bluuebunny/crossref_metadata_2025 huggingface dataset:
Clock transitions versus Bragg diffraction in atom-interferometric dark-matter detection
Authors: Derr Daniel , Giese Enno
Published: December 2023

Atom interferometers with long baselines are envisioned to complement the ongoing search for dark matter. They rely on atomic manipulation based on internal (clock) transitions or state-preserving atomic diffraction. Principally, dark matter can act on the internal as well as the external degrees of freedom to both of which atom interferometers are susceptible. We, therefore, study in this contribution the effects of dark matter on the internal atomic structure and the atom's motion. In particular, we show that the atomic transition frequency depends on the mean coupling and the differential coupling of the involved states to dark matter, scaling with the unperturbed atomic transition frequency and the Compton frequency, respectively. The differential coupling is only of relevance when internal states change, which makes detectors, e.g., based on single-photon transitions sensitive to both coupling parameters. For sensors generated by state-preserving diffraction mechanisms like Bragg diffraction, the mean coupling modifies only the motion of the atom as the dominant contribution. Finally, we compare both effects observed in terrestrial dark-matter detectors.
Inhibition of the lysine demethylase LSD1 modulates the balance between inflammatory and antiviral responses against coronaviruses
Authors: Mazzarella Luca , Santoro Fabio , Ravasio Roberto , Fumagalli Valeria , Massa Paul E. , Rodighiero Simona , Gavilán Elena , Romanenghi Mauro , Duso Bruno A. , Bonetti Emanuele , Manganaro Lara , Pallavi Rani , Trastulli Deborah , Pallavicini Isabella , Gentile Claudia , Monzani Silvia , Leonardi Tommaso , Pasqualato Sebastiano , Buttinelli Gabriele , Di Martino Angela , Fedele Giorgio , Schiavoni Ilaria , Stefanelli Paola , Meroni Giuseppe , de Francesco Raffaele , Steinkuhler Christian , Fossati Gianluca , Iannacone Matteo , Minucci Saverio , Pelicci Pier Giuseppe
Published: December 2023

Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients but are inconsistently infected in vitro, exert critical but conflicting effects by secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for the treatment of coronavirus disease 2019 (COVID-19), indiscriminately suppress both responses, possibly impairing viral clearance. Here, we established in vitro cell culture systems that enabled us to separately investigate the cell-intrinsic and cell-extrinsic proinflammatory and antiviral activities of mouse macrophages infected with the prototypical murine coronavirus MHV-A59. We showed that the nuclear factor κB–dependent inflammatory response to viral infection was selectively inhibited by loss of the lysine demethylase LSD1, which was previously implicated in innate immune responses to cancer, with negligible effects on the antiviral IFN response. LSD1 ablation also enhanced an IFN-independent antiviral response, blocking viral egress through the lysosomal pathway. The macrophage-intrinsic antiviral and anti-inflammatory activity of Lsd1 inhibition was confirmed in vitro and in a humanized mouse model of SARS-CoV-2 infection. These results suggest that LSD1 controls innate immune responses against coronaviruses at multiple levels and provide a mechanistic rationale for potentially repurposing LSD1 inhibitors for COVID-19 treatment.
TB impairs DNA repair
Authors: VanHook Annalisa M.
Published: December 2023

A
Mycobacterium tuberculosis
virulence factor promotes foam cell formation by inhibiting DNA repair.
Rapid detection of
Mycobacterium tuberculosis
in sputum using CRISPR-Cas12b combined with cross-priming amplification in a single reaction
Authors: Peng Lijun , Fang Tingting , Cai Qingshan , Li Hao , Li Huanyu , Sun Haiqiong , Zhu Mingzhi , Dai Lingshan , Shao Yanqin , Cai Long
Published: December 2023

The diagnosis of tuberculosis (TB) still lacks a rapid, user-friendly method. Recent research has revealed the significant diagnostic potential of the CRISPR system in TB detection. However, most current CRISPR-based diagnostic tests involve a two-step process, including nucleic acid amplification followed by CRISPR-guided sequence-specific detection, which raises concerns about cross-contamination and operational complexity. In this study, we introduced TB One-Pot, which combines CRISPR-Cas12b-mediated trans-cleavage with cross-priming amplification, enabling one-pot detection in a single reaction. TB One-Pot achieves a minimum detection limit of 0.8 copies/μL for H37Rv genomic DNA and a quantification limit of 50 CFU/mL. It exhibited no cross-reactivity with common nontuberculous mycobacteria and respiratory pathogens. TB One-Pot employs real-time fluorescence, enabling the process from nucleic acid extraction to result in reporting in just 80 minutes. It also includes a UV-based visual check, eliminating the need for specialized equipment. A retrospective cohort study evaluated the diagnostic performance of this method using a composite reference standard as the gold standard. TB One-Pot demonstrated a sensitivity of 67.2% and an area under the curve (AUC) of 0.820 in sputum samples, surpassing conventional methods such as culture and acid-fast bacilli (AFB) smear. Comparative analysis with Xpert (sensitivity:64.2%, AUC:0.821) showed no statistically significant difference (
P
> 0.05). TB One-Pot exhibited a specificity of 96.7%, similar to Xpert, culture, and AFB smear (
P
> 0.05). TB One-Pot excels in speed, sensitivity, specificity, and practical requirements. Ongoing refinements aim to improve sensitivity, making it a promising solution for overcoming limitations in molecular TB diagnosis, particularly in resource-constrained settings.

IMPORTANCE

In this study, we successfully established a new One-Pot method, named TB One-Pot, for detecting Mtb in sputum by combining CRISPR-cas12b-mediated trans-cleavage with cross-priming amplification (CPA). Our study evaluated the diagnostic performance of TB One-Pot in clinical sputum samples for tuberculosis. The findings provide evidence for the potential of TB One-Pot as a diagnostic tool for tuberculosis.
Genome sequences of four colistin-resistant ESKAPE bacterial strains isolated from patients within the same hospital
Authors: Tunç Merve Nur , Guéneau Virgile , Loux Valentin , del Campo Rosa , Carballido Lopez Rut , Briandet Romain
Published: December 2023

The genomes of four clinical Gram-negative ESKAPE bacterial strains highly resistant to the last-resort antibiotic colistin were sequenced and analyzed. The strains were found to carry multidrug-resistant genes besides colistin-resistant genes.
Introduction of allergenic food to infants and allergic and autoimmune conditions: a systematic review and meta-analysis
Authors: Tuballa Alana , Connell Danique , Smith Mary , Dowsett Caroline , O’Neill Hayley , Albarqouni Loai
Published: December 2023

Objectives

To evaluate the effects of early introduction to allergenic foods compared with late introduction and its impact on food allergy, food sensitisation and autoimmune disease risk.

Design and setting

The systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Four electronic databases (MEDLINE, CENTRAL, EMBASE and CINAHL) were searched from inception till 24 October 2022 using keywords and MeSH without limitations on publication’s language or date. A forward and backwards citation analysis was also conducted. Risk of bias was assessed by three authors independently, in pairs using the Cochrane Risk of Bias Tool 2. Findings were narratively and quantitatively synthesised. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.

Participants

Randomised controlled trials (RCTs) on allergenic food introduction prior to 12 months of age that evaluated its effect on the development of allergic and autoimmune conditions.

Intervention

Early introduction to allergenic foods to infants diet.

Main outcome measures

(1) Food allergy and sensitisation with main measures including oral food challenge, specific-IgE, skin prick testing, physician assessment and parental reporting. (2) Allergic and autoimmune conditions such as asthma and eczema.

Results

Of the 9060 identified records, we included 12 RCTs. We found high to moderate certainty evidence suggested that early introduction of allergen-containing foods reduces the risk of multiple food allergies (4 RCTs, 3854 participants, RR 0.49, 95% CI 0.33 to 0.74), egg (8 RCTs, 5193 participants, RR 0.58, 95% CI 0.44 to 0.78), peanut (3 RCTs, 4183 participants, RR 0.31, 95% CI 0.17 to 0.54) and atopic dermatitis or eczema (4 RCTs, 3579 participants, RR 0.88, 95% CI 0.78 to 1.00). Effects on other food allergies including milk, wheat, fish; autoimmune conditions, and food sensitisation are very uncertain and informed by low and very-low certainty evidence. No important subgroup differences were observed related to baseline risk of allergy and age at introduction. Sensitivity analyses limited to low risk of bias RCTs showed similar results.

Conclusions

This systematic review and meta-analysis shows that early introduction of allergen-containing food from 4 to 12 months of age, was associated with lower risk of multiple food allergy and eczema. Further research on other allergenic foods, and their long-term impact on food allergy and autoimmune risk is essential for enhancing our understanding on development of these conditions and guiding future clinical recommendations.

PROSPERO registration number

CRD42022375679.
Gender disparities in clinical outcomes of urothelial carcinoma linked to X chromosome geneKDM6Amutation
Authors: Liu Zhaopei , Jin Kaifeng , Xu Ziyue , Xu Jingtong , Su Xiaohe , Li Bingyu , Liu Ge , Liu Hailong , Chang Yuan , Wang Yiwei , Xu Le , Zhang Weijuan , Wang Zewei , Zhu Yu , Xu Jiejie
Published: December 2023

Objective

KDM6A, a representative tumour suppressor gene with sex bias, is frequently altered in urothelial carcinoma (UC). The specific impacts ofKDM6Amutations on gender-based clinical outcomes in UC remain poorly understood.

Methods and analysis

We enrolled 2438 patients with UC from seven independent real-world cohorts possessing comprehensive clinical and genomic data. Point mutations and homozygous deletions ofKDM6Aare categorised asKDM6AMut. We assessed the correlation between gender disparities in relation toKDM6Astatus and clinical outcomes, as well as genomic and immunological profiles.

Results

KDM6Amutations were identified in 679 of the 2306 patients with UC (29.4%), with 505 of 1768 (28.6%) in men and 174 of 538 (32.3%) in women.KDM6Amutations correlated with enhanced overall survival exclusively in male patients but were linked to improved outcomes following adjuvant chemotherapy only in female patients. Concerning immunotherapeutic responses,KDM6AMutmale patients displayed the most favourable clinical outcomes, whereasKDM6AMutfemale patients demonstrated the least favourable outcomes. Independent of gender variations,KDM6AMutpatients exhibited heightened androgen receptor and diminished oestrogen receptor 1 filtered regulon activity. Additionally,KDM6AMutmale patients showed increased infiltration of T cells, cytotoxic T cells and NK cells with enriched neoantigens, in contrast toKDM6AMutfemale patients who manifested a more pronounced angiogenesis signature.

Conclusion

Our findings offer preliminary clinical evidence accentuatingKDM6Aalterations as a promising prognostic and predictive biomarker while elucidating the gender disparities observed in patients with UC.
Impact of cellular morphology and three-tiered nuclear grade on progression of conventional renal cell carcinoma
Authors: Domonkos Lilla , Yusenko Maria , Kovacs Gyula , Peterfi Lehel
Published: December 2023

Aims and methods

The aims of this study were to evaluate the prognostic impact of cytomorphology and three-tiered grading on tumour-free survival of patients with conventional renal cell carcinoma (cRCC). Formalin-fixed, paraffin-embedded samples from 710 patients were assessed and the results were evaluated according to the clinical data.

Results

Kaplan-Meier regression model showed that 90.9% of patients with clear cell, and 50.9% with pure eosinophilic cRCC were free of metastasis during follow-up. The three-triered grading showed a good correlation with progression as 95.2% of patients with of G1 tumours, 66.1% with G2 tumours and only 25.3% with G3 tumours were tumour free (p<0.001). The grading was correlated with cytomorphology and coagulation necrosis. In multivariate analysis, tumour grade and stage were independent prognostic markers (p<0.001).

Conclusions

The three-tiered grading predicts the progression of cRCC irrespectively of cytomorphology. However, the cytomorphology and necrosis show a good correlation with three-tiered grading in estimate disease progression.
How should China set ethical guardrails for medical research?
Authors: Xu Jingyi , Liu Zhongxuan , Shi Jiayou , Wang Yue
Published: December 2023

‘Ethics first’ reform in China significantly changes the governance framework for the research of emerging technologies. The misapplication of human genome editing technology reflects the urgent need to reform the governance framework. Strengthening ethics governance in medical research has become a consensus in China, where legal and ethical reforms are proceeding in parallel. The protection of human dignity, the prevention of biosafety risks, as well as the regulation of technological crimes are at the core of the legal system, which has been embodied in numerous fundamental legislations following the CRISPR-babies incident. Establishing a national ethics committee to coordinate ethics governance, and reinforcing ethics review and external oversight are significant steps in ethical reform. Essentially, ethics governance requires implementing the basic concept of ‘ethics first’, focusing on forward-looking and preventive governance rather than delayed intervention, while maintaining openness and collaboration.
Recontact to return new or updatedPALB2genetic results in the clinical laboratory setting
Authors: Panchal Seema , Mahajan Radhika , Aujla Navneet , McKay Paul , Casalino Selina , Di Gioacchino Vanessa , Charames George S , Lefebvre Maude , Metcalfe Kelly A , Akbari Mohammad Reza , McCuaig Jeanna Marie , Lerner-Ellis Jordan
Published: December 2023

Objective

The purpose of this study was to recontact individuals with clinically actionable test results identified through a retrospective research study and to provide a framework for laboratories to recontact patients.

Methods

Genetic testing was conducted on 2977 individuals originally referred forBRCA1andBRCA2hereditary breast and ovarian cancer testing that had a negative genetic test result. A gene panel was used to identify pathogenic variants in known or newly discovered genes that could explain the underlying cause of disease; however, analysis was restricted toPALB2for the purposes of this study. A patient recontact decision tree was developed to assist in the returning of updated genetic test results to clinics and patients.

Results

Novel clinically actionable pathogenic variants were identified in thePALB2gene in 18 participants (0.6%), the majority of whom were recontacted with their new or updated genetic test results. Eight individuals were unable to be recontacted; five individuals had already learnt about their new or updated findings from genetic testing outside the context of this study; three individuals prompted cascade testing in family members; two individuals were deceased.

Conclusion

Novel pathogenic variants inPALB2were identified in 18 individuals through retrospective gene panel testing. Recontacting these individuals regarding these new or updated findings had a range of outcomes. The process of conveying genomic results within this framework can be effectively accomplished while upholding patient autonomy, potentially leading to advantageous outcomes for patients and their families.
Hydrophilic and Hydrophobic Composite Microporous Layer Coated Gas Diffusion Layers for Performance Enhancement of Polymer Electrolyte Fuel Cells
Authors: Wang Peng , Nakajima Hironori , Kitahara Tatsumi
Published: December 2023

A novel microporous layer (MPL) coated gas diffusion layer (GDL) is developed to improve water management of polymer electrolyte fuel cells (PEFCs) by incorporating hydrophobic and hydrophilic pores within the same layer. This MPL expels excess water at the interface between the catalyst layer and MPL through hydrophilic pores while maintaining efficient oxygen transport through hydrophobic pores, reducing oxygen transport resistance under high humidity conditions. The water permeability and relative oxygen permeance tests demonstrate the presence of separate hydrophobic and hydrophilic pores in the appropriate composite MPL. The effects of combinations of hydrophilic and hydrophobic binders used in the composite MPLs on the oxygen transport resistance are evaluated. The hydrophobic polytetrafluoroethylene (PTFE) binder and the hydrophilic polyvinyl alcohol (PVA) binder cannot enhance performance due to mismatched sintering temperatures. Although the hydrophobic polyvinylidene fluoride (PVDF) and PVA binders have the same sintering temperature, the performance was degraded due to the strong hydrophilicity of PVA. Another combination of composite MPL incorporates hydrophobic PVDF and Nafion binders. Hydrophilic TiO2 particles are introduced in the Nafion binder to reinforce the hydrophilicity. The appropriate composite MPL significantly reduced the total oxygen transport resistance compared to those obtained with the hydrophobic MPL.
A Two‐Archive Algorithm with Interactive Mechanism for Many‐Objective Optimization
Authors: Liu Shuren , Li Shuping , Li Changchun , Cai Changning , Cheng Guojian
Published: December 2023

This paper proposes an interactive two‐archive method to solve many‐objective optimization problems. Two updating strategies based on the aggregation‐based framework are presented and incorporated into a two‐archive framework. In addition, we further extend this method by introducing an interactive mechanism in which evolutionary information is passed from the diversity archive to the convergence archive. Given the requirement to balance convergence and diversity, a mating selection method is proposed to regulate the evolutionary speed of these two archives collaboratively. The proposed algorithm has been tested extensively on several problems with different peer algorithms to validate its effectiveness. The results show that the proposed method can outperform several state‐of‐the‐art evolutionary algorithms for handling many‐objective optimization.
Prevalence of Vertical Root Fractures in a University Endodontics Program versus a Private Endodontics Office
Authors: Ek Berit , Zweig Stefan , Roges Ramon G. , Berdan Yaara , Roges Rafael A. , Abulhamael Ayman , Kutbi Abrar , Alqutub Alaa W. , Alothmani Osama S. , Siddiqui Amna Y.
Published: December 2023

Introduction. Vertical root fractures (VRFs) typically have a poor prognosis with an extraction or occasionally root amputation as the preferred treatment. VRFs have been considered an epidemic, motivating changes in the access openings, as well as in the preparation and disinfection protocols of endodontic treatment. Hence, we aimed to evaluate the prevalence of VRFs by tracking cases in both a University Endodontic Program (UEP) and a private endodontics practice (PP). We also evaluated changes in prevalence during COVID-19 along with the alterations in the frequency of cases diagnosed by clinical and radiographic signs which were later confirmed by direct visualization compared to those in which the suspicion was based on clinical and radiographic signs alone. Methods and Materials. This retrospective study looked at the prevalence of VRF in patient records at UEP and a PP. Data for the pre-COVID-19 and COVID-19 time periods were extracted from patient records and referral letters then compared. Data for suspected and confirmed prevalence were compared. Results. The UEP group included 21,156 patients while the PP group comprised 7,209 patients. The prevalence of VRFs in the former cohort was 1.80%, while 2.62% of the latter cohort exhibited VRFs with a combined total of 2.01%. The combined total prevalence of VRFs pre-COVID-19 was 1.72%, increasing from 2.1% to 3.82% during COVID-19 (

p
<
0.0001

). The same applied to suspected cases for both clinical settings. The increase in confirmed cases between the two periods was statistically significant for the UEP group (

p
=
0.0202

) but it was insignificant for the PP group (

p
=
0.0721

). Conclusion. The combined prevalence for VRFs was 2.01% for all years denying the claim that VRF is a pandemic phenomenon. COVID-19 period saw almost a double increase in the prevalence of VRF compared to pre-COVID-19 era. This was consequently associated with a significant increase in the number of suspected VRF cases.
Protective Effects of Sanyar Prebiotic on Immunity and Tissue Changes of Common Carp (Cyprinus carpio) Exposed to CuSO4 Stress
Authors: Rajani Ramezan , Farhangi Mohammad , Jafaryan Hojjatallah , Adineh Hossein , Alizadeh Maryam
Published: December 2023

Prebiotics, as feed additives, can activate the antioxidant and immune systems of fish and significantly improve the survival of aquaculture animals in stressful conditions. The exposure of fish to copper sulfate leads to oxidative stress, suppression of the immune system, and destruction of vital body tissues. This study aimed to investigate the protective effects of Sanyar prebiotic on the immunity and tissue changes of common carp (Cyprinus carpio) exposed to CuSO4 stress. Two hundred common carp fish with an average weight of 12.33 ± 0.93 g were stocked in four treatments (triplicates) for 60 days. The experimental treatments contained Sanyar commercial prebiotics in 100 g of food, which included P1 (1 ml prebiotic liquid), P2 (0.1 g prebiotic powder), P3 (0.5 ml liquid and 0.05 g powder), and treatment C (control treatment without any additives). At the end of the experimental period, the fish were exposed to acute toxicity of Cu (0.1 m/l) for 96 hours. Gill, kidney, and liver tissue samples were collected and evaluated after 96 hours. According to the results obtained, there were significant differences in specific growth rate (SGR) and final weight (

p

 < 0.05). The lowest feed conversion ratio (FCR) was observed in the Sanyar treatments (1.56 ± 0.37), which had a significant difference from the control treatment (1.85 ± 0.35) (

p

 < 0.05). The results showed that immunity indices such as lysozyme, cortisol, and ACH50 increased in the experimental treatments compared to the control treatment (

p

 < 0.05). The highest and lowest lysozyme activities were observed in P2 (16.35 ± 0.57) and control treatments (13.15 ± 1.00), respectively (

p

 < 0.05). Generally, no significant difference was observed between growth and nutrition indices in Sanyar treatments (

p

 < 0.05). Symptoms of kidney, liver, and gill tissue damage were reported from mild (hyperemia and infiltration of inflammatory cells) to severe (hemorrhage and necrosis). The lowest severity of tissue damage was observed in the treatments fed with Sanyar food supplement. In general, the results of this study showed that the addition of Sanyar prebiotic to the diet of common carp improves the growth indicators and immune response and can also be beneficial in increasing fish resistance to copper toxicity.
Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study
Authors: Munster Pamela , Iannotti Nicholas , Cho Daniel C. , Kirkwood John M. , Villaruz Liza C. , Gibney Geoffrey T. , Hodi F. Stephen , Mettu Niharika B. , Jones Mark , Bowman Jill , Smith Michael , Lakshminarayanan Mani , O'Day Steven
Published: December 2023

Purpose:

This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor].

Experimental Design:

Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks).

Results:

A total of 159 patients were enrolled in the study and treated with itacitinib (Part 1, n = 49) or parsaclisib (Part 1, n = 83; Part 2, n = 27) plus pembrolizumab. The maximum tolerated/pharmacologically active doses were itacitinib 300 mg once daily and parsaclisib 30 mg once daily. Most common itacitinib treatment-related adverse events (TRAE) were fatigue, nausea, and anemia. Most common parsaclisib TRAEs were fatigue, nausea, diarrhea, and pyrexia in Part 1, and fatigue, maculopapular rash, diarrhea, nausea, and pruritus in Part 2. In patients receiving itacitinib plus pembrolizumab, four (8.2%) achieved a partial response (PR) in Part 1. Among patients receiving parsaclisib plus pembrolizumab, 5 (6.0%) achieved a complete response and 9 (10.8%) a PR in Part 1; 5 of 27 (18.5%) patients in Part 2 achieved a PR.

Conclusions:

Although combination of itacitinib or parsaclisib with pembrolizumab showed modest clinical activity in this study, the overall response rates observed did not support continued development in patients with solid tumors.

Significance:

PD-1 blockade combined with targeted therapies have demonstrated encouraging preclinical activity. In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations.
FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer
Authors: Dairo Oluwademilade , DePaula Oliveira Lia , Schaffer Ethan , Vidotto Thiago , Mendes Adrianna A. , Lu Jiayun , Huynh Sophie Vo , Hicks Jessica , Sowalsky Adam G. , De Marzo Angelo M. , Joshu Corrine E. , Hanratty Brian , Sfanos Karen S. , Isaacs William B. , Haffner Michael C. , Lotan Tamara L.
Published: December 2023

Fatty acid synthase (FASN) catalyzes the synthesis of long-chain saturated fatty acids and is overexpressed during prostatic tumorigenesis, where it is the therapeutic target in several ongoing trials. However, the mechanism of FASN upregulation in prostate cancer remains unclear. Here, we examine FASN gene CpG methylation pattern by InfiniumEPIC profiling and whole-genome bisulfite sequencing across multiple racially diverse primary and metastatic prostate cancer cohorts, comparing with FASN protein expression as measured by digitally quantified IHC assay and reverse phase protein array analysis or FASN gene expression. We demonstrate that the FASN gene body is hypomethylated and overexpressed in primary prostate tumors compared with benign tissue, and FASN gene methylation is significantly inversely correlated with FASN protein or gene expression in both primary and metastatic prostate cancer. Primary prostate tumors with ERG gene rearrangement have increased FASN expression and we find evidence of FASN hypomethylation in this context. FASN expression is also significantly increased in prostate tumors from carriers of the germline HOXB13 G84E mutation compared with matched controls, consistent with a report that HOXB13 may contribute to epigenetic regulation of FASN in vitro. However, in contrast to previous studies, we find no significant association of FASN expression or methylation with self-identified race in models that include ERG status across two independent primary tumor cohorts. Taken together, these data support a potential epigenetic mechanism for FASN regulation in the prostate which may be relevant for selecting patients responsive to FASN inhibitors.

Significance:

Here, we leverage multiple independent primary and metastatic prostate cancer cohorts to demonstrate that FASN gene body methylation is highly inversely correlated with FASN gene and protein expression. This finding may shed light on epigenetic mechanisms of FASN regulation in prostate cancer and provides a potentially useful biomarker for selecting patients in future trials of FASN inhibitors.
Divide et Vinces, Therapeutic Apheresis in Nephrological Clinical Practice
Authors: Mantilla Juliana , Peña Danna , Molano-Triviño Alejandra , Zúñiga Eduardo , Castellanos-De La Hoz Juan Camilo
Published: December 2023

Therapeutic plasma exchange (TPE) or plasmapheresis has been used in various life-threatening diseases as a primary treatment or in combination with other therapies. It was first successfully employed in the 1960s for diseases like Waldenström’s disease and myeloma. Since then, TPE techniques using apheresis membranes have been introduced. Apheresis therapies separate plasma components from blood using membrane screening or centrifugation methods. TPE aims to remove substances involved in the pathophysiology of diseases. It selectively removes high-molecular-weight molecules, substances with prolonged half-life, and those associated with disease pathogenesis. TPE can be performed using membranes or centrifugation, with replacement of extracted plasma volume using albumin or fresh frozen plasma. TPE requires specific competencies in nephrology and can be prescribed and monitored by nephrologists and performed by dialysis nursing staff. TPE can be combined with adsorption-based therapies to enhance its effect, and this approach is called plasma filtration adsorption. Another variation is double plasma filtration, which selectively removes substances based on molecular size. TPE can also be combined with lipoprotein removal strategies for managing familial hypercholesterolemia. TPE is an affordable extracorporeal therapy that benefits patients with life-threatening diseases. It requires collaboration between nephrologists and other specialists, and our results demonstrate successful TPE without anticoagulation in general hospitalization or outpatient settings.
Cephalosporin-Related Neurotoxicity in a Ceftriaxone-Treated Critically Ill Child: A Case Report
Authors: Sylva Marc , Abdulla Alan , Koch Birgit C.P. , Mulder Jaap
Published: December 2023

Introduction: We describe a child with meningococcal sepsis who suffered cephalosporin-related neurotoxicity. Case Presentation: A four-year-old girl was treated with intravenous ceftriaxone and supportive therapy. After rapid improvement, inotropic and respiratory support was stopped within 2 days. However, she developed renal failure and, on day four, deteriorated neurologically. Research into the cause of her encephalopathy revealed supra-therapeutic ceftriaxone concentrations with greatly increased unbound fractions leading to the diagnosis of cephalosporin-related neurotoxicity. Ceftriaxone treatment was discontinued, and renal replacement therapy was initiated on day six. With both discontinuation of ceftriaxone and renal replacement therapy, the girl’s condition improved rapidly. Conclusion: We postulate that in the described case both renal impairment and hypoalbuminemia played an important role in the development of high unbound ceftriaxone serum levels. We advocate therapeutic drug monitoring for ceftriaxone in critically ill children with renal failure or hypoalbuminemia.
Ablative CO2-Assisted Laser for Topical Drug Delivery in Nail Psoriasis: A Systematic Review
Authors: Tartaglia Jacopo , Piaserico Stefano , Naldi Luigi , Sechi Andrea
Published: December 2023

Background: Nail psoriasis poses challenges for effective treatment, and topical drug delivery through the nail plate is limited. A novel approach to address this challenge involves the use of ablative fractional laser as a pretreatment strategy to enhance topical drug delivery for nail psoriasis. Summary: This systematic review, conducted in accordance with PRISMA guidelines, involved an extensive literature search across PubMed/MEDLINE, EMBASE, and the Cochrane Library up to July 2023. The primary focus was on exploring studies that investigated the application of ablative laser technology to augment drug delivery for nail psoriasis. Key Messages: (1) The review included seven randomized controlled trials, all examining the combination of fractional CO2 laser with topical treatments. These trials demonstrated varying degrees of improvement in nail psoriasis. (2) Patients undergoing laser treatment reported experiencing moderate levels of pain, effectively managed through the application of topical anesthesia. (3) Commonly observed side effects included erythema, swelling, and crusting, with the Koebner phenomenon being a rare occurrence. (4) Notably, patient satisfaction levels with the combined approach of laser and topical treatments were consistently high. In conclusion, the utilization of ablative CO2-assisted laser pretreatment, when used in conjunction with topical therapy, appears to be both effective and well-tolerated for the treatment of nail psoriasis. However, the establishment of optimal parameters and treatment intervals for fractional laser therapy remains an area for further research. Standardized studies are imperative to identify the most effective strategy for enhancing topical drug delivery in the context of nail psoriasis treatment.
Surgical Outcomes of Standardized Endoscopical Deep Medial Orbital Decompression in Dysthyroid Optic Neuropathy
Authors: Li Cheng , Gao Yang , Zhang Zhihui , Lv Xi , Bao Yuekun , Ma Yujun , Chen Rongxin , Cheng Chao , Li Jinmiao , Liu Yaoming , Jin Ling , Luo Guangwei , Shi Jianbo , Lu Rong
Published: December 2023

Introduction: The aim of the study was to standardize the endoscopic deep medial orbital decompression surgery for better relief of optic nerve compression in dysthyroid optic neuropathy (DON). Methods: A total of 128 eyes from patients received the standardized endoscopic deep medial orbital decompression surgery were recruited in this study. The efficacy of the procedure was assessed at a 1-month follow-up by the best-corrected visual acuity (VA), visual field (VF), and visual evoked potential (VEP). Clinical data were collected to explore the factors that affected visual recovery. Oxygen saturation of retinal blood vessels, retinal thickness, and vessel density were measured to demonstrate the potential recovery mechanisms. Results: After surgery, the ratio of extraocular muscle volume in the orbital apex to orbital apex volume significantly decreased from 44.32 ± 22.31% to 36.82 ± 12.02% (p < 0.001). 96.87% of eyes’ final VA improved; average VA improved from 0.93 ± 0.73 to 0.50 ± 0.60 at 1 week (p < 0.001) and 0.40 ± 0.53 at 1 month (p < 0.001). Postoperatively, VF and VEP also improved, the oxygen saturation of retinal arteries increased, and the retinal thickness was reduced. Preoperative VA, visual impairment duration, and clinical activity score evaluation were associated with visual recovery. Conclusion: In this study, we standardized the endoscopic deep medial orbital decompression, of which key point was to relieve pressure in the orbital apex and achieved satisfactory visual recovery in DON patients.
The Reduced Gray Matter Volume and Functional Connectivity of the Cerebellum in Type 2 Diabetes Mellitus with High Insulin Resistance
Authors: Zhang Hui-Yan , Shen Guo , Yang Chen , Tan Jian , Cao Jian-Cang , Tian Jing , Li Zhou-Le , Huang Gang , Zhao Lian-Ping
Published: December 2023

Introduction: Insulin resistance is widely thought to be a critical feature in type 2 diabetes mellitus (T2DM), and there is significant evidence indicating a higher abundance of insulin receptors in the human cerebellum than cerebrum. However, the specific structural or functional changes in the cerebellum related to T2DM remain unclear, and the association between cerebellar alterations, insulin resistance, cognition, and emotion is yet to be determined. Methods: We investigated neuropsychological performance, and structural and functional changes in specific cerebellar subregions in 43 T2DM patients with high insulin resistance (T2DM-highIR), 72 T2DM patients with low insulin resistance (T2DM-lowIR), and 50 controls. Furthermore, the correlation and stepwise multiple linear regression analysis were performed. Results: Compared to the controls, T2DM exhibited lower cognitive scores and higher depressive/anxious scores. Furthermore, T2DM-highIR patients showed reduced gray matter volume (GMV) in the right cerebellar lobules VIIb, Crus I/II, and T2DM showed reduced GMV in left lobules I–IV compared to controls. Additionally, functional connectivity decrease was observed between the right lobules I–V and orbital part of the superior frontal gyrus in T2DM-highIR compared to both T2DM-lowIR and controls. Notably, there were negative correlations between the GMV of the lobules VIIb, Crus I/II, and updated homeostatic model assessment of insulin resistance, and positive correlation with executive/visuospatial performance in T2DM patients. Conclusions: These results suggest that the cerebellar lobules VIIb, Crus I/II, represent vulnerable brain regions in the context of insulin resistance. Overall, this study offers new insights into the neuropathophysiological mechanisms of brain impairment in patients with T2DM.
СУЧАСНІ УЯВЛЕННЯ ПРО ЕТІОЛОГІЮ ТА ПАТОГЕНЕЗ ДЕРМАТОМІКОЗІВ
Authors: Москалюк В. Д. , Кравчук І. І.
Published: December 2023

Представлено узагальнену інформацію про грибкові ураження (дерматомікози) шкіри, її додатків, слизових оболонок порожнини рота та статевих органів.

За спектром збудників і глибиною ураження дерматомікози поділяються на кератомікози; дерматоміцети; кандидоз і глибокі мікози. Грибкові захворювання шкіри переважно зумовлені трьома групами збудників: дерматоміцетами, дріжджоподібними грибами та пліснявою. Висвітлено патогенез захворювань, які спричиняють усі зазначені збудники, їх антигени, фактори вірулентності та патогенності, продуковані антибіотикоподібні речовини, а також здатність модулювати імунну відповідь організму хазяїна.
АНАЛІЗ ЗАХВОРЮВАНОСТІ НА РАК ШКІРИ ТА ОРГАНІЗАЦІЇ НАДАННЯ МЕДИЧНОЇ ДОПОМОГИ ХВОРИМ З ОНКОПАТОЛОГІЄЮ ШКІРИ В ЖИТОМИРСЬКІЙ ОБЛАСТІ
Authors: Парій В. Д.
Published: December 2023

Мета: визначити віково-статеві особливості онкопатології шкіри та стану надання медичної допомоги хворим на рак шкіри в Житомирській області протягом 2012–2022 рр.
Матеріали і методи. Матеріалами дослідження стали офіційні статистичні дані звітів Центру медичної статистики ЦГЗ МОЗ України «Показники захворюваності на злоякісні новоутворення та діяльність онкологічної служби в Україні» за 2012–2022 р.р.
Результати. Значна увага до поширення онкопатології шкіри в Житомирській області (яка значно постраждала в результаті аварії на ЧАЕС) спричинена тим, що у 2022 р. в ній зафіксовано найвищий рівень захворюваності на меланому серед усіх областей України – 8,56 випадку на 100 тис. нас. За рівнем захворюваності на немеланомні новоутворення шкіри Житомирська область посідає 7 місце в рейтингу областей. Встановлено, що за досліджуваний період захворюваність на меланому в Україні знизилася на 21,3 %, а в області зросла на 52,8 %. Загальна і регіональна динаміка захворюваності на інші новоутворення шкіри позитивна, але обласний рівень захворюваності перевищує середньоукраїнський на 49 %. Смертність населення від злоякісних новоутворень при позитивній динаміці щодо зниження в Житомирській області перевищує рівні смертності в Україні від усіх новоутворень на 24,7 %, від меланоми – на 26,6 %, від інших новоутворень шкіри – на 8,5 %. Основні показники надання медичної допомоги онкохворим характеризуються відносною стабільністю. Забезпеченість населення області онкологами збільшилася на 14,3 %, щоправда, кваліфікаційну категорію мають лише 42 % онкологів області.
Висновки. Захворюваність на немеланомні новоутворення шкіри населення Житомирської області протягом останнього десятиріччя знизилась, а на меланому – зросла, рівні захворюваності перевищують відповідні в Україні. Захворюваність на меланому та немеланомні новоутворення шкіри мають певні віково-статеві особливості, найвищі її рівні притаманні чоловікам старшого віку. Актуальною залишається первинна профілактика онкозахворювань з огляду на радіаційне забруднення окремих населених пунктів області. Удосконалення потребує організація медичної допомоги онкохворим, особливо в частині раннього виявлення онкозахворювань, підвищення кваліфікації медичного персоналу.
ДОТРИМАННЯ ПРАВ ЛЮДИНИ У СФЕРІ ГРОМАДСЬКОГО ЗДОРОВ’Я В УМОВАХ ВОЄННОГО СТАНУ
Authors: Калинюк Н. М. , Ліщук Л. Р.
Published: December 2023

Мета: проаналізувати систему прав людини у сфері громадського здоров’я. Розглянути проблеми, які виникають із застосуванням прав людини в умовах воєнного стану в Україні. Дослідити законотворчу діяльність уряду України в умовах воєнного стану.

Матеріали і методи. Дослідження ґрунтувалося на аналізі правових документів, інтернет-ресурсів та літературних джерел. Застосовані методи аналізу, синтезу, порівняння, узагальнення та систематизації літературних джерел.

Результати. Застосування прав людини у сфері громадського здоров’я в умовах воєнного стану є складною та багатогранною проблемою, оскільки воєнний конфлікт може викликати серйозні виклики для забезпечення й захисту прав та гідності людини.

Висновки. Збереження здоровʼя населення є пріоритетним напрямом діяльності для уряду, міжнародних організацій, громадських об’єднань і всіх, хто прагне забезпечити благополуччя та якісне життя людей. Здоровʼя населення є основною складовою стійкого розвитку, оскільки воно впливає на соціальний, економічний та екологічний розвиток країни.

Згідно з міжнародними стандартами та гуманітарним правом, дотримання прав людини у сфері громадського здоров’я під час війни є обов’язковим для всіх сторін конфлікту.

Напрацьована під час війни законодавча база може стати основою для покращення якості медичної допомоги, захисту прав та гідності громадян, а також забезпечення сталого розвитку системи охорони здоровʼя.
ЗАСТОСУВАННЯ ВЕБ-СЕРВІСУ WOLFRAM|ALPHA ПРИ ФОРМУВАННІ ПРОФЕСІЙНОЇ КОМПЕТЕНТНОСТІ У МАЙБУТНІХ МАГІСТРІВ ФАРМАЦІЇ
Authors: Туровська Л. В. , Мойсеєнко М. І. , Кузишин М. М.
Published: December 2023

Практичне використання веб-сервісу Wolfram|Alpha в навчальному процесі з підготовки майбутніх магістрів фармації розглядається на прикладах розв’язання завдань із нормативної навчальної дисципліни «Вища математика та статистика», зокрема при вивченні змістових модулів «Ймовірність випадкових подій», «Аналіз випадкових величин», а також «Дисперсійний, кореляційний і регресійний аналізи». На конкретних прикладах у статті демонструються результати виконання запитів до Wolfram|Alpha, показана ефективність даного веб-сервісу при розв’язанні практично-орієнтованих завдань із даних змістових модулів на практичних заняттях та в процесі індивідуальної самостійної роботи студентів із підготовки до підсумкового модульного контролю. Автори статті вказують на перспективи використання цього веб-сервісу в цілому у навчальному процесі з підготовки фахівців за спеціальністю «Фармація, промислова фармація».
Особливу увагу в статті приділено формуванню вмінь та навичок використання комп’ютерного середовища для створення та вивчення математичних моделей різноманітних явищ та процесів, а також демонстрації практичного застосування математичних методів для їх дослідження. Визначено та обговорено переваги та недоліки використання веб-сервісу Wolfram|Alpha у формуванні предметної математичної компетентності майбутніх фармацевтів. Зокрема, зазначається, що, незважаючи на зручність та доступність, користувачі повинні бути ознайомлені з можливими труднощами та особливостями роботи з цим сервісом.
ВИКОРИСТАННЯ СТРУКТУРНО-ЛОГІЧНИХ СХЕМ ДЛЯ ОПТИМІЗАЦІЇ ВИКЛАДАННЯ ТЕМИ «ІОНІЗУЮЧІ ВИПРОМІНЮВАННЯ. ВИКОРИСТАННЯ В МЕДИЦИНІ»
Authors: Кисільова Т. О. , Фоменко О. З.
Published: December 2023

Стаття присвячена проблемі підвищення ефективності викладання матеріалу за темою «Іонізуючі випромінювання. Використання в медицині» в рамках дисципліни «Медична та біологічна фізика». Невелика кількість годин, яка виділяється на опанування зазначеної теми, накладає певні обмеження щодо масиву інформації. Для оптимізації змісту навчального матеріалу пропонується використання структурно-логічних схем. Розроблені авторами структурно-логічні схеми «Ядерні перетворення» та «Використання іонізуючих випромінювань у діагностиці та терапії» дозволяють впорядкувати та систематизувати значні обсяги інформації за вказаною темою. Студентам треба чітко розрізняти можливі джерела іонізуючого випромінювання та знати основні можливості їх застосування в терапії та діагностиці. Структурно-логічна схема «Ядерні перетворення» демонструє основні види перетворень в ядрах атомів, деталізуючи трансформації нуклонів. Наведені реакції спрощують запам’ятовування видів радіоактивних розпадів та їх рівнянь. Для порівняння властивостей випромінювань при їх взаємодії з речовиною використовується графік «Розподіл поглиненої дози іонізуючих випромінювань у біологічних тканинах». Наочне представлення відстані, на якій відбувається максимум поглинання енергії певного виду випромінювання, сприяє більш повному розумінню біологічних ефектів, що виникають у тканинах, та вибору способу опромінення відповідно до наявної патології. Структурно-логічна схема «Використання іонізуючих випромінювань у діагностиці та терапії» презентує найбільш вживані методи застосування іонізуючих випромінювань у сучасній медичній практиці. Розроблена структура дозволяє легко орієнтуватись у різноманітті діагностичних та терапевтичних методик і типах іонізуючого випромінювання, що в них використовується. Застосування структурно-логічних схем дозволяє стисло, доступно і в достатньому обсязі подати найбільш актуальні та важливі відомості, які стануть підґрунтям для подальшого вивчення студентами радіаційної медицини.