015 and December 2022ResultsThe diseases considered have a seasonal trend and the search peaks between GT and Wikipedia overlap. A temporal correlation was observed between GT and Wikipedia search trends. Google Trends Internet search data showed strong correlation with Wikipedia with a rho statistically significant for Fifth disease (rho = 0.78), Fourth disease (rho = 0.76) and Scarlet-fever (rho = 0.77), moderate correlation for Sixth disease (rho = 0.32).ConclusionsInfectious disease searches using Google and Wikipedia can be useful for public health surveillance and help policy makers implement prevention and information programs for the population, in addition to the fact that increases in searches could represent an early warning in the detection of outbreaks.

Study Design : Retrospective Chart Review.Objectives Incidental durotomies (IDs) are common spine surgery complications. In this study, we present a review on the most commonly utilized management strategies, report our institutional experience with case examples, and describe a stepwise management algorithm.Methods A retrospective review was performed of the electronic medical records of all patients who underwent a thoracolumbar or lumbar spine surgery between March 2017 and September 2019. Additionally, a literature review of the current management approaches to treat IDs and persistent postoperative CSF leaks following lumbar spine surgeries was performed.Results We looked at 1133 patients that underwent posterior thoracolumbar spine surgery. There was intraoperative evidence of ID in 116 cases. Based on our cohort and the current literature, we developed a progressive treatment algorithm for IDs that begins with a primary repair, which can be bolstered by dural sealants or a muscle patch. If this fails, the primary repair can be followed by a paraspinal muscle flap, as well as a lumbar drain. If the patient cannot be weaned from temporary CSF diversion, the final step in controlling postoperative leak is longterm CSF diversion via a lumboperitoneal shunt. In our experience, these shunts can be weaned once the patient has no further clinical or radiographic signs of CSF leak.Conclusions There is no standardized management approach of IDs and CSF leaks in the literature. This article intends to provide a progressive treatment algorithm and contribute to the development process of a treatment consensus.

Children with cochlear implants (CIs) exhibit large individual differences in vocabulary outcomes. We hypothesized that understudied sources of variance are amount of music engagement and exposure and maternal musicality. Additionally, we explored whether objective measures of music exposure captured from the CI data logs and parent reports about music engagement provide converging and/or complementary evidence, and whether these correlate with maternal musicality. Sixteen children with CIs (Mage = 16.7 months, SD = 7.7, range = 9.6–32.9) were tested before implantation and three, six, and 12 months post-CI activation. Music exposure throughout the first year post-activation was extracted from the CI data logs. Children’s vocabulary and home music engagement and maternal musicality were assessed using parent reports. Analyses revealed relatively low home music engagement and maternal musicality. Nonetheless, positive effects emerged for music exposure on children’s early receptive and expressive vocabulary and for maternal musicality on expressive vocabulary three months post-activation. Results underline the importance of combining automatic measures and parent reports to understand children’s acoustic environment and suggest that environmental music factors may affect early vocabulary acquisition in children with CIs. The presence of these effects despite poor music exposure and skills further motivates the involvement of children with CIs and their parents in music intervention programs.

IMPORTANCE: Current reports suggest that the surgeon-scientist phenotype is significantly threatened. However, a significant increase in the proportion of surgeons in the workforce funded by the National Institutes of Health (NIH) from 2010 (0.5%) to 2020 (0.7%) was recently reported and showed that surgeons primarily performed basic science research (78% in 2010; 73% in 2020) rather than clinical research. OBJECTIVE: To provide an update on the status of surgeons funded by the NIH for fiscal year (FY) 2022. EVIDENCE REVIEW: NIH-funded surgeons were identified in FY2012 and FY2022, including those who were awarded grants with more than 1 principal investigator (PI) by querying the internal database at the NIH. The main outcome for this study was the total number of NIH-funded surgeons in FY2012 and FY2022, including total grant costs and number of grants. The secondary analysis included self-reported demographic characteristics of the surgeons in FY2022. The research type (basic science vs clinical) of R01 grants was also examined. FINDINGS: Including multiple PI grants, 1324 surgeon-scientists were awarded $1.3 billion in FY2022. Women surgeons increased to 31.3% (339 of 1084) of the population of surgeon PIs in FY2022 compared with 21.0% (184 of 876) in FY2012. Among surgeon PIs awarded grants, a total of 200 (22.8%) were Asian, 35 (4.0%) were Black or African American, 18 (2.1%) were another race (including American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and more than 1 race), and 623 (71.1%) were White. A total of 513 of 689 R01 grants (74.5%) were for basic science, 131 (19.0%) were for clinical trials, and 45 (6.5%) were for outcomes research. CONCLUSIONS AND RELEVANCE: NIH-funded surgeons are increasing in number and grant costs, including the proportion of women surgeon PIs, and are representative of the diversity among US academic surgical faculty. The results of this study suggest that despite the many obstacles surgeon-scientists face, their research portfolio continues to grow, they perform a myriad of mostly basic scientific research as both independent PIs and on multidisciplinary teams.

Purpose: Information on the general health of transgender and gender diverse (TGD) individuals continues to be lacking. To bridge this gap, the National Institute of Health in Italy together with the National Office against Racial Discriminations, clinical centres, and TGD organizations carried out a cross-sectional study to define the sociodemographic profile, health-related behaviours, and experiences of healthcare access in Italian TGD adult population. Methods: A national survey was conducted by Computer-Assisted Web Interviewing (CAWI) technique. Collected data were compared within the TGD subgroups and between TGD people and the Italian general population (IGP). Results: TGD respondents were 959: 65% assigned female at birth (AFAB) and 35% assigned male at birth (AMAB). 91.8% and 8.2% were binary and non-binary TGD respondents, respectively. More than 20% of the TGD population reported to be unemployed with the highest rate detectable in AMAB and non-binary people. Cigarette smoking and binge drinking were higher in the TGD population compared with IGP (p&lt; 0.05), affecting TGD subgroups differently. A significant lower percentage of AFAB TGD people reported having had screening for cervical and breast cancer in comparison with AFAB IGP (p&lt; 0.0001, in both cases). Over 40% was the percentage of AFAB and non-binary TGD people accessing healthcare who felt discriminated against because of their gender identity. Conclusions: Our results are a first step towards a better understanding of the health needs of TGD people in Italy in order to plan the best policy choices for a more inclusive public health.

Age-related osteoarthritis (OA) is a degenerative joint disease characterized by pathological changes in nearly every intra- and peri-articular tissue that contributes to disability in older adults. Studying the etiology of age-related OA in humans is difficult due to an unpredictable onset and insidious nature. A barrier in developing OA modifying therapies is the lack of translational models that replicate human joint anatomy and age-related OA progression. The purpose of this study was to determine whether the common marmoset is a faithful model of human age-related knee OA. Semi-quantitative microCT scoring revealed greater radiographic OA in geriatric versus adult marmosets, and the age-related increase in OA prevalence was similar between marmosets and humans. Quantitative assessments indicate greater medial tibial cortical and trabecular bone thickness and heterogeneity in geriatric versus adult marmosets which is consistent with an age-related increase in focal subchondral bone sclerosis. Additionally, marmosets displayed an age-associated increase in synovitis and calcification of the meniscus and patella. Histological OA pathology in the medial tibial plateau was greater in geriatric versus adult marmosets driven by articular cartilage damage, proteoglycan loss, and altered chondrocyte cellularity. The age-associated increase in medial tibial cartilage OA pathology and meniscal calcification was greater in female versus male geriatric marmosets. Overall, marmosets largely replicate human OA as evident by similar 1) cartilage and skeletal morphology, 2) age-related progression in OA pathology, and 3) sex differences in OA pathology with increasing age. Collectively, these data suggest that the common marmoset is a highly translatable model of the naturally occurring, age-related OA seen in humans.

Background: Differences in acute COVID-19 associated morbidity based on race, ethnicity, and gender have been well described; however, less is known about differences in subsequent longer term health-related quality of life and well-being. Methods: This prospective cohort study included symptomatic adults tested for SARS-CoV-2 who completed baseline and 3-month follow-up surveys. Using the PROMIS-29 tool, a validated measure of health and well-being, we compared outcomes at 3 months and change in outcomes from baseline to 3 months among groups with different races, ethnicities, and/or sexes. Results: Among 6044 participants, 4113 (3202 COVID +) were included. Among COVID + participants, compared to non-Hispanic White participants, Black participants had better PROMIS T-scores for cognitive function (3.6 [1.1, 6.2]) and fatigue (− 4.3 [− 6.6, − 2.0]) at 3 months and experienced more improvement in fatigue over 3 months (− 2.7 [− 4.7, − 0.8]). At 3 months, compared with males, females had worse PROMIS T-scores for cognitive function (− 4.1 [− 5.6, − 2.6]), physical function (− 2.1 [− 3.1, − 1.0]), social participation (− 2.8 [− 4.2, − 1.5]), anxiety (2.8 [1.5, 4.1]), fatigue (5.1 [3.7, 6.4]), and pain interference (2.0 [0.9, 3.2]). Females experienced less improvement in fatigue over 3 months (3.1 [2.0, 4.3]). Transgender/non-binary/other gender participants had worse 3-month scores in all domains except for sleep disturbance and pain interference. Conclusions: Three months after the initial COVID-19 infection, Black participants reported better cognitive function and fatigue, while females and other gender minoritized groups experienced lower well-being. Future studies are necessary to better understand how and why social constructs, specifically race, ethnicity, and gender, influence differences in COVID-19-related health outcomes.

Background: Hepatic resection combined with intraoperative ablation has been described as a technical solution potentially widening the resectability rate of patients with colorectal liver metastases (CRLM). Nevertheless, the perioperative and oncological benefit provided by this combined approach remains unclear. We hypothesized that textbook outcome (TO), which is a composite measure achieved for patients for whom some desired health indicators are met, may help to refine the indications of this approach. Methods: Patients submitted to hepatectomy with curative intent in combination with radiofrequency ablation or microwave ablation for CRLM ≤ 3 cm in two tertiary referral centers were included. TO was defined according to a recent definition for liver surgery based on a Delphi process including also the achievement of complete radiological response of the ablated lesion/s at 4 weeks. Results: Between 2015 and 2022, 112 patients were enrolled. Among them, 63 (56.2%) achieved a TO. According to multivariate analysis, minimally invasive (MI) approach (OR 2.72, 95% CI 0.99–7.48, p= 0.050), simultaneous CR resection (OR 0.28, 95% CI 0.11–0.70, p= 0.007), tumor burden score (OR 0.89, 95% CI 0.82–0.96, p= 0.004), and major hepatectomy (OR 0.12, 95% CI 0.03–0.52, p= 0.004) were significantly associated with the achievement of TO. Median overall survival was longer in those patients who were able to achieve a TO compared to those who did not. Conclusions: The combination of hepatectomy and ablation constitutes a valuable solution in patients affected by multiple CRLM and it may provide, also using a MI approach, adequate perioperative and oncological outcomes, allowing to achieve TO, however, in a selected number of patients and depending on several factors including the burden of disease.

Leucettinibs are substituted 2-aminoimidazolin-4-ones (inspired by the marine sponge natural product Leucettamine B) developed as pharmacological inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-regulated kinase 1A), a therapeutic target for indications such as Down syndrome and Alzheimer’s disease. Leucettinib-21 was selected as a drug candidate following extensive structure/activity studies and multiparametric evaluations. We here report its physicochemical properties (X-ray powder diffraction, differential scanning calorimetry, stability, solubility, crystal structure) and drug-like profile. Leucettinib-21’s selectivity (analyzed by radiometric, fluorescence, interaction, thermal shift, residence time assays) reveals DYRK1A as the first target but also some “off-targets” which may contribute to the drug’s biological effects. Leucettinib-21 was cocrystallized with CLK1 and modeled in the DYRK1A structure. Leucettinib-21 inhibits DYRK1A in cells (demonstrated by direct catalytic activity and phosphorylation levels of Thr286-cyclin D1 or Thr212-Tau). Leucettinib-21 corrects memory disorders in the Down syndrome mouse model Ts65Dn and is now entering safety/tolerance phase 1 clinical trials.

Sodium-ion batteries have recently aroused the interest of industries as possible replacements for lithium-ion batteries in some areas. With their high theoretical capacities and competitive prices, P2-type layered oxides (NaxTMO2) are among the obvious choices in terms of cathode materials. On the other hand, many of these materials are unstable in air due to their reactivity toward water and carbon dioxide. Here, Na0.67Mn0.9Ni0.1O2(NMNO), one of such materials, has been synthesized by a classic sol–gel method and then exposed to air for several weeks as a way to allow a simple and reproducible transition toward a Na-rich birnessite phase. The transition between the anhydrous P2 to the hydrated birnessite structure has been followed via periodic XRD analyses, as well as neutron diffraction ones. Extensive electrochemical characterizations of both pristine NMNO and the air-exposed one vs sodium in organic medium showed comparable performances, with capacities fading from 140 to 60 mAh g–1in around 100 cycles. Structural evolution of the air-exposed NMNO has been investigated both with ex situ synchrotron XRD and Raman. Finally, DFT analyses showed similar charge compensation mechanisms between P2 and birnessite phases, providing a reason for the similarities between the electrochemical properties of both materials.

AbstractWhen a bullet strikes a surface such as a drywall panel, it may perforate the material leaving a hole in the surface or it may ricochet. When multiple bullet impacts exist, for example through a wall section, the probing method allows for the trajectory of a projectile to be reconstructed. Past studies have shown that low angle impacts are subject to error when applying the probing method. Hence, this study used the probing method to examine bullet impacts in wall sections made of drywall to determine the accuracy of the angle of incidence with respect to a known firing position. To control the angle of incidence, drywall panels were positioned at different angles beginning at 90° and decreasing until the panels were at 10°. The measured angle of incidence was compared to the known angle of incidence to determine the accuracy/error. The study observed how .40 S&W caliber ammunition from four different manufacturers, interacted with drywall panels. For each ammunition type and known angle there were three replicates, for a total of 84 impacts (n = 84). It was observed that as the angle of incidence decreased, the error of the measured value increased. Measurements from panel positions at higher angles (between 60°–90°) were more accurate and precise than measurements from panels positioned at lower angles of incidence (10°–45°). The data collected in this study provides insight into the probing method and how the accuracy of measurements can be impacted while the angle of incidence decreases.

Background: This study aimed at: (1) assessing, in an Italian cohort of non-demented Parkinson’s disease (PD) patients, the construct validity of the Montreal Cognitive Assessment (MoCA) against both first- and second-level cognitive measures; (2) delivering an exhaustive and updated evaluation of its diagnostic properties. Methods: A retrospective cohort of N= 237 non-demented PD patients having been administered the MoCA was addressed, of whom N= 169 further underwent the Mini-Mental State Examination (MMSE) and N= 68 the Parkinson’s Disease Cognitive Rating Scale (PD-CRS). A subsample (N= 60) also underwent a second-level cognitive battery encompassing measures of attention/executive functioning, language, memory, praxis and visuo-spatial abilities. Construct validity was assessed against both the PD-CRS and the second-level cognitive battery. Diagnostics were tested via receiver-operating characteristics analyses against a below-cut-off MMSE score. Results: The MoCA was associated with both PD-CRS scores (p&lt; .001) and the vast majority of second-level cognitive measures (ps &lt; .003). Both raw and adjusted MoCA scores proved to be highly accurate to the aim of identifying patients with MMSE-confirmed cognitive dysfunctions. A MoCA score adjusted for age and education according to the most recent normative dataset and &lt; 19.015 is herewith suggested as indexing cognitive impairment in this population (AUC = .92; sensitivity = .92; specificity = .80). Discussion: The Italian MoCA is a valid and diagnostically sound screener for global cognitive inefficiency in non-demented PD patients. Further studies are nevertheless needed that confirm its diagnostic values against a measure other than the MMSE.

As public agencies and research institutions increasingly pursue involving stakeholders in making decisions, scholars and practitioners are calling for a more rigorous empirical understanding of engagement processes and their outcomes. However, effective research methodologies for stakeholder engagement research are limited due to the complex challenge of both linking engagement contexts, processes, and outcomes and conducting research in ways that meet both practical and scholarly goals. This paper outlines a method for studying stakeholder engagement contexts, processes, and outcomes in water resource management settings developed through stakeholder engagement efforts in five US project sites. In response to methodological needs identified in diverse scholarship on participatory approaches to water resource management, we describe a longitudinal, mixed-methods, case comparison, and participatory research design, for gathering evidence for social, behavioral, and environmental change outcomes while simultaneously supporting engagement processes. This paper describes the research design and data collection procedures we developed to study change through engagement. This design was intended to allow in-depth analysis of place-specific engagement processes and outcomes, as well as the ability to compare across contexts to illuminate drivers of differences. We present this research design as a framework for others considering similar approaches and conclude by discussing benefits and limitations of the research design and tensions across research onand withstakeholder participants.

Stereochemistry can alter small-molecule pharmacokinetics, safety and efficacy. However, it is unclear whether the stereochemistry of a single compound within a multicomponent colloid such as a lipid nanoparticle (LNP) can influence its activity in vivo. Here we report that LNPs containing stereopure 20α-hydroxycholesterol (20α) delivered mRNA to liver cells up to 3-fold more potently than LNPs containing a mixture of both 20α- and 20β-hydroxycholesterols (20mix). This effect was not driven by LNP physiochemical traits. Instead, in vivo single-cell RNA sequencing and imaging revealed that 20mix LNPs were sorted into phagocytic pathways more than 20α LNPs, resulting in key differences between LNP biodistribution and subsequent LNP functional delivery. These data are consistent with the fact that nanoparticle biodistribution is necessary, but not sufficient, for mRNA delivery, and that stereochemistry-dependent interactions between LNPs and target cells can improve mRNA delivery.

Messenger RNA has now been used to vaccinate millions of people. However, the diversity of pulmonary pathologies, including infections, genetic disorders, asthma and others, reveals the lung as an important organ to directly target for future RNA therapeutics and preventatives. Here we report the screening of 166 polymeric nanoparticle formulations for functional delivery to the lungs, obtained from a combinatorial synthesis approach combined with a low-dead-volume nose-only inhalation system for mice. We identify P76, a poly-β-amino-thio-ester polymer, that exhibits increased expression over formulations lacking the thiol component, delivery to different animal species with varying RNA cargos and low toxicity. P76 allows for dose sparing when delivering an mRNA-expressed Cas13a-mediated treatment in a SARS-CoV-2 challenge model, resulting in similar efficacy to a 20-fold higher dose of a neutralizing antibody. Overall, the combinatorial synthesis approach allowed for the discovery of promising polymeric formulations for future RNA pharmaceutical development for the lungs.

Lipid nanoparticles (LNPs) have delivered RNA to hepatocytes in patients, underscoring the potential impact of nonliver delivery. Scientists can shift LNP tropism to the lung by adding cationic helper lipids; however, the biological response to these LNPs remains understudied. To evaluate the hypothesis that charged LNPs lead to differential cellular responses, we quantified how 137 LNPs delivered mRNA to 19 cell types in vivo. Consistent with previous studies, we observed helper lipid-dependent tropism. After identifying and individually characterizing three LNPs that targeted different tissues, we studied the in vivotranscriptomic response to these using single-cell RNA sequencing. Out of 835 potential pathways, 27 were upregulated in the lung, and of these 27, 19 were related to either RNA or protein metabolism. These data suggest that endogenous cellular RNA and protein machinery affects mRNA delivery to the lung in vivo.

ABSTRACTThe article contributes to the debate that links student geographies with urban change. It has been argued that students reshape urban geographies through the creation of distinctive “student areas.” However, the literature has often done so focusing on one specific component (e.g. accommodation or leisure) and one specific city or neighborhood. Therefore, we aim to nuance the debate over student geographies in cities. To this end, we use the “studentscapes” framework and propose a concurrent examination of students’ educational, residential, and leisure activities distributed in the urban space of Lodz, Poland, and Turin, Italy. We show that the presence of higher education students plays a role in the multifaceted and dynamic restructuring of Lodz and Turin as they transition from industrial to post-industrial economies. We also claim that the dichotomous distinction between “student” and “non-student” neighborhoods might miss the wide range of configurations of students’ activities in urban settings.

Background: Ectopic cell cycle reactivation in neurons is associated with neuronal death in Alzheimer’s disease. In cultured rodent neurons, synthetic β-amyloid (Aβ) reproduces the neuronal cell cycle re-entry observed in the Alzheimer’s brain, and blockade of the cycle prevents Aβ-induced neurodegeneration. DNA polymerase-β, whose expression is induced by Aβ, is responsible for the DNA replication process that ultimately leads to neuronal death, but the molecular mechanism(s) linking DNA replication to neuronal apoptosis are presently unknown. Aim: To explore the role of a conserved checkpoint pathway started by DNA replication stress, namely the ATM-ATR/Claspin/Chk-1 pathway, in switching the neuronal response from DNA replication to apoptosis. Methods: Experiments were carried out in cultured rat cortical neurons challenged with toxic oligomers of Aβ protein. Results: Small inhibitory molecules of ATM/ATR kinase or Chk-1 amplified Aβ-induced neuronal DNA replication and apoptosis, as they were permissive to the DNA polymerase-β activity triggered by Aβ oligomers. Claspin, i.e., the adaptor protein between ATM/ATR kinase and the downstream Chk-1, was present on DNA replication forks of neurons early after Aβ challenge, and decreased at times coinciding with neuronal apoptosis. The caspase-3/7 inhibitor I maintained overtime the amount of Claspin loaded on DNA replication forks and, concomitantly, reduced neuronal apoptosis by holding neurons in the S phase. Moreover, a short phosphopeptide mimicking the Chk-1-binding motif of Claspin was able to prevent Aβ-challenged neurons from entering apoptosis. Conclusion: We speculate that, in the Alzheimer’s brain, Claspin degradation by intervening factors may precipitate the death of neurons engaged into DNA replication.

Aortic stenosis (AS) is the most prevalent valvular heart disease in developed countries, associated with reduced survival if severe AS remains untreated. Recent reports note unfavorable outcomes in moderate AS (mAS) patients, challenging optimal intervention timing. Variations in pathophysiology linked to sex differences, involving sex hormones, activation of the renin–angiotensin–aldosterone system, and dysregulation in collagen synthesis, have been observed. Yet, limited data exists on sex–specific differences in mAS outcomes. This single–center, retrospective study included 150 patients (median age 79±13 years, female sex 48%) diagnosed with mAS who underwent comprehensive echocardiography in IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico of Milan from July 2022 to October 2023. Clinical data, encompassing demographics details and therapy, were obtained via record reviews and phone interviews. Death verification relied on the ‘Sistema Informativo Socio–Sanitario Regione Lombardia’ database. Echocardiographic records were digitally stored and post–processed by four independent investigators using Medimatic ComPACS workstation. Men were significantly younger than women (75±10 vs 79±9.7 years, p= 0.016). They exhibited lower left ventricular (LV) ejection fraction, larger LV end–systolic volume and stroke volume compared to women (54±7 vs 59±10%; p=0.028. 55±36 vs 31±13 ml; p<0.001. 83±18 vs 75±18 ml; p=0.030). Men had significantly smaller aortic valve (AV) area index to body surface area (BSA) (0.6±0.09 vs 0.7±0.1 cmq/mq; p<0.001) and lower doppler velocity index (0.32±0.07 vs 0.38±0.11; p<0.001) than women. Coronary artery disease and smoking were more frequent in men (53.3 vs 46.7%; p=0,002. 52.6 vs 47.4%; p<0.001). In survival analysis, 15% of women and 30.8% of men experienced events, with male gender independently associated with the composite outcome (all–cause mortality and AV replacement) over a mean follow–up time of 200 ± 133 days, showing a median survival of 244±16 vs 255±15 days for females (p–value=0.025). In multivariable analysis including relevant clinical variables (hemoglobin and AV index to BSA), male sex remained independently associated with the composite outcome (hazard ratio 2,01; CI 1.0–4.17; p=0.05). Women diagnosed with mAS exhibited a lower incidence of AV replacement and all–cause mortality. These findings may suggest the existence of different clinical and echocardiographic phenotypes among patients with AS.

Poly(ethylene glycol) (PEG)–lipids are used in Food‐and‐Drug‐Administration‐approved lipid nanoparticle (LNP)–RNA drugs, which are safe and effective. However, it is reported that PEG–lipids may also contribute to accelerated blood clearance and rare cases of hypersensitivity; this highlights the utility of exploring PEG–lipid alternatives. Here, it is shown that LNPs containing poly(2‐ethyl‐2‐oxazoline) (PEOZ)–lipids can deliver messenger RNA (mRNA) to multiple cell types in mice inside and outside the liver. In addition, it is reported that LNPs formulated with PEOZ–lipids show reduced clearance from the bloodstream and lower levels of antistealth lipid immunoglobulin Ms than LNPs formulated with PEG–lipids. These data justify further exploration of PEOZ–lipids as alternatives to PEG–lipids in LNP–RNA formulations. Poly(ethylene glycol) (PEG) lipids are used in clinical lipid nanoparticles (LNPs), but are linked to adverse immune reactions. By substituting PEG in LNPs with poly(2‐ethyl‐2‐oxazoline), it is shown that messenger RNA (mRNA) can be delivered to multiple cell types in mice with less drug clearance after multiple doses.

Populations of Blattella germanica(L.) (German cockroach) have been documented worldwide to be resistant to a wide variety of insecticides with multiple modes of action. The phenylpyrazole insecticide fipronil has been used extensively to control German cockroach populations, exclusively in baits, yet the highest reported fipronil resistance is 38-fold in a single population. We evaluated five populations of German cockroaches, collected in 2018–2019 in apartments in North Carolina and assayed in 2019, to determine the status of fipronil resistance in the state. Resistance ratios in field-collected strains ranged from 22.4 to 37.2, indicating little change in fipronil resistance over the past 20 yr. In contrast, resistance to pyrethroids continues to escalate. We also assessed the roles of detoxification enzymes in fipronil resistance with four synergists previously shown to diminish metabolic resistance to various insecticides in German cockroaches—piperonyl butoxide, S,S,S-tributyl phosphorotrithioate, diethyl maleate, and triphenyl phosphate. These enzymes appear to play a variable role in fipronil resistance. We also sequenced a fragment of the Rdl(resistant to dieldrin) gene that encodes a subunit of the GABA receptor. Our findings showed that all field-collected strains are homozygous for a mutation that substitutes serine for an alanine (A302S) in Rdl, and confers low resistance to fipronil. Understanding why cockroaches rapidly evolve high levels of resistance to some insecticides and not others, despite intensive selection pressure, will contribute to more efficacious pest management.

Cells that were previously described as homogeneous are composed of subsets with distinct transcriptional states. However, it remains unclear whether this cell heterogeneity influences the efficiency with which lipid nanoparticles (LNPs) deliver messenger RNA therapies in vivo. To test the hypothesis that cell heterogeneity influences LNP-mediated mRNA delivery, we report here a new multiomic nanoparticle delivery system called single-cell nanoparticle targeting-sequencing (SENT-seq). SENT-seq quantifies how dozens of LNPs deliver DNA barcodes and mRNA into cells, the subsequent protein production and the transcriptome, with single-cell resolution. Using SENT-seq, we have identified cell subtypes that exhibit particularly high or low LNP uptake as well as genes associated with those subtypes. The data suggest that cell subsets have distinct responses to LNPs that may affect mRNA therapies.

The thermal degradation (pyrolysis) of renewable biomass (as crop residues or energy crops) into a carbon-rich byproduct has been proposed as a practice to fight soil degradation and to foster the mitigation of climate change. The pyrolysis conditions and the characteristics of the feedstock influence the quality of the biochar. The present study used a pilot updraft reactor to make a pyrogasification of the biomass of giant reed (Arundo donaxL.). The temperature varied in the range 300–400 °C and the process lasted 60–90 min, conditions specific to slow pyrolysis. The work aimed to compare three airflow rates (0.001 m3s−1, 0.0007 m3s−1, and natural ventilation) and the Arundobiomass collected in winter (February) or summer (June), on the base of known harvesting time. The biochar yield was comparable between February (19.8%) and June (21.8%) but the biochar composition in terms of CHNSO was depending on the airflow rate. The values of the molar ratios indicated that the biochar produced with Arundocollected in winter (February) in presence of the air (0.001 and 0.0007 m3s−1) may have the highest level of aromaticity (H/C ratio), hydrophilicity, and polarity. Germination test on lettuce seeds showed different results: the winter biochar produced at 0.0007 m3s−1gave germination comparable to the control up to a concentration in the substrate up to 2% in weight; the summer biochar reduced the growth of the seedlings already at 0.5% when produced under natural ventilation.

Amyotrophic lateral sclerosis (ALS) is known to represent a collection of overlapping syndromes. Various classification systems based on empirical observations have been proposed, but it is unclear to what extent they reflect ALS population substructures. We aimed to use machine-learning techniques to identify the number and nature of ALS subtypes to obtain a better understanding of this heterogeneity, enhance our understanding of the disease, and improve clinical care.

The aim of this study is to identify likely pathogenic (LP) and pathogenic (P) genetic results for autism that can be returned to participants in SPARK (SPARKforAutism.org): a large recontactable cohort of people with autism in the United States. We also describe the process to return these clinically confirmed genetic findings.

High-entropy oxides with spinel structure (SHEOs) are promising anode materials for next-generation lithium-ion batteries (LIBs). In this work, electrospun (Mn,Fe,Co,Ni,Zn) SHEO nanofibers produced under different conditions are evaluated as anode materials in LIBs and thoroughly characterised by a combination of analytical techniques. The variation of metal load (19.23 or 38.46 wt% relative to the polymer) in the precursor solution and of calcination conditions (700 °C/0.5 h, or 700 °C/2 h followed by 900 °C/2 h) affects the morphology, microstructure, crystalline phase, and surface composition of the pristine SHEO nanofibers and the resulting electrochemical performance, whereas mechanism of Li+storage does not substantially change. Causes of long-term (≥650 cycles) capacity fading are elucidated via ex situ synchrotron X-ray absorption spectroscopy. The results evidence that the larger amounts of Fe, Co, and Ni cations irreversibly reduced to the metallic form during cycling are responsible for faster capacity fading in nanofibers calcined under milder conditions. The microstructure of the active material plays a key role. Nanofibers composed by larger and better-crystallized grains, where a stable solid/electrolyte interphase forms, exhibit superior long-term stability (453 mAh g−1after 550 cycles at 0.5 A g−1) and rate-capability (210 mAh g−1at 2 A g−1).

•Guanosine-based pathway evaluation in different matrices.•Simultaneous HPLC-DAD quantification of guanosine and pterins molecules.•Human extracellular vesicles isolated from different human parts.

Healthcare workers' attitudes toward vaccination have been widely described in the literature, but a restricted amount of studies assessed healthcare students' knowledge, attitudes, and opinions on this issue. This study aimed to estimate the influence of a degree course on knowledge and immunization behavior among healthcare students and to compare medical students with students from other health profession degree programs to identify possible differences.

A 34‐question survey was sent to researchers in chemistry, physics, engineering and environmental sciences, with the aim of identifying their relationship with unsuccessful research results as well as the obstacles to and incentives for their dissemination. Most of the 310 participants were affiliated with French research and teaching institutions. Conducted within the framework of the Datacc project (datacc.org) on research and data management, supported by Lyon and Grenoble Alpes University Libraries, our study fills the gap in literature on the disciplines concerned with reporting negative results in scholarly research. It shows that 81% of the researchers surveyed have already produced relevant negative results and 75% say they are willing to publish this type of data. However, only 12.5% of respondents have had the opportunity to do so in a scientific journal. This gaping contrast between intention and practice raises questions about the barriers and potential solutions.

Nanoparticles are tested in mice and non-human primates before being selected for clinical trials. Yet the extent to which mRNA delivery, as well as the cellular response to mRNA drug delivery vehicles, is conserved across species in vivo is unknown. Using a species-independent DNA barcoding system, we have compared how 89 lipid nanoparticles deliver mRNA in mice with humanized livers, primatized livers and four controls: mice with ‘murinized’ livers as well as wild-type BL/6, Balb/C and NZB/BlNJ mice. We assessed whether functional delivery results in murine, non-human primate and human hepatocytes can be used to predict delivery in the other species in vivo. By analysing in vivo hepatocytes by RNA sequencing, we identified species-dependent responses to lipid nanoparticles, including mRNA translation and endocytosis. These data support an evidence-based approach to making small-animal preclinical nanoparticle studies more predictive, thereby accelerating the development of RNA therapies.

Objective: Faced with the frustration of chronic discomfort and restricted mobility due to osteoarthritis (OA), many individuals have turned to acupuncture for relief. However, the efficacy of acupuncture for OA is uncertain, as much of the evidence is inconclusive. The purpose of this study was to evaluate electroacupuncture (EA) in a rodent model of OA such that conclusions regarding its effectiveness for symptom or disease modification could be drawn.Methods: Ten 12-month-old male Hartley guinea pigs—which characteristically have moderate to advanced OA at this age—were randomly assigned to receive EA for knee OA (n = 5) or anesthesia only (control group, n = 5). Treatments were performed three times weekly for 3 weeks, followed by euthanasia 2 weeks later. Gait analysis and enclosure monitoring were performed weekly to evaluate changes in movement. Serum was collected for inflammatory biomarker testing. Knee joints were collected for histology and gene expression.Results: Animals receiving EA had significantly greater changes in movement parameters compared to those receiving anesthesia only. There was a tendency toward decreased serum protein concentrations of complement component 3 (C3) in the EA group compared to the control group. Structural and antioxidant gene transcripts in articular cartilage were increased by EA. There was no significant difference in total joint histology scores between groups.Conclusion: This study provides evidence that EA has a positive effect on symptom, but not disease, modification in a rodent model of OA. Further investigations into mechanistic pathways that may explain the efficacy of EA in this animal model are needed.