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Background: Single-pill combinations (SPCs) of three low-dose antihypertensive drugs can improve hypertension control but are not widely available. A key issue for any combination product is the contribution of each component to efficacy and tolerability. This trial compared a new triple SPC called GMRx2, containing telmisartan, amlodipine, and indapamide, with dual combinations of components for efficacy and safety., Methods: In this international, randomised, double-blind, active-controlled trial, we enrolled adults with hypertension receiving between zero and three antihypertensive drugs, with a screening systolic blood pressure (SBP) ranging from 140-179 mm Hg (on no drugs) to 110-150 mm Hg (on three drugs). Participants were recruited from Australia, the Czech Republic, New Zealand, Poland, Sri Lanka, the UK, and the USA. In a 4-week active run-in, existing medications were switched to GMRx2 half dose (telmisartan 20 mg, amlodipine 2·5 mg, and indapamide 1·25 mg). Participants were then randomly allocated (2:1:1:1) to continued GMRx2 half dose or to each possible dual combination of components at half doses (telmisartan 20 mg with amlodipine 2·5 mg, telmisartan 20 mg with indapamide 1·25 mg, or amlodipine 2·5 mg with indapamide 1·25 mg). At week 6, doses were doubled in all groups, unless there was a clinical contraindication. The primary efficacy outcome was mean change in home SBP from baseline to week 12, and the primary safety outcome was withdrawal of treatment due to an adverse event from baseline to week 12. Secondary efficacy outcomes included differences in clinic and home blood pressure levels and control rates. This study is registered with ClinicalTrials.gov, NCT04518293, and is completed., Findings: The trial was conducted between July 9, 2021 and Sept 1, 2023. We randomly allocated 1385 participants to four groups: 551 to GMRx2, 276 to telmisartan-indapamide, 282 to telmisartan-amlodipine, and 276 to amlodipine-indapamide groups. The mean age was 59 years (SD 11), 712 (51%) participants self-reported as female and 673 (48·6%) male, and the mean clinic blood pressure at the screening visit was 142/85 mm Hg when taking an average of 1·6 blood pressure medications. Following the run-in on GMRx2 half dose, the mean clinic blood pressure level at randomisation was 133/81 mm Hg and the mean home blood pressure level was 129/78 mm Hg. At week 12, the mean home SBP was 126 mm Hg in the GMRx2 group, which was lower than for each of the dual combinations: -2·5 (95% CI -3·7 to -1·3, p<0·0001) versus telmisartan-indapamide, -5·4 (-6·8 to -4·1, p<0·0001) versus telmisartan-amlodipine, and -4·4 (-5·8 to -3·1, p<0·0001) versus amlodipine-indapamide. For the same comparisons, differences in clinic blood pressure at week 12 were 4·3/3·5 mm Hg, 5·6/3·7 mm Hg, and 6·3/4·5 mm Hg (all p<0·001). Clinic blood pressure control rate below 140/90 mm Hg at week 12 was superior with GMRx2 (74%) to with each dual combination (range 53-61%). Withdrawal of treatment due to adverse events occurred in 11 (2%) participants in the GMRx2 group, four (1%) in telmisartan-indapamide, three (1%) in telmisartan-amlodipine, and four (1%) in amlodipine-indapamide, with none of the differences being statistically significant., Interpretation: A novel low-dose SPC product of telmisartan, amlodipine, and indapamide provided clinically meaningful improvements in blood pressure reduction compared with dual combinations and was well tolerated. This SPC provides a new therapeutic option for the management of hypertension and its use could result in a substantial improvement in blood pressure control in clinical practice., Funding: George Medicines., Competing Interests: Declaration of interests AR, AS, AES, CG, MS, XL, and NW are employed at The George Institute for Global Health (TGI), which holds an interest in George Medicines via its social enterprise arm, George Institute Ventures. None of the TGI staff has a personal financial interest in George Medicines. AR is seconded part-time to George Medicines. TGI holds patents for ultra-low-dose, fixed-dose combination products for the treatment of hypertension and diabetes, and AR is listed as one of the inventors (granted: US 10 369 156, US 10 799 487, US 10 322 117, US 11 033 544, US 11 478 462; pending: US 17/932 982, US 18/446 268, US 17/598 122, US 17/317 614, US 17/527 084, US 17/527 085, US 17/527 087). AR does not have a financial interest in these patents. None of the other authors has a financial interest in George Medicines or has received funding for their independent contribution to the GMRx2 programme. AR reports consulting fees as a data and safety monitoring board member for Idorsia; and a fellowship grant from the National Health and Medical Research Council of Australia (GNT 1160743). AES reports consulting fees or speaker honoraria from OMRON Healthcare, Aktiia, Medtronic, Servier, Abbott, Sanofi, Sun Pharmaceuticals, Novartis, and Skylabs; being co-chair of the National Hypertension Taskforce Australia; being a board member for Hypertension Australia and the Australian Cardiovascular Alliance; and an investigator grant from the National Health and Medical Research Council of Australia (GNT 2017504). DBO reports speaker honoraria from Novartis, AstraZeneca, Servier, Swipha, and Boehringer Ingelheim for speaking at educational meetings. KN reports speaker and consulting honoraria from Bausch Health, Berlin-Chemie/Menarini, Egis, Idorsia, Janssen, Gedeon Richter, Gilead, Krka, Novo Nordisk, Polpharma, Recordati, Sandoz, and Servier; and honoraria from or participation on advisory boards for Polpharma and Zentiva. MPS reports consulting fees or travel and research support from Medtronic, Abbott, Recor, Novartis, Servier, Pfizer, and Boehringer Ingelheim; and being current President of Hypertension Australia and Treasurer of the World Hypertension League. WCC reports institutional grants from Recor and George Medicines; and consulting fees from Alnylam Pharmaceuticals. NRP reports consultancy fees from Servier and Aktiia; support for research projects and staff from Servier and Pfizer; support for arranging and speaking at educational meetings from AstraZeneca, LRI-Therapharma, Napi, Servier, Sanofi, EVA Pharma, Pfizer, Emcure, Dr Reddy's Laboratories, and Zydus; and support by the National Institute for Health Research Senior Investigator Awards, Biomedical Research Centre funding, and the British Heart Foundation Research Centre Excellence Award. DEG reports funding to his department as part of the EU Horizon Hypermarker project. BW reports trial steering committee appointments for Novartis and AstraZeneca; lecture fees for Servier and Novartis; and an unremunerated role as President of the International Society of Hypertension. JTW reports institutional grants from the National Institutes of Health, the Ohio Department of Medicaid, and the Agency for Healthcare Research and Quality; travel support and participation on an advisory board for Medtronic; being chair of the data safety monitoring board for the IMPACTS MIND Trial at Tulane University; and being on the Northeast Ohio Neighbourhood Health Center Community Board of Directors. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The Ferrier rearrangement was utilized to obtain 2,3-unsaturated diosgenyl glycosides. This reaction proceeded with high stereoselectivity, yielding mostly saponins with an α configuration (hexoses) or predominantly with a β configuration (pentoses). The diversity of the glycals used and the glycosides obtained enabled a deep discussion of the Ferrier rearrangement mechanism. The mechanism was supported by DFT calculations concerning the intermediate ions. It was concluded that the vinylogous anomeric effect may influence the reactivity of the glycals. Two possible Ferrier rearrangement intermediates, dioxolenium and allyloxycarbenium ions, were hypothesized to exist in thermodynamic equilibrium that shifted toward the former. The allyloxycarbenium ion participates in the final rearrangement step and determines the reaction regioselectivity. Furthermore, the conformational stability of the 2,3-unsaturated pyranose ring determines the stereoselectivity of the reaction. Factors influencing this stability, as well as the NMR data enabling recognition of the 0 H 5 and 5 H 0 conformations, were identified. Chemoselective hydrogenation of 2,3-unsaturated diosgenyl glycosides provided a series of 2,3-dideoxy analogues. The anticancer, hemolytic, and antibacterial activities of the synthesized saponins are presented alongside a discussion of the structure-activity relationships.

The diverse structural tunability of 2-dimensional π-stacked layered metal-organic frameworks (2D MOFs) enables the control of charge carrier mobility to achieve specific photoconductive characteristics. This study demonstrates the potential of various theoretical methodologies and frameworks in establishing a correlation between structure and functionality for such purposes. Through a focus on the archetypal Ni 3 (HITP) 2 2D MOF, we examine the impact of quantum confinement and stacking fault defects on the absorption spectra using our recently-developed Frenkel-Holstein Hamiltonian. Specifically, the relationship between optical properties and number of layer units along the π-stacking direction is discussed. We employ Marcus rate theory to evaluate vertical carrier mobility subject to inter-layer proximity and different crystal packing which affect van der Waals interactions between layers. The insights presented in this research can inform the development of guidelines for enhancing photoconductive properties in 2D MOF nanosheets.

Hsp70 is a key cellular system counteracting protein misfolding and aggregation, associated with stress, ageing, and disease. Hsp70 solubilises aggregates and aids protein refolding through substrate binding and release cycles regulated by co-chaperones: J-domain proteins (JDPs) and nucleotide exchange factors (NEFs). Here, we elucidate the collaborative impact of Hsp110 NEFs and different JDP classes throughout Hsp70-dependent aggregate processing. We show that Hsp110 plays a major role at initial stages of disaggregation, determining its final efficacy. The NEF catalyses the recruitment of thick Hsp70 assemblies onto aggregate surface, which modifies aggregates into smaller species more readily processed by chaperones. Hsp70 stimulation by Hsp110 is much stronger with class B than class A JDPs and requires the auxiliary interaction between class B JDP and the Hsp70 EEVD motif. Furthermore, we demonstrate for the first time that Hsp110 disrupts the JDP-Hsp70 interaction. Such destabilisation of chaperone complexes at the aggregate surface might improve disaggregation, but also lead to the inhibition above the sub-stoichiometric Hsp110 optimum. Thus, balanced interplay between the co-chaperones and Hsp70 is critical to unlock its disaggregating potential., Competing Interests: WS, HW, MP, KK, MR, KL, AK No competing interests declared, (© 2024, Sztangierska et al.)

Introduction: Premature and low-birthweight infants are at especially high risk of perinatal complications, including impaired thermoregulation, infections and respiratory distress. Such adverse effects and the need for invasive procedures are associated with high mortality among preterms. This study focused on the influence of the innate immune system and tested the levels of collectins, collectin-10 (CL-10), collectin-11 (CL-11) and mannose-binding lectin (MBL) in preterm neonates., Methods: Cord blood was collected from 535 preterms (born at gestational age ≤37 weeks). COLEC10 and COLEC11 polymorphisms were analyzed by real-time PCR and those of MBL2 by PCR/PCR-RFLP. The concentrations of collectins in sera from cord blood were determined with ELISA., Findings: Low concentrations of CL-10 in cord sera (<462 ng/ml corresponding to the 10 th percentile) were significantly associated with births at GA ≤32 weeks. Median levels of both CL-10 and CL-11 were significantly lower in preterms with very low birthweight (<1500 g), low Apgar 1' score and those who needed prolonged hospitalisation. Lower median CL-10 was also observed in fetal growth restriction cases. An important finding was the decreased concentrations of CL-10, CL-11 and MBL in respiratory distress syndrome (RDS). For CL-10 and CL-11, that relationship was confined to infants born at GA ≥33 weeks and/or with body mass at birth ≥1500 g. Only CL-10 was found to influence susceptibility to early-onset infections. COLEC11 heterozygosity for the activity-decreasing polymorphism (rs7567833, +39618 A>G, His219Arg) was more common in preterm premature rupture of membranes (pPROM) cases, compared with corresponding reference groups. Furthermore, C/T or T/T genotypes at COLEC11 at rs3820897 (-9570 C>T) as well as MBL deficiency-associated MBL2 gene variants were more common in preterms diagnosed with RDS than among unaffected newborns., Conclusion: The complement-activating collectins investigated here could be important for maintaining homeostasis in preterm neonates. Despite similar structure and specificity, MBL, CL-10 and CL-11 manifest a different spectrum of clinical associations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gajek, Hansen, Jarych, Kufelnicka-Babout, Świerzko, Kobiela, Szala-Poździej, Chojnacka, Sobczuk, Domżalska-Popadiuk, Mazela, Kalinka, Thiel and Cedzyński.)

Beneath the surface of our ecosystems, microplastics (MPs) silently loom as a significant threat. These minuscule pollutants, invisible to the naked eye, wreak havoc on living organisms and disrupt the delicate balance of our environment. As we delve into a trove of data and reports, a troubling narrative unfolds: MPs pose a grave risk to both health and food chains with their diverse compositions and chemical characteristics. Nevertheless, the peril extends further. MPs infiltrate the environment and intertwine with other pollutants. Worldwide, microplastic levels fluctuate dramatically, ranging from 0.001 to 140 particles.m -3 in water and 0.2 to 8766 particles.g -1 in sediment, painting a stark picture of pervasive pollution. Coastal and marine ecosystems bear the brunt, with each organism laden with thousands of microplastic particles. MPs possess a remarkable ability to absorb a plethora of contaminants, and their environmental behavior is influenced by factors such as molecular weight and pH. Reported adsorption capacities of MPs vary greatly, spanning from 0.001 to 12,700 μg·g -1 . These distressing figures serve as a clarion call, demanding immediate action and heightened environmental consciousness. Legislation, innovation, and sustainable practices stand as indispensable defenses against this encroaching menace. Grasping the intricate interplay between microplastics and pollutants is paramount, guiding us toward effective mitigation strategies and preserving our health ecosystems., 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.)

Research over the past years has compared the enantiomers (S)-ketamine (esketamine) and (R)-ketamine (arketamine) of the previously known racemic mixture called ketamine (R/S-ketamine). Esketamine has been found to be more potent, offering three times stronger analgesic effects and 1.5 times greater anesthetic efficacy than arketamine. It provides smoother anesthesia with fewer side effects and is widely used in clinical settings due to its neuroprotective, bronchodilatory, and antiepileptic properties. Approved by the FDA and EMA in 2019, esketamine is currently used alongside SSRIs or SNRIs for treatment-resistant depression (TRD). On the other hand, arketamine has shown potential for treating neurological disorders such as Alzheimer's, Parkinson's, and multiple sclerosis, offering possible antidepressant effects and anti-inflammatory benefits. While esketamine is already in clinical use, arketamine's future depends on further research to address its safety, efficacy, and optimal dosing. Both enantiomers hold significant clinical value, with esketamine excelling in anesthesia, and arketamine showing promise in neurological and psychiatric treatments.

Objective: Young people are routinely exposed to e-cigarettes advertising. We examined the impact of e-cigarette advertising on e-cigarette use in a large representative sample of adolescents., Methods: Data came from cross-sectional sample of the nationwide study on the health effects of tobacco products called PolNicoYouth, which included adolescents aged 15-18 years ( N  = 7,498). Data were collected through a detailed questionnaire recommended by international health organizations for monitoring tobacco use by adolescents. Simple and multiple logistic regression analyzes were conducted, adjusting for sex, age, type of school, place of residence, smoking of traditional cigarettes and parental smoking. Frequencies and proportions for descriptive statistics, and adjusted odds ratios with 95% confidence intervals for logistic regression models were reported., Results: Approximately, 56% of interviewees had noticed some form of e-cigarettes advertising. Exposure to e-cigarette advertising was significantly associated with ever use of e-cigarettes (OR = 1.29; 95% CI: 1.09-1.53). Exposure to e-cigarette advertising via club/pub/disco was significantly associated with current e-cigarette use (OR = 1.58; 95% CI: 1.06-2.36). Adolescents who have ever used e-cigarettes were more likely than never users to report exposure to advertisements on club/pub/disco (OR = 1.57; 95% CI: 1.08-2.30) and internet (OR = 1.22; 95% CI: 1.01-1.47)., Conclusion: Despite the applicable advertising restrictions, the majority of young people declared contact with e-cigarette advertising, which shows the urgent need for more global action. The internet and advertisements in clubs, pubs and discos seem to be the key places of exposure. These forms of exposure need to be urgently addressed given their clear link to e-cigarette use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Świątkowska, Zajdel, Balwicki and Kaleta.)

Purpose: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) have a poor prognosis. The phase I/II NP30179 study (ClinicalTrials.gov identifier: NCT03075696) evaluated glofitamab monotherapy in patients with R/R B-cell lymphomas, with obinutuzumab pretreatment (Gpt) to mitigate the risk of cytokine release syndrome (CRS) with glofitamab. We present data for patients with R/R MCL., Methods: Eligible patients with R/R MCL (at least one previous therapy) received Gpt (1,000 or 2,000 mg) 7 days before the first glofitamab dose (single dose or split over 2 days if required). Glofitamab step-up dosing was administered once a day on days 8 (2.5 mg) and 15 (10 mg) of cycle 1, with a target dose of 16 or 30 mg once every 3 weeks from cycle 2 day 1 onward, for 12 cycles. Efficacy end points included investigator-assessed complete response (CR) rate, overall response rate (ORR), and duration of CR., Results: Of 61 enrolled patients, 60 were evaluable for safety and efficacy. Patients had received a median of two previous therapies (range, 1-5). CR rate and ORR were 78.3% (95% CI, 65.8 to 87.9) and 85.0% (95% CI, 73.4 to 92.9), respectively. In patients who had received previous treatment with a Bruton tyrosine kinase inhibitor (n = 31), CR rate was 71.0% (95% CI, 52.0 to 85.8) and ORR was 74.2% (95% CI, 55.4 to 88.1). CRS after glofitamab administration occurred in 70.0% of patients, with a lower incidence in the 2,000 mg (63.6% [grade ≥2, 22.7%]) versus 1,000 mg (87.5%; grade ≥2, 62.5%) Gpt cohort. Four adverse events led to glofitamab withdrawal (all infections)., Conclusion: Fixed-duration glofitamab induced high CR rates in heavily pretreated patients with R/R MCL; the safety profile was manageable with appropriate support.

Background: Pancreatic cancer (PC) is one of the most aggressive cancers and is the seventh leading cause of cancer-related death worldwide. PC is characterized by rapid progression and resistance to conventional treatments. Mutations in KRAS, CDKN2A, TP53, SMAD4/DPC4, and MYC are major genetic alterations associated with poor treatment outcomes in patients with PC. Therefore, optimizing PC therapy is a tremendous challenge. Unsymmetrical bisacridines (UAs), synthesized by our group, are new promising compounds that have exhibited high cytotoxicity and antitumor activity against several solid tumors, including pancreatic cancer., Methods: The cellular effects induced by UAs in PC cells were evaluated by MTT assay (cell growth inhibition), flow cytometry, and fluorescence and light microscopy (cell cycle distribution, apoptosis, and senescence detection). Analysis of the effects of UAs on the levels of proteins (c-Myc, p53, SMAD4, p21, and p16) was performed by Western blotting., Results: Apoptosis was the main triggered mechanism of death after UAs treatment, and induction of the SMAD4 protein can facilitate this process. c-Myc, which is one of the molecular targets of UAs, can participate in the induction of cell death in a p53-independent manner. Moreover, UAs can also induce accelerated senescence through the upregulation of p21. Notably, senescent cells can die via apoptosis after prolonged exposure to UAs., Conclusions: UAs have emerged as potent anticancer agents that induce apoptosis by inhibiting c-Myc protein and triggering cellular senescence in a dose-dependent manner by increasing p21 levels. Thus, UAs exhibit desirable features as promising candidates for future pancreatic anticancer therapies., (© 2024. The Author(s).)

Objectives: IMbrella A is a Phase III extension study that allowed rollover from Roche/Genentech-sponsored atezolizumab trials, including IMpower133, a Phase I/III trial of first-line atezolizumab or placebo plus carboplatin/etoposide in extensive-stage small cell lung cancer. We report outcomes from an exploratory analysis of IMpower133 with extended time-to-event data for patients who rolled over to IMbrella A., Materials and Methods: IMpower133 patients could roll over to IMbrella A to receive atezolizumab 1200 mg intravenously every three weeks if they continued to receive atezolizumab at IMpower133 closure or were in survival follow-up after atezolizumab discontinuation. Overall survival and safety were assessed; only serious adverse events and AEs of special interest were collected in IMbrella A., Results: Eighteen of 26 eligible patients rolled over to IMbrella A. At clinical cutoff (March 16, 2023), median follow-up in the atezolizumab plus carboplatin/etoposide arm (IMpower133 and IMbrella A) was 59.4 months. The three-, four-, and five-year overall survival (95 % CI) estimates were 16 % (11 %-21 %), 13 % (8 %-18 %), and 12 % (7 %-17 %), respectively. In IMbrella A, serious adverse events occurred in three patients (16.7 %), and one adverse event of special interest was reported (grade two hypothyroidism)., Conclusion: This long-term analysis of patients from IMbrella A previously enrolled in IMpower133 provides the first report of five-year overall survival outcomes in patients with extensive-stage small cell lung cancer treated with first-line cancer immunotherapy and chemotherapy. While limited by small patient numbers and lack of long-term data for the IMpower133 control arm, exploratory overall survival analyses in patients treated with atezolizumab plus carboplatin/etoposide compared favorably with historical data with chemotherapy alone. NCT03148418., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report editorial support funded by the Sponsor. Martin Reck reports receiving consulting fees, honoraria and travel support from Amgen, AstraZeneca, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Lily, Novartis, Pfizer, Sanofi, Roche, and Regeneron; and participation on a data safety monitoring or advisory board for Sanofi and Daiichi Sankyo. Rafal Dziadziuszko reports receiving honoraria from Roche, AstraZeneca, Amgen, Novartis, MSD, Bristol Myers Squibb, Takeda, and Pfizer; and materials from Novartis. Shunichi Sugawara reports receiving grants (to institution) from AstraZeneca, Chugai Pharma, MSD, Bristol Myers Squibb, and Ono Pharmaceutical; and honoraria from AstraZeneca, Chugai Pharma, MSD, Bristol Myers Squibb, and Ono Pharmaceutical. Steven Kao reports receiving grants (to institution) from AstraZeneca; honoraria from AstaZeneca, Pfizer, MSD, Bristol Myers Squibb, Roche, Amgen, Beigene, and Boehringer Ingelheim; and travel support from MSD. Maximilian Hochmair reports receiving honoraria from MSD, Roche, Lilly, AstraZeneca, Takeda, Bristol Myers Squibb, and Amgen. Florian Huemer declares no conflict of interest. Gilberto de Castro, Jr reports receiving consulting fees from Daiichi-Sankyo; honoraria from AstraZeneca, Bristol Myers Squibb, Jannsen, Lilly, MSD, Novartis, Roche, Amgen, and Daiichi-Sankyo; travel support from Roche, Amgen, Daiichi-Sankyo, MSD, AstraZeneca, and Bristol Myers Squibb; and participation on a data safety monitoring or advisory board for GlaxoSmithKline, AstraZeneca, MSD, and Novartis. Libor Havel declares no conflict of interest. Reyes Bernabé Caro reports receiving an investigational grant from Roche; honoraria from Roche, Bristol Myers Squibb, Pfizer, MSD, Amgen, Takeda, and AstraZeneca; and participation in a data safety monitoring or advisory board for Takeda, Roche, Bristol Myers Squibb, and AstraZeneca. György Losonczy and Jong-Seok Lee declare no conflict of interest. Dariusz M. Kowalski reports participation on an advisory board and consultancy for Roche, Boehringer Ingelheim, Novartis, Bristol Myers Squibb, MSD, Sanofi-Aventis, Takeda, Pfizer, and Johnson & Johnson. Zoran Andric declares no conflict of interest. Raffaele Califano reports receiving grants (to institution) from Roche and MSD; consulting fees from Roche, MSD, Bristol Myers Squibb, and AstraZeneca; and honoraria from Roche, MSD, and AstraZeneca; membership in the EORTC lung cancer group and ESMO educational publication working group; and stock or stock options in The Christie Private Care and Supportive Care UK. Andrea Veatch, Gregory Gerstner, and Marta Batus declare no conflicts of interest. Stefanie Morris reports employment with and stock or stock options in Roche. Monika Kaul, Vaikunth Cuchelkar, Huafei Li, Bradford J. Danner, and Barzin Y. Nabet report employment with Roche. Stephen V. Liu reports receiving grants from AbbVie, Alkermes, Elevation Oncology, Ellipses, Genentech, Gilead, Merck, Merus, Nuvalent, RAPT, and Turning Point Therapeutics; and consulting fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics; and participation on a data safety monitoring for Candel Therapeutics., (Copyright © 2024. Published by Elsevier B.V.)

Williams-Beuren syndrome (WBS) is a congenital multisystem disorder affecting the cardiovascular, central nervous, and musculoskeletal systems. Cardiovascular abnormalities, which consist principally of vascular stenoses, occur in approximately 80% of people with WBS and are the predominant cause of early morbidity and mortality. Supravalvar aortic stenosis and peripheral pulmonary artery stenosis are the most common stenotic lesions in WBS, though other stenoses often occur, including stenoses of the coronary arteries. Approximately one-third of people with WBS undergo cardiovascular interventions. The risk of sudden cardiac death is markedly higher than the general population, with most events occurring in the periprocedural period. Because of the rarity of WBS and the often-complex nature of the cardiovascular abnormalities, most physicians, including cardiologists, have limited experience in caring for patients with WBS. Further, heretofore, clinical cardiovascular management guidelines based on international expert consensus have not been available. This state-of-the-art review provides a comprehensive synopsis of the cardiovascular abnormalities in WBS and presents clinical management guidelines based on the authors' expert consensus.

Background: Young women with breast cancer (BC) have an increased chance of carrying germline BRCA pathogenic variants (PVs). Limited data exist on the prognostic impact of tumor histology (i.e. ductal versus lobular) in hereditary breast cancer., Methods: This multicenter retrospective cohort study included women aged ≤40 years with early-stage breast cancer diagnosed between January 2000 and December 2020 and known to carry germline PVs in BRCA1/2. Histology was locally assessed in each center. The Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival and overall survival., Results: Of 4628 patients included from 78 centers worldwide, 3969 (86%) had pure ductal, 135 (3%) pure lobular, and 524 (11%) other histologies. Compared with ductal tumors, lobular tumors were more often grade 1/2 (57.7% versus 22.1%), stage III (29.6% versus 18.5%), and luminal A-like (42.2% versus 12.2%). Lobular tumors were more often associated with BRCA2 PVs (71.1% BRCA2), while ductal tumors were more often associated with BRCA1 PVs (65.7% BRCA1). Patients with lobular tumors more often had mastectomy (68.9% versus 58.3%), and less often received chemotherapy (83.7% versus 92.9%). With a median follow-up of 7.8 years, no significant differences were observed in disease-free survival (adjusted hazard ratio 1.01, 95% confidence interval 0.74-1.37) or overall survival (hazard ratio 0.96, 95% confidence interval 0.62-1.50) between patients with ductal versus lobular tumors. No significant survival differences were observed according to specific BRCA gene, breast cancer subtype, or body mass index., Conclusions: In this large global cohort of young BRCA carriers with breast cancer, the incidence of pure lobular histology was low and associated with higher disease stage at diagnosis, luminal-like disease and BRCA2 PVs. Histology did not appear to impact prognosis., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Dermoscopy of the nail unit (onychoscopy) is a method which allows for non-invasive observation of the nail structures, increasing the accuracy of clinical diagnosis. Currently, it is used in evaluation of both inflammatory and neoplastic conditions of the nail unit. However, in contrast to the skin, the anatomy of the nail unit prevents direct observation of nail bed or nail matrix structure during classic onychoscopy. Intra-operative onychoscopy is a variant of the technique which uses direct visualization of the nail unit structures after nail plate avulsion. The aim of this systematic review was to summarize the current state of knowledge on intra-operative onychoscopy. The MEDLINE, EMBASE and Cochrane databases were systematically searched in January 2024. All types of study designs assessing intra-operative dermoscopy of the nail unit were included in this study. The risk of bias in included studies was assessed using the Joanna Briggs Institute critical appraisal tools. The qualitative synthesis of 19 studies totalling a number of 218 cases in 217 patients included the following entities: melanoma, nevus, hypermelanosis (melanocytic activation), melanocytic hyperplasia, melanophages accumulation, squamous cell carcinoma, glomus tumour, lichen planus, onychomatricoma, onychomycosis and subungual exostosis. The main limitation of the study was a relatively low number of identified studies, most with low levels of evidence. Intra-operative onychoscopy does not replace histologic examination, though it may be useful in determining the modality of surgical diagnostic procedures., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

T regulatory lymphocytes (Treg) expressing CCR5 exhibit strong suppression activity in various autoimmune disorders. However, there remains a lack of comprehensive understanding regarding their involvement in the development of type 1 diabetes (T1D). In this study, we examined the role of the CCR5/CCL5 axis in regulating inflammatory response and its impact on regulatory T cells in type 1 diabetes (T1D). We hypothesize that dysregulation of the CCR5/CCL5 axis contributes to the development and progression of T1D through modulation of Treg-dependent immune responses. We analyzed the expression levels of CCR5 on Tregs isolated from individuals with T1D, as well as the plasma concentration of its main ligands. We found that Tregs from T1D patients exhibited decreased expression of CCR5 compared to healthy controls. Additionally, we observed a correlation between the expression levels of CCR5 on Tregs and their immunosuppressive function in T1D patients. Our results indicate the impaired migratory capacity of CCR5 + Tregs, suggesting a possible link between the dysregulation of the CCR5/CCL5 axis and impaired immune regulation in T1D. In line with previous studies, our findings support the notion that dysregulation of the CCR5/CCL5 axis contributes to the development and progression of type 1 diabetes (T1D) by modulating Treg-dependent immune responses. The decreased expression of CCR5 on Tregs in T1D patients suggests a potential impairment in the migratory capacity of these cells, which could compromise their ability to suppress autoreactive T cells and maintain immune homeostasis. Furthermore, our study highlights the importance of CCR5 as a biomarker for identifying dysfunctional Tregs in T1D., Competing Interests: Declarations Ethics approval The study followed the principles of the Declaration of Helsinki and was approved by The Ethics Committee of The Medical University of Gdansk (NKBBN/645/2019). From all parents of juvenile participants, written informed consent was obtained. Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Parastomal hernia (PH) is a prevalent complication following ostomy formation, presenting significant challenges in surgical management. This study aims to validate the European Hernia Society classification for PH through the application of the Hybrid Parastomal Endoscopic Repair (HyPER) method. The study focuses on establishing the practical utility of the European Hernia Society classification in a clinical setting, particularly in guiding surgical approaches and improving patient outcomes., Materials and Methods: This retrospective observational study aimed to assess the utility of the European Hernia Society classification in planning surgical strategies for parastomal hernias. The validation of the classification of PH was based on the experience involving 160 patients in single center. Patients were classified according to the European Hernia Society criteria, and data were collected on patient demographics, clinical presentations, and surgical outcomes. Main goal was to assess the consistency and applicability of the European Hernia Society classification in predicting surgical challenges and outcomes., Results: The study found a predominance of complex Type III and IV hernias. The European Hernia Society classification was effective in categorizing PH, aiding in surgical planning and highlighting the increased complication rates associated with more complex hernia types. This study represents the largest single-center cohort treated for PH by a single team, providing a controlled evaluation of the HyPER technique's effectiveness., Conclusions: The validation of the European Hernia Society classification in this study is a significant advancement in the standardization of PH management. The findings demonstrate the classification's utility in enhancing surgical planning and patient-centered care. The study also opens avenues for further research into standardized approaches and techniques in PH treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

The traditional healthcare model is focused on diseases (medicine and natural science) and does not acknowledge patients' resources and abilities to be experts in their own lives based on their lived experiences. Improving healthcare safety, quality, and coordination, as well as quality of life, is an important aim in the care of patients with chronic conditions. Person-centered care needs to ensure that people's values and preferences guide clinical decisions. This paper reviews current knowledge to develop (1) digital care pathways for rhinitis and asthma multimorbidity and (2) digitally enabled, person-centered care. 1 It combines all relevant research evidence, including the so-called real-world evidence, with the ultimate goal to develop digitally enabled, patient-centered care. The paper includes (1) Allergic Rhinitis and its Impact on Asthma (ARIA), a 2-decade journey, (2) Grading of Recommendations, Assessment, Development and Evaluation (GRADE), the evidence-based model of guidelines in airway diseases, (3) mHealth impact on airway diseases, (4) From guidelines to digital care pathways, (5) Embedding Planetary Health, (6) Novel classification of rhinitis and asthma, (7) Embedding real-life data with population-based studies, (8) The ARIA-EAACI (European Academy of Allergy and Clinical Immunology) strategy for the management of airway diseases using digital biomarkers, (9) Artificial intelligence, (10) The development of digitally enabled, ARIA person-centered care, and (11) The political agenda. The ultimate goal is to propose ARIA 2024 guidelines centered around the patient to make them more applicable and sustainable., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The detection of HPV infection and microbial colonization in cervical lesions is currently done through PCR-based viral or bacterial DNA amplification. Our objective was to develop a methodology to expand the metaproteomic landscape of cervical disease and determine if protein biomarkers from both human and microbes could be detected in distinct cervical samples. This would lead to the development of multi-species proteomics, which includes protein-based lateral flow diagnostics that can define patterns of microbes and/or human proteins relevant to disease status. In this study, we collected both non-frozen tissue biopsy and exfoliative non-fixed cytology samples to assess the consistency of detecting human proteomic signatures between the cytology and biopsy samples. Our results show that proteomics using biopsies or cytologies can detect both human and microbial organisms. Across patients, Lumican and Galectin-1 were most highly expressed human proteins in the tissue biopsy, whilst IL-36 and IL-1RA were most highly expressed human proteins in the cytology. We also used mass spectrometry to assess microbial proteomes known to reside based on prior 16S rRNA gene signatures. Lactobacillus spp. was the most highly expressed proteome in patient samples and specific abundant Lactobacillus proteins were identified. These methodological approaches can be used in future metaproteomic clinical studies to interrogate the vaginal human and microbiome structure and metabolic diversity in cytologies or biopsies from the same patients who have pre-invasive cervical intraepithelial neoplasia, invasive cervical cancer, as well as in healthy controls to assess how human and pathogenic proteins may correlate with disease presence and severity., 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. Published by Elsevier B.V.)

Background: The purpose of this study was to compare radiological outcomes of total knee arthroplasty (TKA) in mechanical alignment implant positioning in the coronal and sagittal planes depending on surgeons' handedness and their position at the operating table., Methods: A total number of 200 consecutive patients with idiopathic osteoarthritis and varus knees who underwent TKA were retrospectively included in this research. Patients were operated on by 4 surgeons (50 for each surgeon) selected according to their handedness and position at the operative table. Surgeon I (right-handed, standing at the operating table always on the right side); Surgeon II(left-handed, standing at the operating table always on the left side); Surgeon III (right-handed, standing at the operating table on the side of the operated limb); Surgeon IV (left-handed, standing at the operating table on the side of the operated limb)., Results: Comparing postoperative radiological results statistically significant differences were calculated in the case of deviation from HKA angle (left TKA -1.5°; Interquartile Range [IQR] = -2.6-[-1] vs right TKA -3°; IQR = -4.5-[-2]; p = 0.01) for surgeon II and MPTA for surgeon IV (left TKA 0°; IQR = -1-0.5 vs right TKA 1°; IQR = 0-2; p < 0.01). Higher deviation from the mechanical alignment angles and implant positioning was revealed for a less convenient operation site for the surgeon., Conclusion: We recommend that all surgeons performing TKAs from the less comfortable side should take great care in establishing the MPTA and HKA angles to avoid surgical errors in implant positioning and limb alignment., 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 Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Atherogenic indices: Triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, Atherogenic Index of Plasma (AIP), Atherogenic Coefficient (AC), Castelli's Risk Index I and II (CRI-I, CRI-II) are used in clinical studies as surrogates of major adverse cardiac and cerebrovascular events (MACCE). Risk prediction of MACCE in patients with acute myocardial infarction (AMI) has vital role in clinical practice. We aimed to assess prognostic value of these indices following AMI., Methods: We analyzed patients with AMI with and without T2DM and the prognostic values of atherogenic indices for in-hospital death and MACCE within 12 months after AMI., Results: Of 2461 patients, 152 in-hospital deaths (6.2 %) were reported (74 patients [7.4 %] with T2DM and 78 [5.3 %] without T2DM; p = 0.042). MACCE occurred in 22.7 % of patients (29.7 % with T2DM and 17.9 % without T2DM; p < 0.001). TG/HDL-C and AIP were higher in T2DM patients compared to those without T2DM (p < 0.001). Long-term MACCE was more prevalent in patients with T2DM (p < 0.001). The AUC-ROC for predicting in-hospital death based on TG/HDL-C and AIP was 0.57 (p = 0.002)., Conclusions: None of the atherogenic indices was an independent risk factor for in-hospital death or MACCE at 12-month follow-up in patients with AMI. AIP was an independent risk factor for death at 12-month follow-up., Competing Interests: Declaration of competing interest There is no conflict of interest in this project., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The spread of heavy metals throughout the ecosystem has extremely endangered human health, animals, plants, and natural resources. Hydrochar has emerged as a promising adsorbent for removal of heavy metals from water and wastewater. Hydrochar, obtained from hydrothermal carbonization of biomass, owns unique physical and chemical properties that are highly potent in capturing heavy metals via surface complexation, electrostatic interactions, and ion exchange mechanisms. This review focuses on removing heavy metals by hydrochar adsorbents from water bodies. The article discusses factors affecting the adsorption capacity of hydrochars, such as contact time, pH, initial metal concentration, temperature, and competing ions. Literature on optimization approaches such as surface modification, composite development, and hybrid systems are reviewed to enlighten mechanisms undertaking the efficiency of hydrochars in heavy metals removal from wastewater. The review also addresses challenges such as hydrochar regeneration and reusability, alongside potential issues related to its disposal and metal leaching. Integration with current water purification methods and the significance of ongoing research and initiatives promoting hydrochar-based technologies were also outlined. The article concludes that combining hydrochar with modern technologies such as nanotechnology and advanced oxidation techniques holds promise for improving heavy metal remediation. Overall, this comprehensive analysis provides valuable insights to guide future studies and foster the development of effective, affordable, and environmentally friendly heavy metal removal technologies to ensure the attainment of safer drinking water for communities worldwide., 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.)

Physical exercise both during and after curative cancer treatment has been shown to reduce side effects. Evidence in the metastatic cancer setting is scarce, and interventions that improve health-related quality of life (HRQOL) are much needed for patients with metastatic breast cancer (MBC). The multinational randomized controlled PREFERABLE-EFFECT trial assessed the effects of exercise on fatigue and HRQOL in patients with MBC. In total, 357 patients with MBC and a life expectancy of ≥6 months but without unstable bone metastases were recruited at eight study centers across five European countries and Australia. Participants were randomly assigned (1:1) to usual care (control group, n = 179) or a 9-month supervised exercise program (exercise group, n = 178). Intervention effects on physical fatigue (European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-FA12 scale) and HRQOL (EORTC QLQ-C30 summary score) were determined by comparing the change from baseline to 3, 6 (primary timepoint) and 9 months between groups using mixed models for repeated measures, adjusted for baseline values of the outcome, line of treatment (first or second versus third or higher) and study center. Exercise resulted in significant positive effects on both primary outcomes. Physical fatigue was significantly lower (-5.3 (95% confidence interval (CI), -10.0 to -0.6), Bonferroni-Holm-adjusted P = 0.027; Cohen's effect size, 0.22) and HRQOL significantly higher (4.8 (95% CI, 2.2-7.4), Bonferroni-Holm-adjusted P = 0.0003; effect size, 0.33) in the exercise group than in the control group at 6 months. Two serious adverse events occurred (that is, fractures), but both were not related to bone metastases. These results demonstrate that supervised exercise has positive effects on physical fatigue and HRQOL in patients with MBC and should be recommended as part of supportive care.ClinicalTrials.gov Identifier: NCT04120298 ., (© 2024. The Author(s).)

Three new thiosemicarbazide derivatives are described in terms of synthesis, structure and biological activity. N'-(Morpholine-4-carbonothioyl)-4-(4-phenylpiperazin-1-yl)picolinohydrazonamide 2-methyltetrahydrofuran hemisolvate, 2C 21 H 27 N 7 OS·C 5 H 10 O, 1, determined at 100 K, has orthorhombic (Pca2 1 ) symmetry and exhibits disorder. 4-(4-Phenylpiperazin-1-yl)-N'-(piperidine-1-carbonothioyl)picolinohydrazonamide-dimethylformamide-water (1/1/0.285), C 22 H 29 N 7 S·C 3 H 7 NO·0.285H 2 O, 2, determined at 100 K, has monoclinic (P2 1 /c) symmetry. 4-(4-Phenylpiperazin-1-yl)-N'-(pyrrolidine-1-carbonothioyl)picolinohydrazonamide, C 21 H 27 N 7 S, 3, determined at 100 K, has triclinic (P1) symmetry and exhibits disorder. Compounds 1 and 2 contain solvent molecules in their structure. All three studied compounds adopt the zwitterionic form and were tested for their microbiological activity on a model panel of Gram-positive and Gram-negative bacteria, as well as selected yeasts.

Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents. Their high cytotoxicity towards multiple human cancer cell lines and inhibition of human tumor xenograft growth in nude mice signal their potential for cancer treatment. Therefore, the mechanism of their strong biological activity is broadly investigated. Here, we explore the efflux and metabolism of UAs, as both strongly contribute to the development of drug resistance in cancer cells. We tested two highly cytotoxic UAs, C-2028 and C-2045, as well as their glucuronic acid and glutathione conjugates in human cancer cell lines (HepG2 and LS174T). As a point of reference for cell-based systems, we examined the rate of UA metabolic conversion in cell-free systems. A multiple reaction monitoring (MRM)-mass spectrometry (MS) method was developed in the present study for analysis of UAs and their metabolic conversion in complex biological matrices. Individual analytes were identified by several features: their retention time, mass-to-charge ratio and unique fragmentation pattern. The rate of UA uptake and metabolic transformation was monitored for 24 h in cell extracts and cell culture medium. Both UAs were rapidly internalized by cells. However, C-2028 was gradually accumulated, while C-2045 was eventually released from cells during treatment. UAs demonstrated limited metabolic conversion in cells. The glucuronic acid conjugate was excreted, whereas the glutathione conjugate was deposited in cancer cells. Our results obtained from cell-free and cell-based systems, using a uniform MRM-MS method, will provide valuable insight into the mechanism of UA biological activity in diverse biological models., 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.)

Laser-induced graphene (LIG) has emerged as a promising solvent-free strategy for producing highly porous, 3D graphene structures, particularly for electrochemical applications. However, the unique character of LIG and hydrogel membrane (HM) coated LIG requires accounting for the specific conditions of its charge transfer process. This study investigates electron transfer kinetics and the electroactive surface area of LIG electrodes, finding efficient kinetics for the [Fe(CN) 6 ] 3-/4- redox process, with a high rate constant of 4.89 x 10 -3  cm/s. The impact of polysaccharide HM coatings (cationic chitosan, neutral agarose and anionic sodium alginate) on LIG's charge transfer behavior is elucidated, considering factors like ohmic drop across porous LIG and Coulombic interactions/permeability affecting diffusion coefficient (D), estimated from amperometry.It was found that D of redox species is lower for HM-coated LIGs, and is the lowest for chitosan HM. Chitosan coating results in increased capacitive share in the total current while does not apparently reduce Faradaic current. Experimental findings are supported by ab-initio calculations showing an electrostatic potential map's negative charge distribution upon chitosan chain protonation, having an effect in over a two-fold redox current increase upon switching the pH from 7.48 to 1.73. This feature is absent for other studied HMs. It was also revealed that the chitosan's band gap was reduced to 3.07 eV upon acetylation, due to the introduction of a new LUMO state. This study summarizes the operating conditions enhanced by HM presence, impacting redox process kinetics and presenting unique challenges for prospective LIG/HM systems' electrochemical applications., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Robert Bogdanowicz reports financial support was provided by North Atlantic Treaty Organization. If there are other authors, they 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.)

C4d is the end degradation product of activated complement component C4b that appears during the early steps of the classical and lectin complement pathways. Within the primary sequence of C4d, there is a reactive thioester group that binds covalently to nearby surfaces, thus labeling the locations of complement activation. This feature makes C4d a target for immunohistochemical staining aimed to aid the diagnosis of, among others, the antibody-mediated rejection of transplanted organs, membranous glomerulonephritis, bullous pemphigoid, or inflammatory myopathies. However, the credibility of C4d immunostaining is debatable, as a high background in surrounding tissues and body fluids and diffused patterns of deposits in target structures are experienced with some of the available anti-C4d antibodies. Herein, we present an improved version of a rabbit anti-C4d antibody, originally raised against the C-terminal linear neoepitope of this complement fragment. Minor cross-reactivity with C4b and native C4 proteins, measured by ELISAs, as well as relatively low concentrations necessary for obtaining a specific signal in immunohistochemical analyses of formalin-fixed paraffin-embedded material, makes the improved antibody superior to commercially available rabbit monoclonal anti-C4d antibody SP91 dedicated to ex vivo diagnostics, as demonstrated by the staining of a panel of kidney transplant biopsies.

This study presents an innovative method for producing thermosensitive bioink from chitosan hydrogels saturated with carbon dioxide and agarose. It focuses on a detailed characterisation of their physicochemical properties and potential applications in biomedicine and tissue engineering. The ORO test approved the rapid regeneration of the three-dimensional structure of chitosan-agarose composites in a unidirectional bench press simulation test. The diffusion of dyes through the chitosan-agarose hydrogel membranes strongly depended on the share of both polymers in the composite and the molecular weight of the dyes. Glucose, as a nutrient marker, also diffused through all membranes regardless of composition. Biocompatibility assessment using MTT tests on 46BR.1N fibroblasts and HaCaT keratinocytes confirmed the safety of the bioink. The regenerative potential of the bioink was confirmed by efficient cell migration, especially HaCaT. Long-term viability studies showed that chitosan-agarose scaffolds, unlike the agarose ones, support cell proliferation and survival, especially 14 days after bioink extrusion. Experiments in a skin wound model in mice confirmed the biocompatibility of the tested dressing and the beneficial action of chitosan on healing. Studies on vessel formation in chicken embryos highlight the potential of the chitosan-agarose composition to enhance proangiogenic effects. This composition meets all entry criteria and possesses excellent biological properties.

T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals-collectively known as immune checkpoint inhibitors (ICIs)-can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy., (© 2024. The Author(s).)

Introduction: The growing population of heart failure (HF) patients places a burden on the healthcare system. Patient-centered outcomes such as health-related quality of life (HRQoL) and self-care behaviors are key elements of modern HF management programs. Thus, optimized strategies to improve these outcomes are sought., Purpose: To assess the effects of a new model of medical telecare on HRQoL and self-care in patients with HF (the AMULET study)., Methods: The study was prospective, randomized, open-label, and controlled with two parallel groups: telecare and standard care. In the telecare group, HF nurses performed patient clinical assessments with telemedical support by a cardiologist and provided education focused on the prevention of HF exacerbation. In the standard care group, patients were followed according to standard practices in the existing healthcare system. At the baseline and at 12 months, HRQoL was assessed using the Short Form 36 (SF-36) questionnaire and the Minnesota Living with Heart Failure Questionnaire (MLwHF). The level of self-care was assessed with the 12-item standardized European Heart Failure Self-care Behavior Scale (EHFScBS-12)., Results: In the overall study group, 79% of the subjects were male, the mean age was 67 ± 14 years, and 59% of the subjects were older than 65 years of age. The majority of the subjects (70%) had a left ventricular ejection fraction below 40%. After 12 months, statistically significant increases in physical component of the SF-36 (43.3 vs. 47.4 for telecare vs. 43.4 vs. 46.6 for standard care) and mental component of SF-36 (58.4 vs. 62 for telecare vs. 60.4 vs. 64.2 for standard care) were noted, with no intergroup differences. However, patients receiving telecare showed improvement in specific domains, such as physical functioning, role-physical, bodily pain, vitality, social functioning, role-emotional, and mental health. There was a significant decrease in MLwHF (29 vs. 35.0; lower is better) at follow-up for both groups. Telecare patients had a statistically significant decrease in EHFScBS-12 (lower is better) at 12 months., Conclusion: AMULET outpatient telecare, which is based on nurse-led non-invasive assessments supported by specialist teleconsultations, improved the HRQoL and self-care of HF patients after an episode of acute HF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Piotrowicz, Krzesiński, Galas, Stańczyk, Siebert, Jankowska, Siwołowski, Gutknecht, Murawski, Szalewska, Banasiak, Ponikowski and Gielerak.)

ALPINE (NCT03734016) established the superiority of zanubrutinib over ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL); here we present data from the final comparative analysis with extended follow-up. Overall, 652 patients received zanubrutinib (n=327) or ibrutinib (n=325). At an overall median follow-up of 42.5 months, progression-free survival benefit with zanubrutinib vs ibrutinib was sustained (HR: 0.68 [95% CI, 0.54-0.84]), including in patients with del(17p)/TP53 mutation (HR: 0.51 [95% CI, 0.33-0.78]) and across multiple sensitivity analyses. Overall response rate remained higher with zanubrutinib compared with ibrutinib (85.6% vs 75.4%); responses deepened over time with complete response/complete response with incomplete bone marrow recovery rates of 11.6% (zanubrutinib) and 7.7% (ibrutinib). While median overall survival has not been reached in either treatment group, fewer zanubrutinib patients have died than ibrutinib patients (HR: 0.77 [95% CI, 0.55-1.06]). With median exposure time of 41.2 and 37.8 months in zanubrutinib and ibrutinib arms, respectively, the most common non-hematologic adverse events included COVID-19-related infection (46.0% vs 33.3%), diarrhea (18.8% vs 25.6%), upper respiratory tract infection (29.3% vs 19.8%), and hypertension (27.2% vs 25.3%). Cardiac events were lower with zanubrutinib (25.9% vs 35.5%) despite similar rates of hypertension. Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs six cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile., (Copyright © 2024 American Society of Hematology.)

The presence of Demodex spp. mites on the skin is a common phenomenon in the human population. In most people, it is an asymptomatic infestation, but in some patients, it can contribute to the occurrence of diseases such as demodicosis, rosacea, or blepharitis, as well as non-specific symptoms. In this study, the results of tests assessing the presence of Demodex spp. by direct microscopic examination (DME) in 2508 patients from northern Poland with the suspicion of demodicosis were retrospectively analyzed. A total of 3684 tests were performed. Among them, only 1585 (43.02%) revealed the presence of Demodex spp., while 2099 (56.98%) were negative. It was shown that in the analyzed population of patients with clinical suspicion of demodicosis, the degree of confirmation of the presence of Demodex spp. positively correlated with the patient's age ( p = 0.001) and the mite was mainly found on the edges of eyelids and on the facial skin. Additionally, in men, the presence of Demodex was more often confirmed than in women ( p = 0.004). In conclusion, the proper diagnosis of demodicosis still constitutes an important clinical problem due to the non-specificity of symptoms and the low confirmation of clinical suspicions of infestation by DME, especially in lower age groups.

Background/Objectives: Childhood obesity has emerged as a global health concern with profound implications for long-term health outcomes. In recent years, there has been increasing interest in the potential role of environmental factors in the development of childhood obesity. This comprehensive review aims to elucidate the intricate relationship between various components of air pollution and childhood obesity. Methods: We systematically analyze the existing literature from the past 5 years to explore the mechanistic pathways linking air pollution, including particulate matter (PM), nitrogen oxides (NO x ), sulfur dioxide (SO 2 ), and polycyclic aromatic hydrocarbons (PAHs), to childhood obesity. This systematic review examines 33 epidemiological studies on the link between air pollution and childhood obesity, published from 1 January 2018, to 31 January 2024. Results: Studies from counties with low overall air pollution noticed only low to no impact of the exposure to childhood obesity, unlike studies from countries with higher levels of pollution, suggesting that the mitigation of air pollutants can reduce the chance of it being a negative factor for the development of obesity. This relationship was noticed for PM 2.5 , PM 1 , PM 10 , NO x , and SO 2 but not for PAHs, which showed a negative effect on children's health across 10 out of 11 studies. Conclusions: This review underscores the need for interdisciplinary approaches to address both environmental and socio-economic determinants of childhood obesity. Efforts aimed at reducing air pollution levels and promoting healthy lifestyle behaviors are essential for safeguarding the health and well-being of children worldwide.

Background: The possible existence of an acini-islet-acinar (AIA) reflex, involving mutual amylase and insulin interactions, was investigated in the current acute experiment on pigs., Aim: To confirm the existence of an AIA reflex and justify the placement of the exocrine and endocrine pancreatic components within the same organ., Methods: The study was performed on six pigs under general anesthesia. An intravenous glucose tolerance test was performed, with a bolus infusion of 50% glucose to the jugular vein, while amylase (5000 U/kg) or vehicle intrapancreatic infusions were administered via the pancreaticoduodenalis cranialis artery during 30 min with a 1 mL/min flow rate., Results: The amylase infusion to pancreatic arterial circulation inhibited and delayed the insulin release peak which is usually associated with the highest value of blood glucose and is typically observed at 15 min after glucose infusion, for > 1 h. The intrapancreatic infusion of the vehicle (saline) did not have any effect on the time frame of insulin release. Infusion of 1% bovine serum albumin changed the insulin release curve dramatically and prolonged the high range of insulin secretion, far beyond the glucose peak., Conclusion: Intrapancreatic arterial infusion of amylase interrupted the integrated glucose-insulin interactions. This confirms an AIA reflex and justifies placement of the exocrine and endocrine pancreatic components within the same organ., Competing Interests: Conflict-of-interest statement: The authors of this manuscript have the following competing interests: Stefan Pierzynowski and Kateryna Pierzynowska are the owners of Anara AB, Sweden. Piotr Wychowański is the owner of MED Sp. z o.o., Poland. Stefan Pierzynowski is the owner of Vitanano Sp. z o.o., Poland. Kamil Zaworski received funding from National Science Centre, Poland (Preludium, 2021/41/N/NZ9/01722). All other authors declare no competing interests., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Psychedelic agents have regained the attention of pharmaceutical companies as promising treatments for depressive episodes. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), an atypical psychedelic, is emerging as a potentially effective, novel rapid-acting antidepressant. In this systematic review, we analyze the safety and tolerability evidence from clinical trials., Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, electronic databases (PubMed, SCOPUS, Web of Science, EMBASE, and EBSCO) were searched from inception until 15 May 2024 to identify clinical trials (regardless of phase) reporting on short-term safety and tolerability profile of 5-MeO-DMT using the following keywords in various combinations: 5-methoxy-N, N-dimethyltryptamine, 5-MeO-DMT, safety, adverse, adverse reaction, side effects, tolerability, dropout, healthy volunteer, healthy participant, depression, major depressive disorder. Only studies written in English were considered., Results: Initial search yielded 100 records, out of which 3 met the inclusion criteria. These studies reported on the results from clinical trial phases I and I/II, with a total of 78 participants included; two studies involved healthy volunteers, and one included patients with treatment-resistant depression. Although the data is limited, it confirms a good short-term safety and tolerability profile for 5-MeO-DMT, with no serious adverse events (SAEs) reported. Furthermore, no drop-outs were reported., Conclusion: 5-MeO-DMT administration in human subjects presents favorable short-term safety and tolerability profile. Importantly, no SAEs have been documented, and no adverse events led to participant withdrawal from the studies There is a need for future randomized, double-blind, placebo-controlled trials with larger samples and follow-up to assess potential chronic adverse events., Competing Interests: AK has received research support from Beckley Psytech, GH Research, MSD. AW has received research support from Angelini, Biogen, Eli Lilly and Company, Janssen- Cilag, Lundbeck, Polpharma, Sanofi, Termedia and Valeant. WC has received grants from: Acadia, Alkermes, Allergan, Angelini, Auspex Pharmaceuticals, Beckley Psytech, BMS, Celon, Cephalon, Cortexyme, Ferrier, Forest Laboratories, GedeonRichter, GH Research, GWPharmaceuticals, HMNC Brain Health, IntraCellular Therapies, Janssen, KCR, Lilly, Lundbeck, Minerva, MSD, NIH, Novartis, Orion, Otsuka, Sanofi, Servier. He has received honoraria from: Adamed, Angelini, AstraZeneca, BMS, Celon, GSK, Janssen, KRKA, Lekam, Lundbeck, Minerva, NeuroCog, Novartis, Orion, Pfizer, Polfa Tarchomin, Sanofi, Servier, Zentiva. He is in the following advisory boards: Angelini, Celon terminated, Douglas Pharmaceuticals, GeH Research, Janssen, MSD, Novartis, Sanofi., (Copyright © 2024 Kwaśny, Wilkowska and Cubała.)

Background: Hereditary hemochromatosis (HH) is a genetic condition with fatigue as an essential but not precisely assessed symptom. While some well-specified scales for fatigue assessment in some pathologies exist, data on their usefulness in HH need to be collected. This research aimed to evaluate fatigue in HH using the Fatigue Assessment Scale (FAS), Fatigue Severity Scale (FSS), and Chalder Fatigue Scale (CFQ). Methodology: Seventy-nine HH patients underwent a questionnaire containing items about detailed medical history and the FAS, FSS, and CFQ scales. Twenty-five sex- and age-matched healthy persons constituted the control group (controls); additionally, thirty blood donors (donors) were compared. Results: The fatigue indices were significantly worse in the HH patients than in the controls and donors (HH vs. controls p -value: FAS = 0.003, FSS < 0.001, and CFQ = 0.003; HH vs. donors p -value: FAS = 0.025, FSS < 0.001, and CFQ = 0.041). There were no differences between the severity of fatigue and the specific genotype or the age of the patients. The HH women presented more severe fatigue than the men. High internal consistency and reliability for each scale were revealed: the Cronbach alpha values were as follows: FAS 0.92, FSS 0.95, and CFQ 0.93. Additionally, the construct validity and factorial validity of the implemented scales were confirmed. Conclusions: The HH patients exhibited significantly worse fatigue across all the scales. The FAS, FSS, and CFQ are simple and reliable diagnostic tools for assessing and quantifying fatigue for clinical and research purposes.

Objectives: Falls are associated with increased morbidity, mortality, prolonged hospitalization and an increase in the cost of treatment in hospitals. They contribute to the deterioration of fitness and quality of life, especially among older patients, thus posing a serious social and economic problem. They increase the risk of premature death. Falls are adverse, costly, and potentially preventable. The aim of the study was to analyze the cost-effectiveness of avoiding one fall by nurse care provided by the nurses with higher education, from the perspective of the health service provider., Methods: The economic analysis included and compared only the cost of nurse intervention measured by the hours of care provided with higher education in non-surgical departments (40.5%) with higher time spend by nurses with higher education level an increase in the number of hours by 10% (50.5%) to avoid one fall. The time horizon for the study is 1 year (2021). Cost-effectiveness and Cost-benefit analysis were performed. All registered falls of all hospitalized patients were included in the study., Results: In the analyzed was based on the case control study where, 7,305 patients were hospitalized, which amounted to 41,762 patient care days. Care was provided by 100 nurses, including 40 nurses with bachelor's degrees and nurses with Master of Science in Nursing. Increasing the hours number of high-educated nurses care by 10% in non-surgical departments decreased the chance for falls by 9%; however, this dependence was statistically insignificant (OR = 1.09; 95% CI: 0.72-1.65; p  = 0.65). After the intervention (a 10% increase in Bachelor's Degrees/Master of Science in Nursing hours), the number of additional Bachelor's Degrees/Master of Science hours was 6100.5, and the cost was USD 7630.4. The intervention eliminated four falls. The cost of preventing one fall is CER = USD 1697.1., Conclusion: The results of these studies broaden the understanding of the relationship among nursing education, falls, and the economic outcomes of hospital care. According to the authors, the proposed intervention has an economic justification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wieczorek-Wójcik, Gaworska-Krzemińska, Owczarek and Kilańska.)

Women typically outlive men, yet they often experience greater frailty and a higher incidence of chronic diseases as they age. By exploring the biological foundations of aging, with a particular focus on telomere dynamics, this manuscript aims to describe how dietary and lifestyle choices can significantly influence the aging process. The review comprehensively examines current research, underscoring the power of nutrition to counteract age-related changes, support healthy aging, and maintain vitality and beauty in women. The exploration of telomeres-the protective caps at the ends of chromosomes-reveals how they serve as markers of cellular aging and are potential targets for interventions aimed at enhancing women's longevity and quality of life. This study also emphasizes the importance of sex-specific approaches and precision medicine in understanding the unique health challenges women face as they age. By proposing targeted strategies, the review seeks to address these challenges, offering insights into preventive measures that can foster resilience, promote well-being, and extend healthy life expectancy in women. Ultimately, this work provides a sophisticated understanding of the aging process in women, highlighting the pivotal role of tailored interventions in preserving both health and beauty.

Background and Objective: Robotic adrenalectomy (RA) has attracted interest as an alternative to laparoscopic adrenalectomy (LA) for patients with pheochromocytoma, although its beneficial effects are uncertain. Our aim was to compare RA and LA outcomes for these patients., Methods: Data for patients who underwent RA or LA for pheochromocytoma in 46 international centers between 2012 and 2022 were reviewed. We analyzed baseline characteristics and postoperative complications at discharge, 90 d, and 1 yr. We conducted propensity score matching (PSM; 1:1 ratio) and multivariable analyses to evaluate outcomes and risk factors for the occurrence of complications and higher Comprehensive Complication Index (CCI)., Key Findings and Limitations: Of 1755 patients, 1613 (91.9%) underwent LA and 142 (8.1%) underwent RA. Estimated blood loss, conversion rate, complication rate, and CCI at discharge, 90 d, and 1 yr were similar between the groups. However, RA was associated with a longer operative time in comparison to LA (100 vs 123 min; p < 0.001), but not after PSM (p = 0.120). Multivariable analysis revealed that Charlson comorbidity index (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.07-1.29; p = 0.001), and tumor size per 1-cm increment (OR 1.13, 95% CI 1.07-1.21; p < 0.001) were independently associated with the incidence of complications, but there was no significant difference in complication rates between the LA and RA groups (OR 1.09, 95% CI 0.63-1.87; p = 0.767). After PSM, RA was associated with a lower rate of severe (grade ≥3a) complications in comparison to LA (p = 0.023)., Conclusions and Clinical Implications: RA is a safe alternative to LA and yields similar outcomes for patients with pheochromocytoma. RA may be associated with a lower likelihood of severe complications. Further studies are warranted to determine the role of robotic surgery in pheochromocytoma., Patient Summary: Pheochromocytoma is a rare tumor in the adrenal gland and the gold-standard treatment is surgical removal. We assessed patient outcomes after robot-assisted surgery compared with laparoscopic surgery and found that outcomes are similar, but the rate of severe complications may be lower if a surgical robot is used., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background/objectives: Survival prospects following SARS-CoV-2 infection may extend beyond the acute phase, influenced by various factors including age, health conditions, and infection severity; however, this topic has not been studied in detail. Therefore, within this study, the mortality risk post-acute COVID-19 in the CRIT-COV-U cohort was investigated., Methods: Survival data from 651 patients that survived an acute phase of COVID-19 were retrieved and the association between urinary peptides and future death was assessed. Data spanning until December 2023 were collected from six countries, comparing mortality trends with age- and sex-matched COVID-19-negative controls. A death prediction classifier was developed and validated using pre-existing urinary peptidomic datasets., Results: Notably, 13.98% of post-COVID-19 patients succumbed during the follow-up, with mortality rates significantly higher than COVID-19-negative controls, particularly evident in younger individuals (<65 years). These data for the first time demonstrate that SARS-CoV-2 infection highly significantly increases the risk of mortality not only during the acute phase of the disease but also beyond for a period of about one year. In our study, we were further able to identify 201 urinary peptides linked to mortality. These peptides are fragments of albumin, alpha-2-HS-glycoprotein, apolipoprotein A-I, beta-2-microglobulin, CD99 antigen, various collagens, fibrinogen alpha, polymeric immunoglobulin receptor, sodium/potassium-transporting ATPase, and uromodulin and were integrated these into a predictive classifier (DP201). Higher DP201 scores, alongside age and BMI, significantly predicted death., Conclusions: The peptide-based classifier demonstrated significant predictive value for mortality in post-acute COVID-19 patients, highlighting the utility of urinary peptides in prognosticating post-acute COVID-19 mortality, offering insights for targeted interventions. By utilizing these defined biomarkers in the clinic, risk stratification, monitoring, and personalized interventions can be significantly improved. Our data also suggest that mortality should be considered as one possible symptom or a consequence of post-acute sequelae of SARS-CoV-2 infection, a fact that is currently overlooked.

Purpose: Glial fibrillary acidic protein (GFAP) and neuroglobin (NGB) are important biomarkers of cerebral hypoxia. For this reason, an attempt was made to assess their concentrations in various time intervals and their impact on the severity of neurological symptoms and functional prognosis of thrombolytic ischemic stroke patients., Patients and Methods: The study involved 94 patients reporting to the emergency department of the Collegium Medicum University Hospital in Bydgoszcz within < 4.5 hours of the onset of stroke symptoms. GFAP and neuroglobin levels were measured in plasma at indicated times using a commercial ELISA kit., Results: Based on the data gathered, statistically significant differences were found between the concentration of biomarkers in stroke patients and the control group. The concentrations of both biomarkers, GFAP and NGB, were elevated in patients after ischemic stroke and the changes in their concentrations in the subsequent stages of stroke may suggest their prognostic value strictly dependent on time. NGB was determined on the 7th day, and mRS - after a year (0.35). GFAP measured after 24 h and on day 7 could be a promising biomarker of functional outcome after one year (cut-off point ≤ 0.231 ng/mL, sensitivity 75.0%, specificity 61.2%, cut off point ≤ 0.235 ng/mL, sensitivity 75.0%, specificity 73.9%, respectively) and the severity of the patient's neurological condition. At GFAP concentrations above 0.25 ng/mL, measured within 24 hours, a sharp increase in mortality was observed in stroke patients. In the case of NGB, at the time of stroke occurrence (14 ng/mL) and after 24 hours (10-60 ng/mL). Differences in the concentrations of these biomarkers have been demonstrated in different stroke subtypes., Conclusion: NGB and GFAP are important biomarkers of ischemic brain injury and may also participate in predicting neurological outcomes., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Pawluk et al.)

Composite coatings based on chitosan and zinc nanoparticles (ZnNPs) were successfully produced on Ti13Zr13Nb substrates by cathodic electrophoretic deposition (EPD). The unfavorable phenomenon of water electrolysis-induced nonuniformity was reduced by applying a low voltage (20 V) and a short deposition time (1 min). Surface analysis (roughness and hydrophilicity) reveals the potential of these coatings for enhancing cell attachment and bone-implant integration. However, there is a concern about adhesion and strength; therefore, incorporating ZnNPs shows promise for enhancing mechanical properties, suggesting opportunities for further optimization of the process. The aim of this work was to investigate whether Zn 2+ released from coating yields overt cellular impairment. hFOB1.19 osteoblastic cells were used as a model in this study. A subtoxic, 0.125 mmol/L, Zn concentration did not cause significant negative changes in cultured osteoblastic cells, as there was no significant change in their viability and their mitochondrial metabolism. Moreover, the alkaline phosphatase and lactate dehydrogenase activities were aggravated. However, a high, over 0.175 mmol/L, Zn 2+ concentration caused total cell death. This was caused by the inhibition of mitochondrial enzymes' activities. Our data indicate that composite coatings releasing Zn 2+ may be used as the differentiating factor toward osteoblastic cells.

Introduction: Tuberous sclerosis complex (TSC) is a neurocutaneous disease with a high incidence of epilepsy and damaging effects on cognitive development. To understand the mechanisms leading to abnormal cognitive development, diffusion tensor imaging (DTI) techniques have begun to be used in recent years. The present study is the first to investigate differences in the microstructure and integrity of white matter tracts in adult patients with TSC and with and without epilepsy., Method: A total of 37 patients with TSC (18 with epilepsy, median age 36 years; 19 without epilepsy, median age 35 years) without intellectual disability and autism spectrum disorder were included in the study. The control group (median age 34 years) comprised 37 individuals without psychiatric or neurodevelopmental disorders and neurological and cardiovascular diseases, diabetes, or addictions. A magnetic resonance imaging (MRI) DTI sequence was applied., Results: There were differences in the average values of DTI parameters between patients with TSC and epilepsy and patients with TSC but without epilepsy in five white matter bands. When comparing the average values of DTI parameters between patients with TSC and epilepsy and healthy controls, we found differences in 15 of 20 analysed white matter fibres. White matter tracts in patients with TSC and epilepsy had more abnormalities than in patients with TSC but without epilepsy. The former group presented abnormalities in longer white matter fibres, especially in the left hemisphere. However, the latter group presented abnormalities in more medial and shorter white matter fibres., Conclusion: This DTI study documents the changes in the brain white matter of patients with TSC associated with the presence of epilepsy.

The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In this review we explore innovative approaches in the treatment of hematologic cancers by combining various therapeutic modalities. We discuss the synergistic potential of combining inhibitors targeting different cellular pathways with immunotherapies, molecular therapies, and hormonal therapies. Examples include combining PI3K inhibitors with proteasome inhibitors, NF-κB inhibitors with immunotherapy checkpoint inhibitors, and neddylation inhibitors with therapies targeting the tumor microenvironment. Additionally, we discuss the potential use of small molecules and peptide inhibitors in hematologic cancer treatment. These multidimensional therapeutic combinations present promising strategies for enhancing treatment efficacy and overcoming resistance mechanisms. However, further clinical research is required to validate their effectiveness and safety profiles in hematologic cancer patients.