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Background: Treatment with so-called psychedelic drugs, including psilocybin, lysergic acid diethylamide (LSD), and others, is among the most promising recent developments in psychiatry. This review focuses on psilocybin, a substance found in all mushrooms of the genus Psilocybe, because the largest amount of available evidence relates to this drug., Methods: This review is based on pertinent publications (since 1969) that were retrieved by a selective search carried out in August 2024 in the PubMed and ScienceDirect databases employing the keywords "psilocybin" AND "long-term effects" AND "mental disorders", with an emphasis on randomized, controlled clinical trials (RCTs)., Results: The available RCTs document the efficacy of psilocybin mainly against depression, including otherwise medically refratory depression. Most of the trials revealed a strong effect, with Cohen's d ranging from 0.67 to 2.6; they used a variety of depression scales and follow-up intervals. Evidence was also found for the efficacy of psilocybin against substance use disorders (alcohol in particular) and symptoms of anxiety accompanying life-threatening somatic illnesses, such as cancer. Initial uncontrolled studies have also shown significant improvement after the administration of psilocybin for other indications., Conclusion: Treatment with psilocybin differs fundamentally from classic psychopharmacotherapy. Its potentially transdiagnostic, rapid, and sustainable efficacy and its positive effect on further dimensions of mental health beyond the patient's symptoms and psychopathology imply that it may have disease-modifying and salutogenic mechanisms of action. Psychotherapy accompanied by the administration of psychedelic drugs may turn out to be the first disease-modifying treatment in the history of psychiatry.

Sphingosine-1-phosphate (S1P) receptor (S1PR) agonists, such as fingolimod (FTY720), alleviate nociception in preclinical pain models by either activation (agonism) or inhibition (functional antagonism) of S1PR type-1 (S1PR1). However, the dose-dependence and temporal relationship between reversal of nociception and modulation of S1PR1 signaling has not been systematically investigated. This study examined the relationship between FTY720-induced antinociception and S1PR1 adaptation using a sciatic nerve chronic constriction injury (CCI) model of neuropathic pain in male and female C57Bl/6J mice. Daily injections of FTY720 for 14 days dose-dependently reversed CCI-induced mechanical allodynia without tolerance development, and concomitantly resulted in a dose-dependent reduction of G-protein activation by the S1PR1-selective agonist SEW2871 in the lumbar spinal cord and brain. These findings indicate FTY720-induced desensitization of S1PR1 signaling coincides with its anti-allodynic effects. Consistent with this finding, a single injection of FTY720 reversed mechanical allodynia while concomitantly producing partial desensitization of S1PR1-stimulated G-protein activation in the CNS. However, mechanical allodynia returned 24-hr post injection, despite S1PR1 desensitization at that time, demonstrating a dissociation between these measures. Furthermore, CCI surgery led to elevations of sphingolipid metabolites, including S1P, which were unaffected by daily FTY720 administration, suggesting FTY720 reversed mechanical allodynia by targeting S1PR1 rather than sphingolipid metabolism. Supporting this hypothesis, acute administration of the S1PR1-selective agonist CYM-5442 mimicked the anti-allodynic effect of FTY720. In contrast, the S1PR1-selective antagonist NIBR-0213 prevented the anti-allodynic effect of FTY720, but NIBR-0213 given alone did not affect nociception. These results indicate that FTY720 alleviates CCI-induced allodynia through a mechanism distinct from functional antagonism., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction/objectives: To identify the frequency, correlates and progression of frailty in systemic sclerosis (SSc)., Method: All Australian Scleroderma Cohort Study participants meeting ACR/EULAR criteria with a calculable FRAIL Scale score were included. FRAIL Scale scores were calculated annually and were used to group participants as 'robust', 'pre-frail' or 'frail'. Progression of frailty over time was examined by comparing first-recorded, highest-recorded and last-recorded FRAIL Scale scores for each participant. Determinants of frailty at each visit were evaluated with ordinal logistic regression. Survival was analysed using Cox hazard modelling., Results: Of 1703 participants, 14% and 53% met criteria for frailty or pre-frailty respectively, with 33% consistently robust. Among initially frail participants, 40% remained frail and 60% improved to pre-frailty/robustness. Of pre-frail participants, 15% became frail while 32% improved to robustness. One-third of initially robust participants progressed to pre-frailty/frailty. SSc-specific determinants of frailty included diffuse SSc (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.1-1.8, p < 0.01), pulmonary arterial hypertension (OR 7.1, 95% CI 5.1-9.9, p < 0.01), interstitial lung disease (OR 1.6, 95% CI 1.3-2.0, p < 0.01), proximal weakness (OR 1.5, 95% CI 1.2-2.0, p < 0.01) and lower-tract gastrointestinal symptoms (OR 1.5, 95% CI 1.3-1.8, p < 0.01). Older age (OR 1.1, 95% CI 1.1-1.2, p < 0.01), raised CRP (OR 1.7, 95% CI 1.4-2.0, p < 0.01) and anaemia (OR 1.4, 95% CI 1.2-1.7, p < 0.01) were also significantly associated with frailty. A graded risk of death was observed with the diagnosis of pre-frailty and frailty states (hazard ratio (HR) 3.5, 95% CI 2.6-4.8, p < 0.01; and HR 9.8, 95% CI 6.8-14.1, p < 0.01 respectively). Frailty and pre-frailty were associated with reduced health-related quality-of-life and physical function (p < 0.05)., Conclusions: Frailty and pre-frailty are common in SSc and contribute to morbidity and mortality. Both SSc and non-SSc determinants of frailty exist. Frailty in SSc is a dynamic phenomenon with potential to deteriorate or improve over time., Competing Interests: Compliance with ethical standards. Competing interests: SP has received honoraria from Janssen and Boehringer Ingelheim. JS and JW have received honoraria from Boehringer Ingelheim Pty Ltd. WS has received consultancies from Jansen and Boehringer-Ingelheim. MN has received honoraria or consultancies from Janssen, AstraZeneca, GlaxoSmithKlein, Boehringer-Ingelheim and Bristol-Myers Squibb. JF has received conference sponsorship from Pfizer and honoraria from Boehringer-Ingelheim. LH has been a paid speaker for the Limbic publication and received honoraria from Janssen and Abbvie. The other authors declare no competing interests. Disclosures: None., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Aim: To identify the essential characteristics of therapeutic relational connection (TRC) as viewed by nurse practitioners (NPs) in the practice of their virtual visits caring for young adults living with chronic illness., Design: This is a qualitative descriptive study of data obtained from open-ended items on an online questionnaire., Methods: The sample was recruited through an electronic listserv sent by the National Association of Pediatric Nurse Practitioners (NAPNAP) to access a national sample. Study data were collected and managed using REDCap electronic data capture tools. Data analysis was conducted through open and axial coding towards grounded theory. The 'towards grounded theory' approach adapts and evolves grounded theory principles to incorporate broader perspectives, enhancing flexibility and contextual sensitivity in the co-construction of knowledge between researcher and participants. TRC was the central phenomenon., Results: Four themes emerged from the data including Characteristics of TRC, Behavioural Manifestations, Potential Outcomes and Environment., Conclusion: The transfer of skills from in-person clinic visits to the virtual setting is not synonymous. As virtual visits continue to be implemented as a mode to provide quality healthcare, identification of best practises for establishing an intentional use of TRC during virtual visits may be an essential component in the patient-provider relationship. Educational interventions can be designed to train providers to identify their current practices and ways in which they might adapt their in-person approach to the virtual visit., Impact: Identifying essential elements of TRC in virtual visits may achieve improved outcomes as an emergent healthcare delivery model for young adults with chronic illness., Patient Contribution: No patient or public contribution. Patient or public contribution was not indicated in this study as the aim was to identify the characteristics of TRC from NPs., (© 2024 John Wiley & Sons Ltd.)

Health related quality of life (HRQoL) is increasingly assessed in oncology research and routine care, which has led to the inclusion of HRQoL in prediction models. This review aims to describe the current state of oncological prediction models incorporating HRQoL. A systematic literature search for the inclusion of HRQoL in prediction models in oncology was conducted. Selection criteria were a longitudinal study design and inclusion of HRQoL data in prediction models as predictor, outcome, or both. Risk of bias was assessed using the PROBAST tool and quality of reporting was scored with an adapted TRIPOD reporting guideline. From 4747 abstracts, 98 records were included in this review. High risk of bias was found in 71% of the publications. HRQoL was mainly incorporated as predictor (78% (55% predictor only, 23% both predictor and outcome)), with physical functioning and symptom domains selected most frequently as predictor. Few models (23%) predicted HRQoL domains by other or baseline HRQoL domains. HRQoL was used as outcome in 21% of the publications, with a focus on predicting symptoms. There were no difference between AI-based (16%) and classical methods (84%) in model type selection or model performance when using HRQoL data. This review highlights the role of HRQoL as a tool in predicting disease outcomes. Prediction of and with HRQoL is still in its infancy as most of the models are not fully developed. Current models focus mostly on the physical aspects of HRQoL to predict clinical outcomes, and few utilize AI-based methods., Competing Interests: Declarations. Competing interests: TvdH: None to declare, KdL: None to declare, SvdM: None to declare, NH: None to declare, BH: None to declare, LvdP: None to declare, BdR: None to declare. Ethical approval: No approval needed for this literature review., (© 2024. The Author(s).)

Processing bodies (P-bodies) are cytoplasmic membrane-less organelles which host multiple mRNA processing events. While the fundamental principles of P-body organization are beginning to be elucidated in vitro, a nuanced understanding of how their assembly is regulated in vivo remains elusive. Here, we investigate the potential link between ER exit sites and P-bodies in Drosophila melanogaster egg chambers. Employing a combination of live and super-resolution imaging, we find that P-bodies associated with ER exit sites are larger and less mobile than cytoplasmic P-bodies, indicating that they constitute a distinct class of P-bodies. Moreover, we demonstrate that altering the composition of ER exit sites has differential effects on core P-body proteins (Me31B, Cup, and Trailer Hitch), suggesting a potential role for ER exit sites in P-body organization. Furthermore, we show that in the absence of ER exit sites, P-body integrity is compromised and the stability and translational repression efficiency of the maternal mRNA, oskar, are reduced. Together, our data highlights the crucial role of ER exit sites in governing P-body organization., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2024. The Author(s).)

Advancements in genomic and proteomic technologies have powered the creation of large gene and protein networks ("interactomes") for understanding biological systems. However, the proliferation of interactomes complicates the selection of networks for specific applications. Here, we present a comprehensive evaluation of 45 current human interactomes, encompassing protein-protein interactions as well as gene regulatory, signaling, colocalization, and genetic interaction networks. Our analysis shows that large composite networks such as HumanNet, STRING, and FunCoup are most effective for identifying disease genes, while smaller networks such as DIP, Reactome, and SIGNOR demonstrate stronger performance in interaction prediction. Our study provides a benchmark for interactomes across diverse biological applications and clarifies factors that influence network performance. Furthermore, our evaluation pipeline paves the way for continued assessment of emerging and updated interaction networks in the future., Competing Interests: Disclosure and competing interests statement. TI is a co-founder, member of the advisory board, and has an equity interest in Data4Cure and Serinus Biosciences. TI is a consultant for and has an equity interest in Ideaya Biosciences. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies. TI is a member of the Advisory Editorial Board of The EMBO Journal. This has no bearing on the editorial consideration of this article for publication., (© 2024. The Author(s).)

This paper describes an iridium-catalyzed allylation of ring-fused pyrazolones that proceeds with excellent regio-, diastereo- and enantio-selectivities. The approach exploits unactivated, racemic allylic alcohols as a source of allyl building blocks. Asymmetric syntheses of a series of biologically relevant, chiral pyrazolones highlight the utility of the methodology. The use of Cu(OTf) 2 as a co-catalyst greatly enhances the regioselectivity of the reaction and permits selective syntheses of branched allylation products.

Infertility, defined as the inability to achieve pregnancy after one year of unprotected, frequent sexual intercourse, is a global burden that affects approximately 15% of couples, or 190-230 million people worldwide, who are trying to start a family. The male contributes significantly, directly accounting for 30-35% and up to 52% of total couple infertility, affecting approximately 7-8% of all men. This work aims to present, in a didactic and objective way, a standardization of the initial steps toward a thorough evaluation of subfertile and infertile men. We have focused on the evaluation of initial management, emphasizing the need for a comprehensive evaluation that includes a detailed history, physical examination, and semen analysis as the golden triple helix of basic evaluation of the infertile male. General and genital physical examinations are highly valuable due to the wealth of information they provide, from potential diagnoses to pregnancy prognoses. Comprehensive and quality-controlled semen analysis provides reliable information as a baseline test to evaluate the patency of the reproductive tract and to evaluate basic sperm parameters and fertility potential. However, it is not a fertility determinant. Most cases of infertility require evaluation by a specialist in andrology. However, knowledge of the initial assessment can be undertaken by non-specialists, thus improving the care and counseling of couples facing this troubling issue and avoiding unnecessary use of assisted reproductive technologies since most cases of male infertility can be treated by medical or surgical interventions, and the fertility status can be restored., Competing Interests: Conflicts of Interest None of the authors involved in this article report any conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: In the search for new antimicrobial secondary metabolites of fungi, optimizing culture conditions remains a critical challenge, as standard laboratory approaches often result in low yields. While non-selective methods, such as modifying culture media, have been effective in expanding the chemical diversity of fungal metabolites, they have not yet established a direct link to key process parameters crucial for further optimization. This study investigates the capacity of Diaporthe caliensis as a biofactory for biologically active secondary metabolites, employing tailored culture media to explore the relationship between chemical diversity and critical process variables., Results: The metabolomic profiles, antibacterial activities, and production yields of the extracts were analyzed to progressively adjust the culture conditions. This study was conducted in five steps, evaluating carbon and nitrogen source concentration, nitrogen source type, salt supplementation, and pH adjustment. Altering the rice starch concentration affected biomass yield per unit of oxygen consumed, while modifications to the nitrogen source concentration influenced both the bioactivity and chemical space by Diaporthe caliensis. Despite changes at the metabolome level, the extracts consistently exhibited potent antibacterial activities, influenced by the nitrogen source, added salts and pH adjustments. For instance, when using corn steep liquor and rice starch, supplemented with micronutrients, different metabolites were produced depending on whether buffer or water was used, though both conditions showed similar antibacterial activities (IC 50  ≈ 0.10 mg mL - 1 against Staphylococcus aureus and ≈ 0.14 mg mL - 1 against Escherichia coli). In the treatment where buffer was used to stabilize pH change, there was an increase in the production of phomol-like compounds which are associated with known antibiotic properties. In contrast, in the treatments using water, the drop in pH stimulated the production of previously unidentified metabolites with potential antimicrobial activity., Conclusions: This study proposes a strategic methodology for the tailored formulation of culture media aiming to promote the biosynthesis of diverse secondary metabolites. This approach revealed the critical role of nutrient limitation and pH regulation in stimulating the production of polyketide-lactone derivatives, including the antibiotic phomol. Ultimately, the systematic, custom-designed culture conditions developed in this work offer a promising strategy for expanding the chemical diversity of Diaporthe caliensis, while providing valuable insights into the key parameters needed for optimizing this fungal biofactory., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The presence of sibling (cryptic) species among bloodsucking black flies can be a serious problem in assessing both their diversity and the role of individual species in the transmission of dangerous human and animal pathogens. The peculiarities of molecular genetic structure of populations and ecology of black flies of Simulium reptans s.l. (complex of Simulium reptans (Linnaeus) and Simulium reptantoides Carlsson) in European and Asian parts of Russia and Northern Kazakhstan in comparison with populations from Central and Northern Europe were investigated. Using restriction analysis of the COI gene and subsequent sequencing, we searched for unique mtDNA variants that could belong to previously undescribed forms of the studied group. In the north of the European part of Russia (north of Eastern Europe), only S. reptans A was registered, and in the Asian part of Russia (Siberia) and Northern Kazakhstan, only S. reptans B was found. Using phylogenetic analysis of the total data, three branches of S. reptans B were revealed and named in accordance with the areas of their distribution-East European, Eurasian and Asian. Simulium reptantoides Carlsson has currently been found only in Europe. The peculiarities of distribution and possible adaptations to different habitats of S. reptantoides and representatives of individual groups within S. reptans are discussed. Based on the characteristics of the sampling sites of the studied specimens, as well as the samples available in the NCBI database, the ecological and geographical features of the habitats of the molecular forms of Simulium reptans A and B were revealed. To obtain more accurate information on the distribution of S. reptans A and B forms in Eurasia, taking into account the elevational zonation, it is necessary to conduct additional studies in the mountainous regions of South-Western Europe, Siberia and Northern China. Based on the sequences presented in the DNA database, a method (AS-PCR COI variant) for separating the cryptic species-Simulium reptans (Linnaeus) and S. reptantoides Carlsson-was proposed. During testing of this method on the material collected in Russia and Northern Kazakhstan, only S. reptans was identified (S. reptantoides was absent), which completely coincided with the sequencing results. To further confirm the effectiveness of the method, it is necessary to conduct testing on material including representatives of the both species.

In spatiotemporal trend analysis, selective inference occurs when researchers are only interested in significant trends based on a fixed threshold (α, often 0.05), without considering the total number of statistical tests performed. Using simultaneous inference in gridded data involves thousands of trend tests, one for each pixel, leading to multiple testing or multiplicity problems. Multiplicity increases the chance of false discoveries in an unknown way unless the p-values of all tests performed are appropriately considered and adjusted. This discussion paper provides a selective and non-exhaustive review of the problems of multiplicity and selective inference. We discuss some appropriate methods to cope with the inflation of spurious results and comment on some examples based on gridded data in the context of research on spatiotemporal trend analysis. In addition, we suggest some good practices in transparency to facilitate the replicability of studies. The effects of uncorrected multiplicity and selective interference can be likened to a ghostly layer over the data, projecting illusions of significance that vanish with rigorous correction methods, revealing the true statistical skeleton of the results. The basis for addressing these problems is to assume that, although it may sometimes seem counterintuitive, the reality of what we perceive as statistically significant (i.e., p-values <0.05) also depends on the number (and value) of what we perceive as non-significant (i.e., p-values ≥0.05). Indeed, in a multiplicity context, one cannot correctly decide what is statistically significant until the whole story is known. Uncorrected selective inference precisely involves ignoring part of the story., Competing Interests: Declaration of competing interest The authors affirm no conflicts of interest in this research article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The maternal population residing in rural areas, tribal lands or near the United States-Mexico border are at high risk for adverse pregnancy complications, notably gestational diabetes mellitus (GDM). Few studies have considered the socioeconomic status (SES) attributes of neighbourhoods on maternal health during gestation. Given that the national and global rate of GDM is rising, this analysis moves beyond individual-level factors and investigates the role of neighbourhood deprivation on GDM risk., Objective: To investigate the relationship between neighbourhood deprivation and risk of GDM using Arizona state birth records., Methods: This population-based study of singleton live births (N = 481,113) utilised birth certificates from 2014 to 2020 from the AzPEARS study. Using American Community Survey (5-year data) linked to 2010 US Census tracts, a composite neighbourhood deprivation index (NDI) score (continuous and quartiles) was derived from 8 socioeconomic indicators. Risk ratios (RR) and 95% confidence intervals (95% CI) were used to examine the association between NDI and GDM risk, adjusting for maternal age, maternal education, race/ethnicity, parity, rurality, and birth year., Results: The state-wide incidence of GDM was 7.8% (n = 37,636) with variation by neighbourhoods (4% to 12%). GDM risk was highest for Native Americans (17.6%), Asian/Pacific Islanders (13.7%) and Hispanic/Latinas (8.3%). Compared to mothers living in areas with the lowest quartile of NDI, mothers living in neighbourhoods with the highest deprivation had an adjusted risk ratio of 1.21 for developing GDM (95% CI 1.18, 1.26)., Conclusions: We observed that neighbourhood deprivation was positively associated with a higher risk of GDM for each increase in quartile. These results suggest that NDI, a proxy for neighbourhood socioeconomic status, may contribute to GDM risk. Identifying high-risk neighbourhoods for place-based interventions targeting the most vulnerable birthing populations may be an effective strategy in the prevention of GDM., (© 2024 John Wiley & Sons Ltd.)

Background: Adequate hip joint and surgical incision analgesia represent a challenge in the postoperative period of primary total hip arthroplasty (THA). This study aimed to evaluate whether the combination of the lateral femoral cutaneous nerve block (LFCN block) and the pericapsular nerve group block (PENG block) influences postoperative analgesia and rescue opioids, in primary THA surgeries., Methods: A trial was proposed with 74 patients for THA surgeries under spinal anesthesia, where 37 received PENG block (GPENG) and the other 37, PENG block and LFCN block (GPENG+LFC). The primary outcome was the presence and intensity of pain at rest and on movement, using the Numeric Rating Scale. The secondary main outcome was the total consumption of opioids. The follow-up was 48 h., Results: Significantly fewer patients reported pain in the GPENG+LFC compared to GPENG: at rest, in 4 h (17 [45.95%] vs. 28 [75.68%] respectively, P=0.088), 12 h (4 [10.81%] vs. 17 [45.95%] respectively, P=0.016), and 24 h (4 [10.81%] vs. 13 [35.14%] respectively, P=0.0252); on movement, in 4 h (17 [45.95%] vs. 30 [81.08%] respectively, P=0.0002), 12 h (4 [10.81%] vs. 19 [51.35%] respectively, P=0.0003), and 24 h (5 [13.51%] vs. 14 [37.84%] respectively, P=0.0166). Total opioid consumption was significantly lower in GPENG+LFC compared to GPENG up to 48 hours postoperatively (1200 mg of tramadol and 6 mg of nalbuphine vs. 2400 mg and 21 mg respectively, P=0.0188)., Conclusions: The combination of the LFCN block and the PENG block, compared to the sole PENG block, results in better analgesia at rest and on movement up to 24 h and a reduction in the total consumption of opioids up to 48 h after THA.

Background: Many patients with advanced cancer are unaware of their limited prognosis, however little is known about the change in awareness during the last year of their lives., Aim: To investigate changes in the perception of prognosis in the last year of life of patients with advanced cancer and its associated factors., Design: Prospective, longitudinal, multicentre, observational study in patients with advanced cancer (eQuiPe). Patients completed 3-monthly follow-up questionnaires until death., Setting/participants: Adult patients diagnosed with advanced cancer were recruited by their treating physician or self-enrolled in one of the forty Dutch hospitals. Only deceased patients with available prognostic data were included for analysis ( n  = 801)., Results: Perception of prognosis changes in the last year of life with an increase in the percentage of patients who are aware of their limited prognosis (from 15% to 40%). Especially in the last 6 months of life, most of the changes were towards a more realistic perception of prognosis. Patients who did not want to know their prognosis remained relatively stable in their wish not to know (range: 14%-18%). Time to death was associated with having a perception of prognosis of < 1 year, >1 year or not knowing the prognosis, but was not associated with not wanting to know the prognosis., Conclusion: Becoming aware of their limited prognosis may make patients with advanced cancer more receptive to start end-of-life discussions. Although some patients prefer not to know their prognosis, it remains important to respectfully explore their preferences and wishes for end-of-life care., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Frailty is a complex condition characterized by a decline in multiple physiological systems, compromising an individual's ability to maintain homeostasis. The onset and progression of frailty are linked to negative health outcomes such as disability, hospitalization, and mortality. To better understand frailty mechanisms, animal models have become valuable due to their accessibility to critical tissues and the ability to control variables. This study investigates frailty in female C57BL/6JN mice by comparing the two most widely accepted frailty assessment tools-the Physical Phenotype (PP) and the Frailty Index (FI). While FI relies on the accumulation of health deficits, PP focuses on functional physical performance. Our results suggest that these tools are complementary rather than interchangeable, each targeting distinct markers of frailty. To address the limitations of both, we propose a new combined assessment tool, the Vitality Phenotype (VP), which integrates physical performance and health deficits into a more comprehensive evaluation. We also explore the challenges in standardizing frailty cutoff values and the need for a reference group to enhance the accuracy of frailty identification. Lastly, we investigate the correlation between frailty criteria and biological markers, particularly bone mineral density (BMD), which shows a significant relationship with physical performance metrics such as grip strength and voluntary wheel activity, highlighting its potential role in frailty pathophysiology., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Echinococcosis is a parasitic invasion caused by a cestode of the genus Echinococcus . Kyrgyzstan is a country in Central Asia known for an extremely high incidence of echinococcosis. A total of 10 093 subjects were screened in the Osh, Naryn and Batken regions of Kyrgyzstan in 2015–2017 by ultrasound and questioned for potential risk factors. Cystic echinococcosis (CE) prevalence (combined newly diagnosed and post-surgery cases) ranged between 0.2 and 25.2% across the study regions. Typical factors, such as dog or livestock ownership, weakly affected CE risk (odds ratio [OR] = 1.18–1.83). Use of water from a well and owning a cat had a greater effect on CE risk (OR = 2.02–2.28). The risk factors of CE were highly dissimilar among the study regions, with patterns not always compatible with classical biohelminthosis transmission routes (no risk from livestock in certain areas, significant risk from using well water, owning cats). Therefore, the CE epidemic in Kyrgyzstan is not holistic in terms of potential mechanisms and risk factors, and certain areas can greatly benefit from preventive measures that will have limited efficiency elsewhere.

Autophagy is a key innate immune defense mechanism in intestinal epithelial cells. Bacterial invasion of epithelial cells activates antibacterial autophagy through a process that requires the innate immune adaptor protein MYD88, yet how MYD88 signaling connects to the autophagy machinery is unknown. Here, we show that the mouse intestinal pathogen Salmonella enterica Serovar Typhimurium ( Salmonella Typhimurium) triggers MYD88 signaling that regulates binding of the anti-autophagy factor B cell lymphoma 2 (BCL2) to the essential autophagy protein Beclin1 (BECN1) in small intestinal enterocytes, a key epithelial cell lineage. Salmonella infection activated the kinase c-Jun N-terminal protein kinase 1 (JNK1) downstream of MYD88. JNK1 induced enterocyte BCL2 phosphorylation, promoting dissociation of the inhibitory BCL2-BECN1 complex and releasing BECN1 to initiate autophagy. Mice with BCL2 phosphorylation site mutations that prevent BCL2-BECN1 dissociation showed increased Salmonella invasion of enterocytes and dissemination to extraintestinal sites. These findings reveal that BCL2 links MYD88 signaling to enterocyte autophagy initiation, providing mechanistic insight into how invading bacteria trigger autophagy in the intestinal epithelium., Competing Interests: Competing interests statement:The authors declare no competing interest.

Survivors of COVID-19 are susceptible to diminished health-related quality of life (HRQoL) and adverse psychological health, which may be exacerbated by their experiences of fear and the impact of the pandemic itself. This study aims to identify distinct fear and impact patterns related to the COVID-19 pandemic among survivors through latent profile analysis (LPA) and examine the associations of fear and impact patterns with post-traumatic stress symptoms (PTSS) and HRQoL. A total of 5,890 Vietnamese COVID-19 survivors completed the COVID-19 Impact Battery- Disability Scale (CIB-D), the Fear of COVID-19 Scale (FCoV-19 S), the Impact of Event Scale-Revised for PTSS, and the 36-Item Short Form Survey (SF-36) for HRQoL. Four distinct groups of fear and impact were identified: "Fearful and highly impacted" (26.8%), "moderately impacted yet not fearful" (22.9%), "less impacted and less fearful" (18.6%), and "mildly impacted and neutral" (31.7%). Survivors who were "less impacted and less fearful" exhibited significantly higher HRQoL scores (regression coefficient, B: 10.9; 95% confidence interval (CI): 10.0 - 11.7), both in terms of physical (B: 12.0; 95%CI: 11.1 - 12.9) and mental health (B: 19.4; 95%CI: 9.6 - 11.1), and lower PTSS levels (B: -24.5; 95%CI: -25.8 - -23.3) compared to those who were "highly impacted and fearful". It is imperative to acknowledge the intricate association between fear, impact, and mental health to comprehensively address the diverse needs of this distinct population post-COVID-19. These findings provide insights for designing interventions and support mechanisms for COVID-19 survivors., Competing Interests: Declarations. Ethics Approval and Consent to Participate: The study protocol received approval from the Institutional Ethical Review Committee of Hanoi University of Public Health (No. 400/2021/YTCC-HD3 and 45/2022/YTCC-HD3). All participants gave consent online consent after receiving information about the study and before joining the survey. Consent for Publication: This study is approved by the respective ethics review board for publication. All authors approve this manuscript for submission and publication. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: To evaluate general practitioners' (GPs) experiences with providing cancer survivorship care and explore readiness for implementation., Methods: This cross-sectional survey study was nested within two randomized-controlled trials conducted in the Netherlands between 2015 and 2023, comparing GP- with specialist-led survivorship care for patients with colon or prostate cancer. An adapted version of the normalisation measure development (NoMAD) survey was distributed among participating GPs. NoMAD assesses the implementation of complex interventions and includes seven items on experiences (score ranges, 0-10) and 19 core items (expressed as % agreement). Higher scores indicate greater normalization, that is, embedding in primary care., Results: In total, 214 GPs participated (response rate, 69%). The overall experience with providing survivorship care was 7.0 ± 1.6 for prostate cancer and 6.4 ± 1.8 for colon cancer. Lowest scores were seen for willingness to provide care (5.9 ± 2.4 and 5.0 ± 2.5, respectively), expected future involvement (6.6 ± 2.0 and 5.6 ± 2.5), and appropriateness of involvement (6.4 ± 2.1 and 5.6 ± 2.7). GPs in both trials agreed (±75%) there was potential value for patients, but not for their own work (±50%). Survivorship care for colon cancer was often perceived as different from usual care (74%). GPs' self-reported knowledge of care was high in the prostate cancer trial (62%), but not in the colon cancer trial (41%). GPs from both trials agreed that they could easily integrate management of physical and psychosocial effects into their work (±70%), but integrating routine check-ups was rated less positively (±55%). Financial compensation was deemed necessary (±80% agreed). Twenty-one percent was willing to provide care for other cancer types., Conclusion: GPs recognize value of providing survivorship care for patients, but experiences differ on the basis of cancer type. Implementation of prostate versus colon cancer survivorship care appears more feasible.

Background: Several studies have suggested an association between infertility and risk of endometrial cancer. However, most studies have evaluated this relationship in premenopausal people, yet the mean age of endometrial cancer is 60 years, after the average age of menopause., Methods: Our study included Women's Health Initiative participants who self-reported whether they had a history of infertility. Cox proportional hazards models were used to examine the association between infertility and incident endometrial cancer. Given that all infertility diagnoses occurred prior to study enrollment, we conducted secondary analyses using logistic regression examining prevalent endometrial cancer cases diagnosed before study baseline., Results: Approximately 18% of participants reported a history of infertility. No statistically significant association was observed between infertility and risk of incident endometrial cancer overall [incident cases = 1,622; HR = 1.12; 95% confidence interval (CI) = 0.99-1.26]. Although point estimates suggested an increase in risk of endometrial cancer among women with body mass index (BMI) ≥25 (HR = 1.15; 95% CI = 0.99-1.33), none of the associations were statistically significant. There was an association between history of infertility and prevalent endometrial cancer cases (OR = 1.19; 95% CI = 1.06-1.34), with the strongest association for infertility diagnosis due to endometriosis (OR 2.42; 95% CI = 1.83-3.19)., Conclusions: In a population of postmenopausal participants, we observed a modest, but not statistically significant, association between overall infertility and incident endometrial cancer, with the suggestion of a higher risk among those with a BMI ≥ 25., Impact: Our findings highlight, as observed in previous studies, that risk factors for endometrial cancer may vary by BMI., (©2024 American Association for Cancer Research.)

Objective: In the phase 2 OVARIO trial (NCT03326193) investigating niraparib-bevacizumab first-line maintenance, median progression-free survival was 14.2 months (95% confidence interval (CI) 8.6 to 16.8) for patients with homologous recombination (HR)-proficient (HRp) epithelial ovarian cancer, and 12.1 months (95% CI8.0-not evaluated) for patients with undefined HR status. However, real-world data are limited for patients who receive niraparib-bevacizumab first-line maintenance therapy. The COMB1NE study describes real-world clinical outcomes (time to treatment discontinuation; time to next treatment) in patients with epithelial ovarian cancer who received niraparib-bevacizumab first-line maintenance, regardless of first-line bevacizumab use., Methods: This real-world, retrospective study used a US nationwide electronic health record-derived deidentified database. Eligible patients were 18 years or older at initial epithelial ovarian cancer diagnosis and initiated niraparib-bevacizumab first-line maintenance (January 1, 2017-September 2, 2022) following first-line treatment. The index date was the start of first-line maintenance. Patients were followed until death, last clinical activity, or end of study, whichever occurred first. Time to treatment discontinuation and time to next treatment, a proxy for real-world progression-free survival, were estimated using the Kaplan-Meier method., Results: Among 59 included patients, the median age was 67 years (interquartile range (IQR) 61-76), and 81.4% had stage III/IV epithelial ovarian cancer at diagnosis. Overall, 83.1% of patients had BRCA wild-type with either HRp or HR status unknown disease. Median time to treatment discontinuation of first-line maintenance was 11.8 months (95% CI 8.7 to 13.5). Median time to next treatment was 14.1 months (95% CI 11.3 to 16.6). At 6 months after index, 77.9% of patients had not initiated second-line treatment; at 12 months, 61.3% had not., Conclusion: In this real-world study of patients receiving niraparib-bevacizumab first-line maintenance, the majority of whom had HRp/HR status unknown, the median time to next treatment was consistent with observed progression-free survival in patients with similar HR status in the OVARIO study., Competing Interests: Competing interests: PHT has served on advisory boards for Aadi Pharmaceuticals, Agenus, AstraZeneca, Clovis Oncology, Eisai, GSK, ImmunoGen, Iovance, Merck, Mersana, Novocure, R-Pharm, Seagen, Imunon, Verastem, and Zentalis and has received grants from GSK and Merck. TACB, SB, JL, JH, LVK, JMS, JAH, and AKG are all employees of GSK and may hold stock in GSK., (© IGCS and ESGO 2024. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Comet 67P/Churyumov-Gerasimenko (hereafter 67P) was the primary target of ESA's Rosetta mission. Hyperspectral images acquired by the Mapping channel of the Visible and InfraRed Thermal Imaging Spectrometer aboard Rosetta can be used to derive physical and compositional surface properties by detailed spectrophotometric analyses. This calls for a precise spatial co-registration between measurements and geometry information. In this work, we improve the wavelength-dependent co-registration and also the spatial consistency of the radiometric calibration. This is accomplished by applying a feature-based image matching method comparing measured 67P nucleus images from the entire mission to corresponding photometric simulations. The derived geometric distortions suggest previously unaccounted optical aberrations of the instrument, in conjunction with non-systematic spacecraft pointing and perspective errors, and discrepancies between the true nucleus shape at data acquisition time and the used digital shape model., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Numerous areas of the Semipalatinsk Test Site (STS) were subjected to radioactive contamination, including tritium. The tritium content in plants was determined in free water (TFWT) and in the organic component (OBT). It has been established that the OBT content in plants for the "Sary-Uzen" site between combat boreholes ranges from <7-125 Bq/kg and the background OBT content is 21.5 Bq/kg. The maximum OBT values in plants have been recorded in the vicinity of boreholes and range from 7.1 (near the borehole numbered 106) to 200,000 Bq/kg (near the borehole numbered 101). Overall, the tritium content in the vegetation cover at the "Sary-Uzen" site is negligible and does not pose a threat. Isolated cases of tritium content in drinking water exceeding the intervention level have been identified in plants in the "Lazurit" area, as well as near combat boreholes numbered 125 and 101., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Mind-wandering is a pervasive human brain state and, when in excess, may promote negative affect and neuropsychiatric conditions. Mindfulness meditation may promote alternate brain states, improving affect and reducing stress. An understanding of the neural basis between these brain states could thus advance treatment of neuropsychiatric conditions, including those associated with epilepsy., Methods: To explore the neural basis of mindfulness meditation versus mind-wandering, we enrolled eight patients in a trial of structured mindfulness meditation and open mind-wandering who underwent stereo electroencephalography (sEEG) within the mesial temporal lobe for seizure localization. Electrophysiology was compared between mind-wandering and mindfulness separately for epileptic and non-epileptic MTL. Using fitting-one-over-f modeling, periodic components of electrophysiology were compared in canonical frequency bands of theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), and gamma (30-55 Hz). Aperiodic components of the power spectra were assessed by the model offset, knee, and exponent., Results: We found a significant reduction in gamma power (30-55 Hz) within the mesial temporal lobe (MTL) during mindfulness meditation compared with mind-wandering in non-epileptic (p = 1.20E-4) but not in epileptic MTL (p = 0.352).There was also a significant difference between epileptic versus non-epileptic MTL in gamma power between conditions (p = 0.011). There were no significant changes in power across any frequency band within epileptic mesial temporal MTL between brain states. Conversely, there were significant differences between mind-wandering and mindfulness within epileptic MTL in aperiodic components (offset, knee, and exponent, all p < 0.05), while no differences in aperiodic components were seen in non-epileptic MTL (all p > 0.70)., Significance: Intracranial electrophysiologic modulations between brain state (mind-wandering versus mindfulness) may differ between epileptic and non-epileptic MTL. Modulations in gamma activity in non-epileptic MTL may represent functional changes in brain state, while aperiodic changes in epileptic MTL may modulate propensity for seizures., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Fedor Panov, MD is a paid speaker for NeuroPace. The remaining authors have no conflicts of interest. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A paradigm shift in drug development is the discovery of small molecules that harness the ubiquitin-proteasomal pathway to eliminate pathogenic proteins. Here we provide a modality for targeted protein degradation in lysosomes. We exploit an endogenous lysosomal pathway whereby protein arginine methyltransferases (PRMTs) initiate substrate degradation via arginine methylation. We developed a heterobifunctional small molecule, methylarginine targeting chimera (MrTAC), that recruits PRMT1 to a target protein for induced degradation in lysosomes. MrTAC compounds degraded substrates across cell lines, timescales and doses. MrTAC degradation required target protein methylation for subsequent lysosomal delivery via microautophagy. A library of MrTAC molecules exemplified the generality of MrTAC to degrade known targets and neo-substrates-glycogen synthase kinase 3β, MYC, bromodomain-containing protein 4 and histone deacetylase 6. MrTAC selectively degraded target proteins and drove biological loss-of-function phenotypes in survival, transcription and proliferation. Collectively, MrTAC demonstrates the utility of endogenous lysosomal proteolysis in the generation of a new class of small molecule degraders., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The density of wood is a key indicator of the carbon investment strategies of trees, impacting productivity and carbon storage. Despite its importance, the global variation in wood density and its environmental controls remain poorly understood, preventing accurate predictions of global forest carbon stocks. Here we analyse information from 1.1 million forest inventory plots alongside wood density data from 10,703 tree species to create a spatially explicit understanding of the global wood density distribution and its drivers. Our findings reveal a pronounced latitudinal gradient, with wood in tropical forests being up to 30% denser than that in boreal forests. In both angiosperms and gymnosperms, hydrothermal conditions represented by annual mean temperature and soil moisture emerged as the primary factors influencing the variation in wood density globally. This indicates similar environmental filters and evolutionary adaptations among distinct plant groups, underscoring the essential role of abiotic factors in determining wood density in forest ecosystems. Additionally, our study highlights the prominent role of disturbance, such as human modification and fire risk, in influencing wood density at more local scales. Factoring in the spatial variation of wood density notably changes the estimates of forest carbon stocks, leading to differences of up to 21% within biomes. Therefore, our research contributes to a deeper understanding of terrestrial biomass distribution and how environmental changes and disturbances impact forest ecosystems., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The evolution of SARS-CoV-2 has led to the emergence of numerous variants of concern (VOCs), marked by changes in the viral spike glycoprotein, the primary target for neutralising antibody (nAb) responses. Emerging VOCs, particularly omicron sub-lineages, show resistance to nAbs induced by prior infection or vaccination. The precise spike protein changes contributing to this resistance remain unclear in infectious cell culture systems. In the present study, a large panel of infectious SARS-CoV-2 mutant viruses, each with spike protein changes found in VOCs, including omicron JN.1 and its derivatives KP.2 and KP.3, was generated using a reverse genetic system. The susceptibility of these viruses to antibody neutralisation was measured using plasma from convalescent and vaccinated individuals. Synergistic roles of combined substitutions in the spike receptor binding domain (RBD) were observed in neutralisation resistance. However, recombinant viruses with the entire spike protein from a specific VOC showed enhanced resistance, indicating that changes outside the RBD are also significant. In silico analyses of spike antibody epitopes suggested that changes in neutralisation could be due to altered antibody binding affinities. Assessing ACE2 usage for entry through anti-ACE2 antibody blocking and ACE2 siRNA revealed that omicron BA.2.86 and JN.1 mutant viruses were less dependent on ACE2 for entry. However, surface plasmon resonance analysis showed increased affinity for ACE2 for both BA.2.86 and JN.1 compared to the ancestral spike. This detailed analysis of specific changes in the SARS-CoV-2 spike enhances understanding of coronavirus evolution, particularly regarding neutralising antibody evasion and ACE2 entry receptor dependence.

Purpose: Research is underway worldwide to investigate the feasibility, acceptability, and utility of sequencing-based newborn screening. Different methods have been used to select gene-condition pairs for screening, leading to highly inconsistent gene lists across studies., Methods: Early Check developed and utilized actionability-based frameworks for evaluating gene-condition pairs for inclusion in newborn panels (panel 1-high actionability, panel 2-possible actionability). A previously developed framework, the Age-based Semi Quantitative Metric (ASQM), was adapted. Increasing ASQM scores, with a maximum of 15, suggest greater actionability. Wilcoxon tests were performed to compare panel 1 gene-condition pairs on the Recommended Uniform Screening Panel (RUSP) with non-RUSP pairs., Results: In our first round of assessment, Early Check identified 178 gene-condition pairs for inclusion in panel 1 and 29 for panel 2. Median ASQM scores of RUSP conditions on panel 1 was 12 (range 4 to 15) and non-RUSP was 13 (range 9 to 15). Median scores for panel 2 was 10 (range 6 to 14)., Conclusion: The Early Check frameworks provide a transparent, semiquantitative, and reproducible methodology for selecting gene-condition pairs for newborn screening sequencing pilot studies that may inform future integration of genomic sequencing into population-level newborn screening. Collaborative efforts among newborn sequencing studies to establish shared criteria is needed to enhance cross-study comparisons., Competing Interests: Conflict of Interest Rebekah S. Zimmerman, Sharon F. Suchy, Amber Begtrup, Katherine G. Langley, Kristin G. Monaghan, Christina Kraczkowski, Kathleen S. Hruska, and Paul Kruszka were employees of GeneDx, LLC at the time of this study. All other authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide only symptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs., Competing Interests: Competing interests: L.V.K. has received research support from Canadian Institutes of Health Research (CIHR), Cure Parkinson’s, Krembil Foundation, Michael J. Fox Foundation for Parkinson’s Research (MJFF), Natural Sciences and Engineering Research Council of Canada, and Parkinson Canada; consultancy fees from Cure Ventures, Ipsen, Knight Therapeutics, Right Brain Bio, and UCB; and honoraria from Canadian Movement Disorders Society, Critical Path for Parkinson’s, International Parkinson and Movement Disorder Society, and IOS Press. A.B.-O. has received personal fees for advisory board participation and/or consulting from Abata, Accure, Atara Biotherapeutics, Biogen, Bristol Myers Squibb (BMS)/Celgene/Receptos, GlaxoSmithKline, Gossamer, Horizon Therapeutics, Immunic, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sangamo, Sanofi-Genzyme, and Viracta; and institutional grant support from Biogen Idec, Roche/Genentech, Merck/EMD Serono, and Novartis. R.B. has received research support from Biogen, Eli Lilly, and Roche Genentech, and consulting fees from EMD Serono, Novartis, TG Therapeutics, and Horizon, Jansen. S.F. has received consultancy or speaker fees from Abbvie, Bial, Ipsen, and Lundbeck. U.J.K. holds stock options as a Scientific Advisory Board member for Amprion and has received consultancy fees as a Scientific Advisory Board member for NurrOn and as a member of the data monitoring committee for UCB. E.C.K. has received research funding from Abbvie, Biogen, and Genentech and consulting fees from Banner Life Sciences, EMO Serano, Galen/Atlantica, Greenwich Biosciences, INmune Bio, Myrobalan Therapeutics, OM 1, and TG Therapeutics. M.K. has received travel support and honoraria for advisory boards from Biogen, Roche, Novartis, and EMD Serono. S.K. has received institutional grant support from Biogen, Roche, and Sanofi-Genzyme. A.E.L. has acted as an adviser for AbbVie, Alector, Amylyx, Aprinoia, Biogen, BioAdvance, BlueRock, Biovie, BMS, Denali, Janssen, Jazz, Lilly, Novartis, Paladin, Pharma 2B, PsychoGenetics, Retrophin, Roche, Sun Pharma, and UCB; has received honoraria from Sun Pharma, AbbVie, and Sunovion; has received grants from Brain Canada, CIHR, Edmond J Safra Philanthropic Foundation, MJFF, Ontario Brain Institute, Parkinson Foundation, Parkinson Canada, and W. Garfield Weston Foundation; has acted as an expert witness in litigation related to paraquat and Parkinson disease; and has received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. M.J.M. has received travel support and honoraria for advisory boards from Ipsen, Merz, and Abbvie. D.O. has received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, Bristol Myers Squibb, and Novartis and consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche, Novartis, Pipeline Therapeutics, and Merck. R.S. has received grants from MS Society of Canada and J.P. Bickell Foundation; consulting fees from Novartis; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Biogen Idec, Sanofi-Genzyme, EMD Serono, and Roche; has served on advisory boards for Novartis; and has received support to attend a scientific meeting from EMD Serono. J.O. has received personal compensation for consulting from Biogen Idec, BMS, Eli Lilly, EMD Serono, Novartis, Roche, and Sanofi-Genzyme, and institutional grant support from Biogen Idec and Roche. A.A., N.A., D.G.D.L., E.A.F., K.K.L., Z.G.-O., J.L.G., M.R.L., P.A.M., T.A.M., V.E.M., M.W.C.R., M.G.S. and A.J.S. declare no competing interests., (© 2024. Springer Nature Limited.)

Background: Women with Sjögren's Disease are more likely to experience pregnancy complications compared to their counterparts without the disease. Attention to detail and familiarity with the most recent research and guidelines in this field are required to achieve optimal maternal and fetal outcomes. Such complications include pregnancy induced hypertension, fetal growth restriction, thromboembolic events, and preterm delivery. Among the most life-threatening sequela of maternal Sjogren's Disease is fetal autoimmune congenital heart block (ACHB), which has high potential to cause intrauterine fetal death, neonatal mortality, developmental delay, and other long-term pediatric complications. Currently, surveillance with weekly echocardiograms and obstetric sonograms in the second trimester are recommended to screen for ACHB with the goal of early detection and intervention before progression from first- or second- of heart block to complete heart block., Objective: We describe a case of maternal Sjogren's Disease, which prompted us to raise questions regarding the optimal frequency of obtaining fetal echocardiograms, and the ideal management in case a prolonged PR interval was to be found. We use this case to provide a springboard for discussion on updated antenatal management strategies for ACHB prevention., Methods: To conduct this analysis, we searched PubMed for articles published over the last 10 years, with attention focused on articles written since 2016. Additionally, updated guidelines by other specialties such as Rheumatology, Cardiology and Pediatrics on this issue were reviewed., Results: Thorough search of the literature yielded several meta-analyses concurring that the mothers with Sjogren's Disease had increased rates of premature birth, pregnancy induced hypertension, increased risks of delivering infants with intrauterine growth restriction (IUGR), with the most life-threatening risk being that of congenital heart block. Literature supporting prophylactic hydroxychloroquine and the use of steroids to reverse or halt the progression of congenital heart block at the time of diagnoses appeared at the forefront of search results., Conclusion: Pregnant women with SS have an increased risk for complications such as intrauterine growth restriction, thromboembolic events, pregnancy-induced hypertension, preterm delivery, and cesarean delivery and should prioritize obtaining pre- or peri-conceptional counseling. In women with anti SSA/SSB antibodies, a medication regimen should be considered with the object of decreasing the concentration of these antibodies, and hence decrease the risks of ACHB. Current literature supports the inclusion of hydroxychloroquine for this purpose, even prior to conception. Although the most recent studies recommend against prophylactic use of steroids, their potential to prevent progression to complete block should be weighed against their potential negative effects. Short and long-term treatment with corticosteroids has been associated with increased maternal risk of infection, weight gain, osteonecrosis, hypertension and bone mineral density disorders. Intrauterine growth restriction, oligohydramnios, and adrenal suppression have been among the fetal risks associated with steroids while improved infant survival or decreased need for pacing have not been demonstrated. Management of these pregnancies is complex and should include a multidisciplinary approach involving a maternal-fetal medicine sub-specialist, a rheumatologist, a pediatrician, a neonatologist, and the patient herself with her family in a model of shared decision-making.

Objectives: To evaluate junior resident self-assessments and utilization of effective coaching principles by chief resident coaches in a resident peer surgical coaching program., Design: All residents underwent the Surgical Coaching for Operative Performance Enhancement (SCOPE) coaching curriculum. Junior residents ("coachees") were paired with chief resident coaches. A case was selected for coaching. The coaching structure was: 1) junior resident preoperative goal setting, 2) unscrubbed, intraoperative case observation by the coach, 3) postoperative coaching debrief. Debriefs were recorded to determine frequency of junior resident self-assessment and use of the effective coaching principles (goal setting, collaborative analysis, constructive feedback, action planning). Deductive thematic analysis was conducted., Setting: A general surgery residency at a single, large academic medical center., Participants: 16 junior resident (PGY1-3) coachees and 6 chief resident (PGY5) coaches., Results: There were 18 recorded coaching debrief sessions that lasted an average of 12.65 minutes (range 4-31 minutes). All debrief sessions included self-assessments by the junior resident coachees. There were numerous examples of the 4 effective coaching principles with all debriefs including use of at least 3. The most commonly used were collaborative analysis and constructive feedback. For technical skills, these highlighted body positioning, needle angles, and dissection techniques, including instrument choice, laparoscopic instrument technique, and use of electrocautery. Collaborative analysis of nontechnical skills emphasized communication with the attending surgeon, specifically operative decision-making and advocating for resident autonomy. Nontechnical constructive feedback addressed strategies the coaches themselves used for managing stress, interacting with attendings, and excelling in the operating room., Conclusions: Self-assessments and use of effective coaching principles were frequent throughout peer coaching debriefs. Collaborative analysis and constructive feedback were employed to promote operative technical and nontechnical skill development. Within a peer coaching program, residents are able to employ high level teaching and coaching techniques to encourage operative performance enhancement., (Copyright © 2024 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

International studies measuring wellbeing/multidimensional mental health before/ during the COVID-19 pandemic, including representative samples for >2 years, identifying risk groups and coping strategies are lacking. COH-FIT is an online, international, anonymous survey measuring changes in well-being (WHO-5) and a composite psychopathology P-score, and their associations with COVID-19 deaths/restrictions, 12 a-priori defined risk individual/cumulative factors, and coping strategies during COVID-19 pandemic (26/04/2020-26/06/2022) in 30 languages (representative, weighted non-representative, adults). T-test, χ 2 , penalized cubic splines, linear regression, correlation analyses were conducted. Analyzing 121,066/142,364 initiated surveys, WHO-5/P-score worsened intra-pandemic by 11.1±21.1/13.2±17.9 points (effect size d=0.50/0.60) (comparable results in representative/weighted non-probability samples). Persons with WHO-5 scores indicative of depression screening (<50, 13% to 32%) and major depression (<29, 3% to 12%) significantly increased. WHO-5 worsened from those with mental disorders, female sex, COVID-19-related loss, low-income country location, physical disorders, healthcare worker occupations, large city location, COVID-19 infection, unemployment, first-generation immigration, to age=18-29 with a cumulative effect. Similar findings emerged for P-score. Changes were significantly but minimally related to COVID-19 deaths, returning to near-pre-pandemic values after >2 years. The most subjectively effective coping strategies were exercise and walking, internet use, social contacts. Identified risk groups, coping strategies and outcome trajectories can inform global public health strategies., Competing Interests: Declaration of competing interest Conflict of interest statements of all authors are detailed in eTable 8., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Since the development of consensus-recommended indicators for pediatric malnutrition in 2014, screening and diagnosis of pediatric malnutrition have improved, but the indicators are not always used; malnutrition continues to be underdiagnosed in some community and healthcare settings. In particular, mid-upper arm circumference (MUAC) is underused as a screening indicator for pediatric malnutrition, despite its unique advantages and usefulness in several clinical situations. In December 2022, a scientific roundtable was held to bring together several experts in pediatric malnutrition. One of the goals of the scientific roundtable was to discuss the clinical use of anthropometric measures as screening tools for pediatric malnutrition status, with a focus on the use of MUAC. This article arose from that event and is intended as an educational tool to aid clinicians in implementing MUAC measurements. In addition to describing the use of MUAC as a screening tool, the article discusses several clinical situations in which MUAC is especially useful. Additionally, the article reviews practical aspects of measuring and interpreting MUAC values, provides links to additional educational resources, and briefly reviews areas in which further research is needed regarding the use of MUAC for screening of nutrition status in children., (© 2024 The Author(s). Nutrition in Clinical Practice published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Background: Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFRm) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFRm NSCLC and as adjuvant treatment for resected EGFRm NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFRm NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here., Patients and Methods: Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints., Results: Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo., Conclusions: Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A total of 1019 samples collected on 726 Spanish swine farms suffering from outbreaks of respiratory disease were screened for influenza A viruses (IAVs) using a RT-qPCR method. A subset of positive samples was further analyzed using a subtype-specific RT-qPCR method (n: 142) and Sanger sequencing (n: 64). A total of 19.4% samples from 23% farms tested positive, with infection being most common in suckling (53.6%) and weaning pigs (30.2%). Viruses belonging to four HA subtypes (H1av, H1hu, H1pdm, H3) were detected, with subtypes H1avN2, H1huN2 and H1avN1 accounting for over half of the specimens. An optimized protocol with newly designed primers allowed the detection of H3 viruses in a significant number of samples (21%). A comparison of antigenic positions revealed that circulating strains exhibited mutations with vaccine strains in a significant percentage of amino acid residues, both in the NA protein (27.8-43.3%) and particularly in the HA protein (51-75.3%)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The gastrointestinal tract (GIT) is the most commonly affected internal organ in systemic sclerosis (SSc). We sought to determine the prevalence and impact of GIT symptoms on survival and patient-reported outcomes., Methods: A total of 907 consecutive patients from the Australian Scleroderma Cohort Study who had prospectively completed the University of California, Los Angeles, Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 Questionnaire (UCLA GIT) between 2015 and 2021 were included. The associations between UCLA GIT scores and physical function (Scleroderma Health Assessment Questionnaire), quality of life (QoL; Short Form 36), mood (Patient-Reported Outcomes Measurement Information System [PROMIS] anxiety and depression domains), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue score), and employment were investigated using multivariable population-averaged panel models using generalized estimating equations (GEEs). Kaplan-Meier curves and multivariable Cox proportional hazard regression models were used to evaluate survival according to total UCLA GIT scores., Results: GIT symptoms were reported in 87% of participants, with 46% to 52% reporting moderate to very severe symptoms of reflux, distension, diarrhea, and constipation. Higher total UCLA GIT scores were associated with worse QoL, physical function, fatigue, anxiety, and depression (P < 0.001). In the multivariable GEE analysis, moderate and severe to very severe total scores, reflux scores, and distension scores were associated with worse physical function, QoL, fatigue, anxiety, and depression compared to mild scores (P < 0.05). Patients with severe total scores and diarrhea scores were more likely to be unemployed compared to those with mild scores (P < 0.05). UCLA GIT total scores were not independently associated with death in our cohort., Conclusion: GIT manifestations are common in SSc and negatively impact QoL, physical function, and employment but are not directly associated with increased death., (© 2024 The Author(s). Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Purpose: There is a lack of literature evaluating outcomes of the ligament-guided approach in medial unicompartmental knee arthroplasty (UKA). An improved comprehension of the distribution of coronal plane alignment of the knee (CPAK) phenotypes and sagittal tibial wear patterns and their associations with patient-reported outcome measures (PROMs) and implant survivorship could provide insights into its further application in daily practice., Methods: A registry was reviewed for patients with a minimal 2-year follow-up who underwent robotic-assisted, ligament-guided, medial UKA between 2008 and 2016. Survivorship and postoperative PROMs were collected. CPAK phenotypes and sagittal tibial wear patterns were determined. Survivorship, Knee Injury and Osteoarthritis Outcome Score (KOOS), Kujala and patient satisfaction were compared between phenotypes and sagittal tibial wear patterns., Results: A total of 618 knees were included at a mean follow-up of 4.1 [2.0-9.6] years. Four-year conversion to the TKA survival rate was 98.9% [98.4%-99.3%] and 94.3% [93.3%-95.3%] for all-cause revision. Patients with preservation of the CPAK phenotype (84.5 ± 14.9, 81.8 ± 15.5, p = 0.033) and restoration of prearthritic coronal alignment (84.1 ± 14.9, 81.7 ± 15.9, p = 0.045) had a significantly higher Kujala score. No other significant differences in survivorship or PROMs were observed between phenotypes or sagittal tibial wear patterns. Additionally, no difference in survival rates was observed between preserved or altered phenotypes., Conclusion: This study demonstrated that preservation of CPAK phenotype and preservation of prearthritic coronal alignment yielded a significantly higher Kujala score. No other significant differences in PROMs or implant survivorship were observed, suggesting that robotic-assisted, ligament-guided medial UKA provides equal outcomes for all observed phenotypes and sagittal tibial wear patterns in medial compartment OA as long as preoperative CPAK phenotype is preserved postoperatively., Level of Evidence: Level III., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Lay Abstract: Timely identification of autism spectrum conditions is a necessity to enable children to receive the most benefit from early interventions. Emerging technological advancements provide avenues for detecting subtle, early indicators of autism from routinely collected health information. This study tested a model that provides a likelihood score for autism diagnosis from baby wellness visit records collected during the first 2 years of life. It included records of 591,989 non-autistic children and 12,846 children with autism. The model identified two-thirds of the autism spectrum condition group (boys 63% and girls 66%). Sex-specific models had several predictive features in common. These included language development, fine motor skills, and social milestones from visits at 12-24 months, mother's age, and lower initial growth but higher last growth measurements. Parental concerns about development or hearing impairment were other predictors. The models differed in other growth measurements and birth parameters. These models can support the detection of early signs of autism in girls and boys by using information routinely recorded during the first 2 years of life., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (ACR) are insensitive biomarkers for early detection of hypertension-mediated organ damage (HMOD). In this nationwide cross-sectional study, we assessed potential biomarkers for early HMOD in healthy persons and patients with hypertension. We hypothesised that plasma levels of biomarkers: (1) are different between healthy controls and patients with hypertension, (2): can classify patients with hypertension according to the degree of hypertension severity., Design and Methods: Patients with hypertension prescribed ≥2 antihypertensive agents were selected from a multicentre study. Healthy controls were selected from an ongoing study of living kidney donor candidates. Uncontrolled hypertension was defined as systolic daytime ambulatory blood pressure ≥135 mmHg. Kidney HMOD was defined by ACR > 3.0 mg/mmol or eGFR < 60 mL/min/1.73 m 2 . Patients with hypertension were categorised into three groups: (1) controlled hypertension; (2) uncontrolled hypertension without kidney HMOD; (3) uncontrolled hypertension with kidney HMOD. Fifteen biomarkers were analysed using a Luminex bead-based immunoassay, and nine fell within the specified analytical range., Results: Plasma levels of Interleukin 1 receptor antagonist (IL-1RA), neutrophil gelatinase-associated lipocalin (NGAL) and uromodulin were significantly different between healthy controls ( n  = 39) and patients with hypertension ( n  = 176). In regression models, with controlled hypertension ( n  = 55) as the reference category, none of the biomarkers were associated with uncontrolled hypertension without ( n  = 59) and with ( n  = 62) kidney HMOD. In models adjusted for cardiovascular risk factors and eGFR, osteopontin (OPN) was associated with uncontrolled hypertension without kidney HMOD (odds ratio (OR) 1.77 (1.05-2.98), p  = 0.03), and regulated upon activation normal T-cell expressed and secreted (RANTES) with uncontrolled hypertension with kidney HMOD (OR 0.57 (0.34-0.95), p  = 0.03)., Conclusions: None of the biomarkers could differentiate our hypertension groups when established risk factors were considered. Plasma OPN may identify patients with uncontrolled hypertension at risk for kidney HMOD.

Objective: To establish a normal reference interval for amniotic sac diameter (ASD) between 7 + 0 and 9 + 6 weeks' gestation and its relative size in relation to gestational sac diameter (GSD) and the embryo crown-rump length (CRL)., Methods: This was a prospective, cross-sectional study of consecutive women presenting to the Early Pregnancy Unit, University College Hospital, London, UK, between August 2022 and June 2023. We included live, normally sited, singleton pregnancies with a normal 20-week anomaly scan. We collected 120 cases per gestational week, from 7 + 0 to 9 + 6 weeks' gestation, totaling 360 cases. We performed an inter- and intraobserver variability assessment in the measurement of mean ASD in 30 patients. Regression analyses were used to establish reference intervals for GSD and CRL, ASD and CRL, GSD and ASD, and GSD/ASD ratio and CRL. A fitted regression line was calculated, along with a 90% prediction interval and R 2 value., Results: There was good interobserver agreement (mean ± SD difference, 0.007 ± 1.105 mm (95% limits of agreement (LoA), -2.160 to 2.174 mm)) and good intraobserver agreement for Observer A (mean ± SD difference, -0.080 ± 0.741 mm (95% LoA, -1.532 to 1.372 mm)) and Observer B (mean ± SD difference, -0.014 ± 0.919 mm (95% LoA, -1.814 to 1.786 mm)) in the measurement of mean ASD. Regression analyses showed a statistically significant association between each pair of values (P < 0.001 for all). There was a significant quadratic association between mean GSD and CRL (R 2  = 56%), mean GSD and ASD (R 2  = 60%) and GSD/ASD ratio and CRL (R 2  = 68%), and a significant cubic association between mean ASD and CRL (R 2  = 90%). The regression equations were used to quantify the values of ASD and GSD/ASD ratios for a range of CRL values and gestational ages., Conclusion: Our study has produced comprehensive reference intervals for amniotic sac size in early pregnancy, which could be used in routine clinical practice. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Biological age is a construct that seeks to evaluate the biological wear and tear process of the organism that cannot be observed by chronological age. We estimate individuals' biological age based on biomarkers from multiple systems and validate it through its association with mortality from natural causes. Biological age was estimated in 12,109 participants (6621 women and 5488 men) from the first visit of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) who had valid data for the biomarkers used in the analyses. Biological age was estimated using the Klemera and Doubal method. The difference between chronological age and biological age (Δage) was computed. Cox proportional hazard models stratified by sex were used to assess whether Δage was associated with mortality risk after a median follow-up of 9.1 years. The accuracy of the models was estimated by the area under the curve (AUC). Δage had equal mean for men and women, with greater variability for men. Cox models showed that every 1-year increase in Δage was associated with increased mortality in men (HR (95% CI) 1.21; 1.17-1.25) and women (HR (95% CI) 1.24; 1.15-1.34), independently of chronological age. Results of the AUC demonstrated that the predictive power of models that only included chronological age (AUC chronological age = 0.7396) or Δage (AUC Δage = 0.6842) was lower than those that included both, chronological age and Δage (AUC chronological age + Δage = 0.802), in men. This difference was not observed in women. We demonstrate that biological age is strongly related to mortality in both genders and is a valid predictor of death in Brazilian adults, especially among men., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Objective: This study was undertaken to establish the potential therapeutic profile of neutrophil-derived extracellular vesicles (EVs) in experimental inflammatory arthritis and associate pharmacological activity with specific EV components, focusing on microRNAs., Methods: Neutrophil EVs were administered intra-articularly through a prophylactic or therapeutic protocol to male C57BL/6 mice undergoing serum-transfer-induced inflammatory arthritis. Transcriptomic analysis of knees was performed on joints following EV administration, naive and arthritic mice (untreated; n = 4/group) and EV-treated diseased mice (intra-articular administration) with contralateral (vehicle-treated; n = 8/group). Comparison of healthy donor and patients with rheumatoid arthritis (RA) neutrophil EVs was performed., Results: EVs afforded cartilage protection with an increase in collagen-II and reduced collagen-X expression within the joint. To gain mechanistic insights, RNA sequencing of the arthritic joints was conducted. A total of 5,231 genes were differentially expressed (P < 0.05), with 257 unique to EV treatment. EVs affected key regenerative pathways involved in joint development, including Wnt and Notch signaling. This wealth of genomic alteration prompted to identify microRNAs in EVs, 10 of which are associated with RA. As a proof of concept, we focused on miR-455-3p, which was detected in both healthy donor and RA EVs. EV addition to chondrocyte cultures elevated miR-455-3p and exerted anticatabolic effects upon interleukin-1β stimulation; these effects were blocked by actinomycin or miR-455-3p antagomir., Conclusion: Neutrophils from patients with RA yielded EVs with composition, efficacy, and miR-455-3p content similar to those of healthy volunteers, suggesting that neutrophil EVs could be developed as an autologous treatment to protect and repair joint tissue of patients affected by inflammatory arthritides., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To establish an image acquisition and post-processing workflow for the determination of the proton density fat fraction (PDFF) in calf muscle tissue at 7 T., Materials and Methods: Echo times (TEs) of the applied vendor-provided multi-echo gradient echo sequence were optimized based on simulations of the effective number of signal averages (NSA*). The resulting parameters were validated by measurements in phantom and in healthy calf muscle tissue (n = 12). Additionally, methods to reduce phase errors arising at 7 T were evaluated. Finally, PDFF values measured at 7 T in calf muscle tissue of healthy subjects (n = 9) and patients with fatty replacement of muscle tissue (n = 3) were compared to 3 T results., Results: Simulations, phantom and in vivo measurements showed the importance of using optimized TEs for the fat-water separation at 7 T. Fat-water swaps could be mitigated using a phase demodulation with an additional B 0 map, or by shifting the TEs to longer values. Muscular PDFF values measured at 7 T were comparable to measurements at 3 T in both healthy subjects and patients with increased fatty replacement., Conclusion: PDFF determination in calf muscle tissue is feasible at 7 T using a chemical shift-based approach with optimized acquisition and post-processing parameters., Competing Interests: Declarations. Conflict of interest: This work was supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung [BMBF]) under the project Molecular Assessment of Signatures Characterizing the Remission of Arthritis (MASCARA, No. 01EC1903A) and by the German Research Foundation (DFG) under the project MR biosignatures at UHF (500888779 / RU5534). Gast L started employment at Siemens Healthineers AG (Erlangen, Germany), and Zeiger P at Bechtle GmbH (Nürnberg, Germany) during drafting of the manuscript. The authors have no further relevant financial or non-financial interests to disclose. Ethical standards: All measurements involving human participants have been approved by the local ethics committee in accordance with the principles of the 1964 Helsinki declaration and its later amendments. All participants gave written informed consent prior to their examination., (© 2024. The Author(s).)

Regenerative approaches towards neuronal loss following traumatic brain or spinal cord injury have long been considered a dogma in neuroscience and remain a cutting-edge area of research. This is reflected in a large disparity between the number of studies investigating primary and secondary injury as therapeutic targets in spinal cord and traumatic brain injuries. Significant advances in biotechnology may have the potential to reshape the current state-of-the-art and bring focus to primary injury neurotrauma research. Recent studies using neural-glial factor/antigen 2 (NG2) cells indicate that they may differentiate into neurons even in the developed brain. As these cells show great potential to play a regenerative role, studies have been conducted to test various manipulations in neurotrauma models aimed at eliciting a neurogenic response from them. In the present study, we systematically reviewed the experimental protocols and findings described in the scientific literature, which were peer-reviewed original research articles (1) describing preclinical experimental studies, (2) investigating NG2 cells, (3) associated with neurogenesis and neurotrauma, and (4) in vitro and/or in vivo, available in PubMed/MEDLINE, Web of Science or SCOPUS, from 1998 to 2022. Here, we have reviewed a total of 1504 papers, and summarized findings that ultimately suggest that NG2 cells possess an inducible neurogenic potential in animal models and in vitro. We also discriminate findings of NG2 neurogenesis promoted by different pharmacological and genetic approaches over functional and biochemical outcomes of traumatic brain injury and spinal cord injury models, and provide mounting evidence for the potential benefits of manipulated NG2 cell ex vivo transplantation in primary injury treatment. These findings indicate the feasibility of NG2 cell neurogenesis strategies and add new players in the development of therapeutic alternatives for neurotrauma., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Objective: To examine the relationship between the penetration (or reach) of a national program aiming to integrate mental health clinicians into all primary care clinics (PC-MHI) and rates of guideline-concordant follow-up and treatment among clinic patients newly identified with depression in the Veterans Health Administration (VA)., Data Sources/study Setting: 15,155 screen-positive patients 607,730 patients with 2-item Patient Health Questionnaire scores in 82 primary care clinics, 2015-2019., Study Design: In this retrospective cohort study, we used established depression care quality measures to assess primary care patients who (a) newly screened positive (score ≥3) and (b) were identified with depression by clinicians via diagnosis and/or medication (n = 15,155; 15,650 patient-years). Timely follow-up included ≥3 mental health, ≥3 psychotherapy, or ≥3 primary care visits for depression. Minimally appropriate treatment included ≥4 mental health visits, ≥3 psychotherapy, or ≥60 days of medication. In multivariate regressions, we examined whether higher rates of PC-MHI penetration in clinic (proportion of total primary care patients in a clinic who saw any PC-MHI clinician) were associated with greater depression care quality among cohort patients, adjusting for year, healthcare system, and patient and clinic characteristics., Data Collection/extraction Methods: Electronic health record data from 82 VA clinics across three states., Principal Findings: A median of 9% of all primary care patients were seen by any PC-MHI clinician annually. In fully adjusted models, greater PC-MHI penetration was associated with timely depression follow-up within 84 days (∆P = 0.5; SE = 0.1; p < 0.001) and 180 days (∆P = 0.3; SE = 0.1; p = 0.01) of a positive depression screen. Completion of at least minimal treatment within 12 months was high (77%), on average, and not associated with PC-MHI penetration., Conclusions: Greater PC-MHI program penetration was associated with early depression treatment engagement at 84-/180-days among clinic patients newly identified with depression, with no effect on already high rates of completion of minimally sufficient treatment within the year., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Aim      To evaluate the role of iron deficiency (ID) identified by various criteria, anemia, and the combination of ID and anemia in determining the severity of the clinical course of chronic heart failure (CHF) in a retrospective analysis of data from 498 patients who participated in the ID-CHF-RF Russian multicenter program.Material and methods  ID was diagnosed by the following three criteria established by the European Society of Cardiology (ESC) and the Russian Society of Cardiology (RSC): 1) ferritin concentration &lt;100 μg/l or ferritin concentration 100-299 μg/l in combination with a decreased transferrin saturation (TS) &lt;20%; 2) ID criteria that showed a high sensitivity and specificity when compared with bone marrow morphology (BMM): TS ≤19.8% or serum iron (SI) ≤13 μmol/l; and 3) a composite index including a ferritin concentration &lt;100 μg/l in combination with TS &lt;20% and SI ≤13 μmol/l. The presence of anemia was defined as a hemoglobin concentration of less than 12.0 g/dl in women and less than 13.0 g/dl in men according to the criteria of the World Health Organization.Results Concomitant anemia was detected in 40.3% of patients with CHF; in 85.1% of cases, anemia was combined with the SI concentration below normal. CHF patients with concomitant anemia were significantly older and had low levels of not only red blood cells and hemoglobin but also all parameters of iron metabolism, i.e., SI, ferritin concentration, and TS. The mean deviation of the red blood cell size, that characterizes the degree of anisocytosis, was significantly increased in patients with anemia, especially with a low SI. These patients had a higher CHF functional class, elevated levels of N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) and walked a shorter distance in the 6-minute walk test, which reflects significantly more severe manifestations of CHF with concomitant anemia, particularly in combination with a low SI. The incidence of ID was 83.1% (including 23.3% in combination with anemia) according to the ESC/RSC criteria; 74.5% (including 43.3% with anemia) according to the BMM criteria; and 51.6% (including 51.7% with anemia) according to the composite index, which seems to be stricter compared to the first two criteria. Regardless of the assessment method (by total weighted average data), in ID combined with anemia, not only the hemoglobin concentration was significantly reduced but all three analyzed parameters of iron metabolism were also significantly reduced (SI 9.0 μmol/l vs. 10.4 μmol/l; ferritin 41 μg/l vs. 59 μg/l; TS 8.5% vs. 12.9%) compared to ID without anemia, respectively. The CHF severity and the NT-proBNP concentration were also maximum for the combination of ID and anemia, in contrast to ID without anemia, regardless of the ID criterion used. A more accurate comparison of the methods for determining ID in CHF in the context of their prognostic value will be obtained by analyzing the data of a two-year follow-up of patients in this study, which will be the subject of the next article.Conclusion      This analysis suggests that the presence of concomitant ID without anemia or anemia without ID moderately affects the severity of clinical manifestations of CHF and may be rather markers than factors determining the course of the disease, and in this case, does not require special correction with iron medications. And only ID anemia (a combination of ID with anemia) in patients with CHF can be considered a condition requiring special correction (for example, with intravenous medication) in addition to optimal therapy for CHF. This conclusion does not change depending on the used criteria for ID and requires verification in new RCTs.

Purpose: For younger, more active patients, a cementless unicompartmental knee arthroplasty (UKA) might be more advantageous than cemented fixation. Therefore, this study aimed to compare implant survivorship and patient-reported outcome measures (PROMs) between cementless and hybrid fixation (cemented femur and cementless tibial fixation) in a novel tibial blade-anchored, medial UKA design., Methods: Two surgeon's registries were reviewed for patients who underwent primary cementless or hybrid medial UKA for medial osteoarthritis between 2019 and 2022. Patients were included if implant survivorship and one-year postoperative PROMs (UCLA-activity score, Oxford Knee Score (OKS), Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR), pain (VAS) and satisfaction) were registered. Variables were compared using independent two-sample t-tests or the Chi-square test. Survival rates were determined using the Kaplan-Meier models and compared using the Log-rank test., Results: A total of 132 knees were included (cementless 58.3%; cemented 41.7%; mean follow-up 3.1 ± 0.6 years). Three-year all-cause revision survival rate was significantly superior for the hybrid fixation (hybrid: 100%; cementless 88.5%[84.7%-92.3%], p = 0.026). However, the difference in three-year conversion rate to total knee arthroplasty (TKA) did not reach statistical significance. The one-year postoperative OKS (hybrid: 42.9 ± 4.8; cementless: 39.8 ± 6.4, p = 0.003) and KOOS-JR (hybrid:81.5 ± 13.7; cementless: 74.4 ± 12.1, p = 0.002) were significantly superior for the hybrid fixation. Three-year conversion rate to TKA and two-year postoperative PROMs did not significantly differ., Conclusion: The cementless medial UKA demonstrated a significantly inferior short-term all-cause survival rate and inferior postoperative one-year OKS and KOOS-JR compared to the hybrid medial UKA design with a cemented femoral component., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)