The treatment of bacterial biofilms cultivated on knee arthroplasty implants using the bioelectric effect.

Introduction: The formation of bacterial biofilms on knee arthroplasty implants can have catastrophic consequences. The aim of this study was to analyze the effectiveness of the bioelectric effect in the elimination of bacterial biofilms on cultivated knee arthroplasty implants. Methods: A novel device was designed to deliver a bioelectric effect on the surface of knee arthroplasty implants. 4-femoral prosthetic implants were cultivated with a staphylococcus aureus inoculum for 15 days. The components were divided into four different groups: A (not treated), B (normal saline 20-minutes), C (bioelectric effect 10-minutes), D (bioelectric effect 20-minutes). The implants were sonicated, and the detached colonies were quantified as the number of colony-forming unit (CFUs). The implants were sterilised and the process was repeated in a standardized manner four more times, to obtain a total of five samples per group. Results: The number of the CFUs after a 10-minute exposure to the bioelectric effect was of 208.2 ± 240.4, compared with 6,041.6 ± 2010.7 CFUs in group A, representing a decrease of 96.5% ± 4.3 (p = 0.004). And a diminution of 91.8% ± 7.9 compared with 2,051.0 ± 1,364.0 CFUs in group B (p = 0.109). The number of bacterial colonies after a 20-minute exposure to the bioelectric effect was 70 ± 126.7 CFUs, representing a decrease of 98.9% ± 1.9 (p = 0.000) compared with group A. And a decrease of 97.8% ± 3.0 (p = 0.019) compared with group B. Conclusions: The bioelectric effect was effective in the elimination of bacterial biofilm from knee arthroplasty implants. This method could be used in the future as part of conventional surgical procedures.

Quantitative and Qualitative Research in the Field of 'Spirituality and Health': An Introductory How-to-Guide from a Brazilian Perspective.

The present article aims to describe the different steps on how to design, develop and conduct quantitative and qualitative Spirituality and Health (S/H) studies from a Brazilian perspective, discussing definitions and instruments, and proposing a "how-to guide" for those interested in this field of research. A narrative review of the literature has been conducted by experts in the field of S/H aiming to develop a "how-to-guide". Spirituality is a very complex concept that has several challenges in the current scientific literature, including the lack of consensus in the definitions, the numerous dimensions assessed, the diverse instruments for measurement, the criticisms from other scholars, the great diversity of religious and cultural traditions and the growing number of "spiritual but not religious" individuals. This review supports that S/H studies may follow the high scientific standards, using consolidated research procedures and solid methods for both qualitative and quantitative research. Some peculiarities of the research methods for this field are discussed. S/H research is still under development, and there are several future directions for S/H studies, aiming to minimize previous criticisms and generating stronger evidence.

Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies.

ABSTACT: To our knowledge, venetoclax is the first example of personalized medicine for multiple myeloma (MM), with meaningful clinical activity as a monotherapy and in combination in patients with myeloma harboring the t(11:14) translocation. However, despite the high response rates and prolonged progression-free survival, a significant proportion of patients eventually relapse. Here, we aim to study adaptive molecular responses after the acquisition of venetoclax resistance in sensitive t(11:14) MM cell models. We therefore generated single-cell venetoclax-resistant t(11:14) MM cell lines and investigated the mechanisms contributing to resistance as well as the cells' sensitivity to other treatments. Our data suggest that acquired resistance to venetoclax is characterized by reduced mitochondrial priming and changes in B-cell lymphoma-2 (BCL-2) family proteins' expression in MM cells, conferring broad resistance to standard-of-care antimyeloma drugs. However, our results show that the resistant cells are still sensitive to immunotherapeutic treatments, highlighting the need to consider appropriate sequencing of these treatments after venetoclax-based regimens.

Store-and-forward teledermatology in a Spanish health area significantly increases access to dermatology expertise.

INTRODUCTION: Teledermatology is the practice of dermatology through communication technologies. The aim of this study is to analyze its implementation in a Spanish health area during its first two years. METHODS: Cross-sectional descriptive study. It included interconsultations between dermatologists and family physicians in the Salamanca Health Area (Spain) after the implementation of the non-face-to-face modality over a period of two consecutive years. A total of 25,424 consultations were performed (20,912 face-to-face and 4,512 non-face-to-face); 1000 were selected by random sampling, half of each modality. MAIN MEASURES: referral rate, response time and resolution time, type of pathology, diagnostic concordance, and quality of consultation. RESULTS: The annual referral rate was 42.9/1000 inhabitants (35.3 face-to-face and 7.6 non-face- to-face). The rate of face-to-face referrals was higher in urban areas (37.1) and the rate of non- face-to-face referrals in rural areas (10.4). The response time for non-face-to-face consultations was 2.4 ± 12.7 days and 56 ± 34.8 days for face-to-face consultations (p < 0.001). The resolution rate for non-face-to-face consultations was 44%. Diagnostic concordance, assessed by the kappa index, was 0.527 for face-to-face consultations and 0.564 for non-face-to-face consultations. Greater compliance with the quality criteria in the non-attendance consultations. CONCLUSIONS: Teledermatology appears to be an efficient tool in the resolution of dermatological problems, with a rapid, effective, and higher quality response for attention to skin pathologies. REGISTRY: ClinicalTrials.gov Identifier: NCT05625295. Registered on 21 November 2022 ( https://clinicaltrials.gov/ct2/show/ NCT05625295).

Oxidative Stress Markers in Multiple Sclerosis.

The pathogenesis of multiple sclerosis (MS) is not completely understood, but genetic factors, autoimmunity, inflammation, demyelination, and neurodegeneration seem to play a significant role. Data from analyses of central nervous system autopsy material from patients diagnosed with multiple sclerosis, as well as from studies in the main experimental model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), suggest the possibility of a role of oxidative stress as well. In this narrative review, we summarize the main data from studies reported on oxidative stress markers in patients diagnosed with MS and in experimental models of MS (mainly EAE), and case-control association studies on the possible association of candidate genes related to oxidative stress with risk for MS. Most studies have shown an increase in markers of oxidative stress, a decrease in antioxidant substances, or both, with cerebrospinal fluid and serum/plasma malonyl-dialdehyde being the most reliable markers. This topic requires further prospective, multicenter studies with a long-term follow-up period involving a large number of patients with MS and controls.

Individual Prognostication of Disease Activity and Disability Worsening in Multiple Sclerosis With Retinal Layer Thickness z Scores.

BACKGROUND AND OBJECTIVES: Retinal optical coherence tomography (OCT) provides promising prognostic imaging biomarkers for future disease activity in multiple sclerosis (MS). However, raw OCT-derived measures have multiple dependencies, supporting the need for establishing reference values adjusted for possible confounders. The purpose of this study was to investigate the capacity for age-adjusted z scores of OCT-derived measures to prognosticate future disease activity and disability worsening in people with MS (PwMS). METHODS: We established age-adjusted OCT reference data using generalized additive models for location, scale, and shape for peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layer (GCIP) thicknesses, involving 910 and 423 healthy eyes, respectively. Next, we transformed the retinal layer thickness of PwMS from 3 published studies into age-adjusted z scores (pRNFL-z and GCIP-z) based on the reference data. Finally, we investigated the association of pRNFL-z or GCIP-z as predictors with future confirmed disability worsening (Expanded Disability Status Scale score increase) or disease activity (failing of the no evidence of disease activity [NEDA-3] criteria) as outcomes. Cox proportional hazards models or logistic regression analyses were applied according to the original studies. Optimal cutoffs were identified using the Akaike information criterion as well as location with the log-rank and likelihood-ratio tests. RESULTS: In the first cohort (n = 863), 172 PwMS (24%) had disability worsening over a median observational period of 2.0 (interquartile range [IQR]:1.0-3.0) years. Low pRNFL-z (≤-2.04) were associated with an increased risk of disability worsening (adjusted hazard ratio (aHR) [95% CI] = 2.08 [1.47-2.95], p = 3.82e-5). In the second cohort (n = 170), logistic regression analyses revealed that lower pRNFL-z showed a higher likelihood for disability accumulation at the two-year follow-up (reciprocal odds ratio [95% CI] = 1.51[1.06-2.15], p = 0.03). In the third cohort (n = 78), 46 PwMS (59%) did not maintain the NEDA-3 status over a median follow-up of 2.0 (IQR: 1.9-2.1) years. PwMS with low GCIP-z (≤-1.03) had a higher risk of showing disease activity (aHR [95% CI] = 2.14 [1.03-4.43], p = 0.04). Compared with raw values with arbitrary cutoffs, applying the z score approach with optimal cutoffs showed better performance in discrimination and calibration (higher Harrell's concordance index and lower integrated Brier score). DISCUSSION: In conclusion, our work demonstrated reference cohort-based z scores that account for age, a major driver for disease progression in MS, to be a promising approach for creating OCT-derived measures useable across devices and toward individualized prognostication.

Ibuprofen and Other Arylpropionics: The Relevance in Immediate Hypersensitivity Drug Reactions.

BACKGROUND: Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), is the most frequent medication to be involved in hypersensitivity drug reactions (HDRs). Other analgesic/anti-inflammatory drugs in the arylpropionic group are also relevant, albeit to a lesser extent. Ibuprofen is widely consumed by people of all ages, both on medical prescription and over the counter; moreover, it is an organic contaminant of surface waters and foods. While numerous drugs cause HDR, ibuprofen's underlying mechanisms are more intricate and involve both specific immunological and non-immunological mediated reactions. SUMMARY: we concentrate on immediate responses, including urticaria with or without angioedema, anaphylaxis, and angioedema, classifying reactions according to whether they are caused by single or multiple NSAIDs and based on the mechanisms at play. Both groups may experience anaphylaxis, defined as an immediate, severe systemic reaction involving at least two organs, though the frequency and severity can vary. Following this classification, more clinical manifestations can be identified. Diagnosis is partly based on a detailed clinical history, including information about ibuprofen and/or other arylpropionic derivatives involved, the interval between drug intake and symptoms onset, clinical manifestations, number of episodes, and the patient's tolerance or response to other medications - mainly non-chemically related NSAID - both before and after reactions to ibuprofen and/or other arylpropionic drugs. A drug provocation test is frequently necessary to make a diagnosis. KEY MESSAGE: Because ibuprofen is the most widely prescribed NSAID, it is reasonable to assume its role as the leading cause of HDR will only become more important.

Focused ultrasound therapy in movement disorders: management roadmap toward optimal pathway organization.

MRI-guided focused ultrasound (MRgFUS) lesioning is an innovative, safe and effective treatment which provides an innovative development in the field of minimally invasive stereotactic neurosurgery. Based on the application of focused ultrasound energy under full MR planning and thermal imaging control, unilateral lesioning of the thalamus, subthalamic nucleus, and globus pallidus is indicated for the treatment of movement disorders, including essential tremor, Parkinson's disease, and dystonia. We started to apply this technique in February 2019 for the treatment of patients with movement disorders. The authors developed a diagnostic therapeutic care pathway, which is herewith proposed and applied as an explication of standard clinical practice in use. The project was the result of the application of different methods such as Health Technology Assessment (HTA), Strengths, Weaknesses, Opportunities and Threats analysis (SWOT) and Demin -Plan, Do, Check, Act (PDCA) cycle. The aim of this project was to standardize the MRgFUS diagnostic-therapeutic pathway (DTP), describe its application and the appropriateness of different phases (patient selection, intervention phase and follow-up). Here, we described in detail our experience in the DTP application from 2019 up to now in 610 patients with movement disorders.

Survival in pregnancy-associated breast cancer patients compared to non-pregnant controls.

BACKGROUND: Pregnancy-associated breast cancer (PABC) is a rare entity whose prognosis has previously been studied and is subject to controversy. METHODS: Survival of patients with PABC diagnosed between 2009 and 2021 with breast cancer during pregnancy or until 1 year after childbirth was compared with non-pregnant patients with breast cancer from the same period at La Paz University Hospital. Cox proportional hazards regression was used to compare disease-free (DFS) and overall (OS) survival between the groups, adjusting for grade and pathologic stage. RESULTS: Among the 89 included patients with breast cancer, 34 were diagnosed during pregnancy, and 55 were not pregnant. The pregnant patients were more likely to have grade 3 tumors (61.3% vs 37%, p = 0.023) and an advanced stage (pathologic stage III-IV: 44.1% vs 17.6%, p = 0.008). Median follow-up was 47 months for the pregnant group and 46 months for the control group. After adjustments for tumor grade and pathologic stage, OS was comparable between the groups (HR 2.03; 95% CI 0.61 to 6.79; P = 0.25). CONCLUSIONS: The outcome of women diagnosed with PABC is comparable to young non-pregnant controls. However, it should be taken into account that PABC has a more aggressive phenotype.

Are lead, cadmium and mercury risk factors for resistant hypertension?

BACKGROUND: Lead (Pb), cadmium (Cd) and mercury (Hg) are toxic trace elements that represent a public health problem as risk factors for cardiovascular disease and hypertension (HT) and could also contribute to the development of resistant hypertension (rHT) AIMS: To compare the blood concentrations of Pb, Cd and Hg in subjects with resistant and non-resistant HT and to define whether there is a relationship between its levels and rHT. METHODS: Cross-sectional study. Subjects aged ≥ 21 to ≤ 80 years with a body mass index < 40 kg/m2 were recruited on a discretionary basis from October 2001 to October 2004 in a hypertension unit of a tertiary hospital amongst those sent to the hypertension unit by their family physician. Resistant hypertension was defined according to the American Heart Association (AHA) criteria. Whole blood concentrations of Cd, Pb and Hg were measured by electrothermal atomic absorption spectrometry. RESULTS: 46 out of 73 included subjects (63%) suffered from rHT. Blood Pb median: HT 3.9 (IQR 2.7-5.2) vs. rHT 3.6 (IQR 2.8-6.0) µg/dL (p=0.941). Blood Cd median: HT 0.07 (IQR 0.07-0.80) vs. rHT 0.30 (IQR 0.07-0.65) µg/L (p=0.681). Blood Hg median: HT 7.9 (IQR 5.8-12.9) vs. rHT 7.3 (IQR 4.6-13.3) µg/L (p=0.611). Considering the 75th percentile of each element (Pb: 5.55 µg/dL, Cd: 0.75 µg/L, Hg: 13.15 µg/L), a multiple logistic regression analysis (adjusted for age, BMI, diabetes mellitus, clearance of creatinine and only for Cd the smoking habit) showed an OR = 3.44 (0.84-14.10, p=0.086) for Pb, OR = 1.80 (0.39-8.24, p=0.451), for Cd and OR = 2.31 (0.59-9.14, p=0.232) for Hg. Moreover, the stratified analyses showed that men with Pb ≥5.55 µg/dL have a 14 times higher risk of suffering from rHT (p=0.026). Interestingly, a 9-fold increased risk was found for non-obese subjects with elevated Pb levels, above 5.55 µg/dL (p=0.029). Also in men, the probability of suffering from rHT was more than 7 times higher if Cd levels were ≥ 0.75 µg/L (p=0.076). Most smokers had higher Cd levels, with a high risk of suffering from rHT (ORa 12.6 (0.8-200.2), p=0.072). CONCLUSION: A higher blood Pb levels, defined by the 75th percentile (Pb ≥ 5.55 µg/dL), is associated with a greater risk of suffering from rHT and to a lesser extent in the case of Cd and Hg.

Immune Analysis Using Vitreous Optical Coherence Tomography Imaging in Rats with Steroid-Induced Glaucoma.

Glaucoma is a multifactorial pathology involving the immune system. The subclinical immune response plays a homeostatic role in healthy situations, but in pathological situations, it produces imbalances. Optical coherence tomography detects immune cells in the vitreous as hyperreflective opacities and these are subsequently characterised by computational analysis. This study monitors the changes in immunity in the vitreous in two steroid-induced glaucoma (SIG) animal models created with drug delivery systems (microspheres loaded with dexamethasone and dexamethasone/fibronectin), comparing both sexes and healthy controls over six months. SIG eyes tended to present greater intensity and a higher number of vitreous opacities (p < 0.05), with dynamic fluctuations in the percentage of isolated cells (10 µm2), non-activated cells (10-50 µm2), activated cells (50-250 µm2) and cell complexes (>250 µm2). Both SIG models presented an anti-inflammatory profile, with non-activated cells being the largest population in this study. However, smaller opacities (isolated cells) seemed to be the first responder to noxa since they were the most rounded (recruitment), coinciding with peak intraocular pressure increase, and showed the highest mean Intensity (intracellular machinery), even in the contralateral eye, and a major change in orientation (motility). Studying the features of hyperreflective opacities in the vitreous using OCT could be a useful biomarker of glaucoma.

Corrigendum to "Laponite for biomedical applications: An ophthalmological perspective" [Mater. Today Bio 24 (2024) 100935].

[This corrects the article DOI: 10.1016/j.mtbio.2023.100935.].

Oxidative Stress and Migraine.

The pathogenesis of migraine is not completely understood, but inflammation and oxidative stress seem to be involved, according to data from an experimental model of the disease. This narrative review summarizes data from studies on oxidative stress markers in migraine patients, case-control association studies on the possible association of candidate genes related to oxidative stress with the risk for migraine, studies showing the presence of oxidative stress in experimental models of migraine, and studies on the efficacy of antioxidant drugs in migraine therapy. Many studies have addressed the value of concentrations of prooxidant and antioxidant substances or the activity of antioxidant enzymes in different tissues (mainly in serum/plasma or in blood cells) as possible biomarkers for migraine, being thiobarbituric acid (TBA) reactive substances (TBARS) such as malonyl dialdehyde acid (MDA) and 4-hydroxynonenal, and nitric oxide (this at least during migraine attacks in patients with migraine with aura (MWA) the most reliable. In addition, the possible usefulness of antioxidant treatment is not well established, although preliminary short-term studies suggest a beneficial action of some of them such as Coenzyme Q10 and riboflavin. Both topics require further prospective, multicenter studies with a long-term follow-up period involving a large number of migraine patients and controls.

A rare case of hepatoid gastric adenocarcinoma.

Hepatoid gastric adenocarcinoma (HGA) is a rare subtype of gastric cancer. It usually presents with non-specific digestive tract symptoms and is usually diagnosed in advanced stages. It has radiological and histological similarities to hepatocarcinoma (HCC), and serum elevation of alpha-fetoprotein (AFP) is characteristic, as is positive staining for this marker on immunohistochemistry. Given the low incidence and poor prognosis of this type of tumour, it is essential to make a correct differential diagnosis and to initiate early surgical treatment in localised stages and systemic treatment in those where the disease is disseminated. In this context, we present the case of a GHA diagnosed this year in our centre.

Preparing the Frontlines: Delivering Special Pathogen Training to Maryland Hospital Staff.

Healthcare workers (HCWs) at community hospitals, also known as frontline hospitals (FLHs), may encounter patients with possible infectious diseases, including those caused by high-consequence pathogens such as Zaire ebolavirus. We created and piloted a 1-day, in-person, didactic and skills training program to determine the feasibility and acceptability of implementing an educational program to enhance the knowledge and skills needed to respond when a patient with a potential high-consequence pathogen presents to an FLH. The Maryland Department of Health queried all 104 state FLHs to identify their interest in participating in the pilot training program. HCWs from 12 (75%) of the 16 interested FLHs participated in the program before it was interrupted by the COVID-19 pandemic. In addition to pathogen-specific training based on the Identify, Isolate, and Inform framework, we provided skills training in the proper use of personal protective equipment, spill cleanup, and removal of an incapacitated HCW from an isolation area. We conducted a paired pretraining and posttraining knowledge assessment and measured a significant learning gain among 135 participants (2-tailed t test, P<.05). Over 95% of the participants reported that the training was relevant to their daily work and the clinical simulations and reference material were useful and appropriate for their learning level. Findings from this pilot program demonstrated the feasibility and acceptability of a 1-day combined didactic and skills training program focused on high-consequence pathogens. We plan to reengage the original FLHs and add regional FLHs in an updated training effort based on our findings.

Developments in pharmacogenetics, pharmacogenomics, and personalized medicine.

The development of Pharmacogenetics and Pharmacogenomics in Western Europe is highly relevant in the worldwide scenario. Despite the usually low institutional support, many research groups, composed of basic and clinical researchers, have been actively working for decades in this field. Their contributions made an international impact and paved the way for further studies and pharmacogenomics implementation in clinical practice. In this manuscript, that makes part of the Special Issue entitled Spanish Pharmacology, we present an analysis of the state of the art of Pharmacogenetics and Pharmacogenomics research in Europe, we compare it with the developments in Spain, and we summarize the most salient contributions since 1988 to the present, as well as recent developments in the clinical application of pharmacogenomics knowledge. Finally, we present some considerations on how we could improve translation to clinical practice in this specific scenario.

The macular retinal ganglion cell layer as a biomarker for diagnosis and prognosis in multiple sclerosis: A deep learning approach.

PURPOSE: The macular ganglion cell layer (mGCL) is a strong potential biomarker of axonal degeneration in multiple sclerosis (MS). For this reason, this study aims to develop a computer-aided method to facilitate diagnosis and prognosis in MS. METHODS: This paper combines a cross-sectional study of 72 MS patients and 30 healthy control subjects for diagnosis and a 10-year longitudinal study of the same MS patients for the prediction of disability progression, during which the mGCL was measured using optical coherence tomography (OCT). Deep neural networks were used as an automatic classifier. RESULTS: For MS diagnosis, greatest accuracy (90.3%) was achieved using 17 features as inputs. The neural network architecture comprised the input layer, two hidden layers and the output layer with softmax activation. For the prediction of disability progression 8 years later, accuracy of 81.9% was achieved with a neural network comprising two hidden layers and 400 epochs. CONCLUSION: We present evidence that by applying deep learning techniques to clinical and mGCL thickness data it is possible to identify MS and predict the course of the disease. This approach potentially constitutes a non-invasive, low-cost, easy-to-implement and effective method.